bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–10–06
84 papers selected by
Henver Brunetta, Karolinska Institutet
  1. Characterizing age-related changes in intact mitochondrial proteoforms in murine hearts using quantitative top-down proteomics.
  2. Oxidised phosphatidylcholine induces sarcolemmal ceramide accumulation and insulin resistance in skeletal muscle.
  3. Potential Mechanisms of Epicardial Adipose Tissue Influencing Heart Failure with Preserved Ejection Fraction.
  4. Afterload-induced Decreases in Fatty Acid Oxidation Develop Independently of Increased Glucose Utilization.
  5. Cold Exposure Rejuvenates the Metabolic Phenotype of Panx1-/- Mice.
  6. Improving effect of physical exercise on heart failure: Reducing oxidative stress-induced inflammation by restoring Ca2+ homeostasis.
  7. p38α kinase governs muscle strength through PGC1α in mice.
  8. Impact of Sex on the Therapeutic Efficacy of Rosiglitazone in Modulating White Adipose Tissue Function and Insulin Sensitivity.
  9. A long-term high fat diet induces differential gene expression changes in spatially distinct adipose tissue of male mice.
  10. Empagliflozin alleviates obesity-related cardiac dysfunction via the activation of SIRT3-mediated autophagosome formation.
  11. miR-10a regulates cell death and inflammation in adipose tissue of male mice with diet-induced obesity.
  12. Omega-3 Fatty Acids Modify Drp1 Expression and Activate the PINK1-Dependent Mitophagy Pathway in the Kidney and Heart of Adenine-Induced Uremic Rats.
  13. 1,2-Dicinnamoyl-sn-glycero-3-phosphocholine Improves Insulin Sensitivity and Upregulates mtDNA-Encoded Genes in Insulin-Resistant 3T3-L1 Adipocytes: A Preliminary Study.
  14. SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
  15. Epicardial Fat in Heart Failure with Preserved Ejection Fraction Compared with Reduced Ejection Fraction.
  16. Leveraging metabolism for better outcomes in heart failure.
  17. Oct-B: A derivative of L-BAIBA significantly alleviating high-fat diet-induced obesity in mice.
  18. Reduced Hydrogen Sulfide Bioavailability Contributes to Cardiometabolic Heart Failure with Preserved Ejection Fraction.
  19. Increased cGMP improves microvascular exercise training adaptations independent of endothelial nitric oxide synthase.
  20. The role of PINK1-Parkin in mitochondrial quality control.
  21. Changes in epicardial adipose tissue volume before and after cryoballoon ablation in patients with atrial fibrillation: supporting the "AF begets EAT" theory.
  22. Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation.
  23. GTPBP8 mitigates nonalcoholic steatohepatitis (NASH) by depressing hepatic oxidative stress and mitochondrial dysfunction via PGC-1α signaling.
  24. Advances in the Insulin-Heart Axis: Current Therapies and Future Directions.
  25. HM-chromanone attenuates obesity and adipose tissue inflammation by downregulating SREBP-1c and NF-κb pathway in high-fat diet-fed mice.
  26. Sirtuin 3 reinforces acylcarnitine metabolism and maintains thermogenesis in brown adipose tissue of aging mice.
  27. Role of epicardial adipose tissue in cardiac remodeling.
  28. The ABA/LANCL1-2 Hormone/Receptors System Controls ROS Production in Cardiomyocytes through ERRα.
  29. Adalimumab Treatment Effects on Inflammation and Adipose Tissue Mitochondrial Respiration in Hidradenitis Suppurativa.
  30. Cannabidiol treatment changes myocardial lipid profile in spontaneously hypertensive rats.
  31. Molecular composition of skeletal muscle in infants and adults: a comparative proteomic and transcriptomic study.
  32. Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors.
  33. Diosgenin Alleviates Obesity-Induced Insulin Resistance by Modulating PI3K/Akt Signaling Pathway in Mice Fed a High-Fat Diet.
  34. Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.
  35. Mitochondrial antioxidant SkQ1 attenuates C26 cancer-induced muscle wasting in males and improves muscle contractility in female tumor-bearing mice.
  36. Longitudinal characterization of the muscle metabolome in dairy cows during the transition from lactation cessation to lactation resumption.
  37. Prenatal and progressive coenzyme Q10 administration to mitigate muscle dysfunction in mitochondrial disease.
  38. Integration of metabolomic and transcriptomic analyses reveals novel regulatory functions of the ChREBP transcription factor in energy metabolism.
  39. Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling.
  40. Construction of a metabolism-malnutrition-inflammation prognostic risk score in patients with heart failure with preserved ejection fraction: a machine learning based Lasso-Cox model.
  41. The Rate of Leg Fat Oxidation Is Not Attenuated During Incremental Intensity One-Leg Knee Extensor Exercise.
  42. Elevated plasma bile acids coincide with cardiac stress and inflammation in young Cyp2c70-/- mice.
  43. Mechanisms in Endocrinology: Hypogonadism and metabolic health in men - novel insights into pathophysiology.
  44. Essential Role of the RIα Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development.
  45. Usp20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality.
  46. Aerobic Exercise Training Protects Against Insulin Resistance, Despite Low-Sodium Diet-Induced Increased Inflammation and Visceral Adiposity.
  47. Insights into Transient Dimerisation of Carnitine/Acylcarnitine Carrier (SLC25A20) from Sarkosyl/PAGE, Cross-Linking Reagents, and Comparative Modelling Analysis.
  48. Association between appendicular skeletal muscle mass and myocardial glucose uptake measured by 18F-FDG PET.
  49. Capsinoids Increase Antioxidative Enzyme Activity and Prevent Obesity-Induced Cardiac Injury without Positively Modulating Body Fat Accumulation and Cardiac Oxidative Biomarkers.
  50. Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs).
  51. Effects of Polyunsaturated Fatty Acid/Saturated Fatty Acid Ratio and Different Amounts of Monounsaturated Fatty Acids on Adipogenesis in 3T3-L1 Cells.
  52. Fontan hemodynamics in adults with obesity compared to overweight and normal body mass index: a retrospective invasive exercise study.
  53. Diagnostic and therapeutic practice for HFpEF across continents and regions: An international survey.
  54. Nonfunctional coq10 mutants maintain the ERMES complex and reveal true phenotypes associated with the loss of the coenzyme Q chaperone protein Coq10.
  55. Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy.
  56. Downregulation of Iron-Sulfur Cluster Biogenesis May Contribute to Hyperglycemia-Mediated Diabetic Peripheral Neuropathy in Murine Models.
  57. Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific and individualized regulatory mechanisms.
  58. Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.
  59. Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.
  60. Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner.
  61. Bixin Combined with Metformin Ameliorates Insulin Resistance and Antioxidant Defenses in Obese Mice.
  62. Diet induced mitochondrial DNA replication instability in Rad51c mutant mice drives sex-bias in anemia of inflammation.
  63. A multimodal approach identifies lactate as a central feature of right ventricular failure that is detectable in human plasma.
  64. Adipokines in the Crosstalk between Adipose Tissues and Other Organs: Implications in Cardiometabolic Diseases.
  65. New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis.
  66. Interplay of ROS, mitochondrial quality, and exercise in aging: Potential role of spatially discrete signaling.
  67. The yellow brick road to understanding the RyR2 signalosome.
  68. Sodium Houttuybonate Promotes the Browning of White Adipose Tissue by Inhibiting Ferroptosis via the AMPK-NRF2-HO1 Pathway.
  69. Ziziphus jujuba (Jujube) in Metabolic Syndrome: From Traditional Medicine to Scientific Validation.
  70. Contractile Effects of Semaglutide in the Human Atrium.
  71. Study on the Role of Dihuang Yinzi in Regulating the AMPK/SIRT1/PGC-1α Pathway to Promote Mitochondrial Biogenesis and Improve Alzheimer's Disease.
  72. Curcumol effectively improves obesity through GDF15 induction via activation of endoplasmic reticulum stress response.
  73. KLF6 aggravates myocardial fibrosis by promoting mitochondrial division.
  74. Generational Diet-Induced Obesity Remodels the Omental Adipose Proteome in Female Mice.
  75. Inspiratory muscle strength training to improve cardiometabolic health in patients with type 2 diabetes mellitus: protocol for the diabetes inspiratory training clinical trial.
  76. [Mitochondrial metabolism in AML cells].
  77. The effect of exogenous mitochondria in enhancing the survival and volume retention of transplanted fat tissue in a nude mice model.
  78. Insulin Resistance Surrogates May Predict HTN-HUA in Young, Non-Obese Individuals.
  79. Reduction of Mitochondrial Calcium Overload via MKT077-Induced Inhibition of Glucose-Regulated Protein 75 Alleviates Skeletal Muscle Pathology in Dystrophin-Deficient mdx Mice.
  80. Cardiac Myosin Inhibitors: Is the Emperor Wearing Any Clothes, or Is it Placebo?
  81. M2 Macrophage Exosomes Reverse Cardiac Functional Decline in Mice with Diet-Induced Myocardial Infarction by Suppressing Type 1 Interferon Signaling in Myeloid Cells.
  82. Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.
  83. Filbertone Reduces Senescence in C2C12 Myotubes Treated with Doxorubicin or H2O2 through MuRF1 and Myogenin.
  84. Differential impacts of body composition on oxygen kinetics and exercise tolerance of HFrEF and HFpEF patients.
  1. Clin Proteomics. 2024 Sep 30. 21(1): 57
    Characterizing age-related changes in intact mitochondrial proteoforms in murine hearts using quantitative top-down proteomics.
    Andrea Ramirez-Sagredo, Anju Teresa Sunny, Kellye A Cupp-Sutton, Trishika Chowdhury, Zhitao Zhao, Si Wu, Ying Ann Chiao.
       BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and the prevalence of CVDs increases markedly with age. Due to the high energetic demand, the heart is highly sensitive to mitochondrial dysfunction. The complexity of the cardiac mitochondrial proteome hinders the development of effective strategies that target mitochondrial dysfunction in CVDs. Mammalian mitochondria are composed of over 1000 proteins, most of which can undergo post-translational modifications (PTMs). Top-down proteomics is a powerful technique for characterizing and quantifying proteoform sequence variations and PTMs. However, there are still knowledge gaps in the study of age-related mitochondrial proteoform changes using this technique. In this study, we used top-down proteomics to identify intact mitochondrial proteoforms in young and old hearts and determined changes in protein abundance and PTMs in cardiac aging.
    METHODS: Intact mitochondria were isolated from the hearts of young (4-month-old) and old (24-25-month-old) mice. The mitochondria were lysed, and mitochondrial lysates were subjected to denaturation, reduction, and alkylation. For quantitative top-down analysis, there were 12 runs in total arising from 3 biological replicates in two conditions, with technical duplicates for each sample. The collected top-down datasets were deconvoluted and quantified, and then the proteoforms were identified.
    RESULTS: From a total of 12 LC-MS/MS runs, we identified 134 unique mitochondrial proteins in the different sub-mitochondrial compartments (OMM, IMS, IMM, matrix). 823 unique proteoforms in different mass ranges were identified. Compared to cardiac mitochondria of young mice, 7 proteoforms exhibited increased abundance and 13 proteoforms exhibited decreased abundance in cardiac mitochondria of old mice. Our analysis also detected PTMs of mitochondrial proteoforms, including N-terminal acetylation, lysine succinylation, lysine acetylation, oxidation, and phosphorylation. Data are available via ProteomeXchange with the identifier PXD051505.
    CONCLUSION: By combining mitochondrial protein enrichment using mitochondrial fractionation with quantitative top-down analysis using ultrahigh-pressure liquid chromatography (UPLC)-MS and label-free quantitation, we successfully identified and quantified intact proteoforms in the complex mitochondrial proteome. Using this approach, we detected age-related changes in abundance and PTMs of mitochondrial proteoforms in the heart.
    Keywords:  Cardiac aging; Label-free quantitation; Mitochondria; Post-translational modifications; Top-down proteomics
    DOI:  https://doi.org/10.1186/s12014-024-09509-1
  2. Diabetologia. 2024 Sep 30.
    Oxidised phosphatidylcholine induces sarcolemmal ceramide accumulation and insulin resistance in skeletal muscle.
    Karin A Zemski Berry, Amanda Garfield, Purevsuren Jambal, Simona Zarini, Leigh Perreault, Bryan C Bergman.
       AIMS/HYPOTHESIS: Intracellular ceramide accumulation in specific cellular compartments is a potential mechanism explaining muscle insulin resistance in the pathogenesis of type 2 diabetes. Muscle sarcolemmal ceramide accumulation negatively impacts insulin sensitivity in humans, but the mechanism explaining this localised accumulation is unknown. Previous reports revealed that circulating oxidised LDL is elevated in serum of individuals with obesity and type 2 diabetes. Oxidised phosphatidylcholine, which is present in oxidised LDL, has previously been linked to ceramide pathway activation, and could contribute to localised ceramide accumulation in skeletal muscle. We hypothesised that oxidised phosphatidylcholine inversely correlates with insulin sensitivity in serum, and induces sarcolemmal ceramide accumulation and decreases insulin sensitivity in muscle.
    METHODS: We used LC-MS/MS to quantify specific oxidised phosphatidylcholine species in serum from a cross-sectional study of 58 well-characterised individuals spanning the physiological range of insulin sensitivity. We also performed in vitro experiments in rat L6 myotubes interrogating the role of specific oxidised phosphatidylcholine species in promoting sarcolemmal ceramide accumulation, inflammation and insulin resistance in skeletal muscle cells.
    RESULTS: Human serum oxidised phosphatidylcholine levels are elevated in individuals with obesity and type 2 diabetes, inversely correlated with insulin sensitivity, and positively correlated with sarcolemmal C18:0 ceramide levels in skeletal muscle. Specific oxidised phosphatidylcholine species, particularly 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), increase total ceramide and dihydroceramide and decrease total sphingomyelin in the sarcolemma of L6 myotubes by de novo ceramide synthesis and sphingomyelinase activation. POVPC also increases inflammatory signalling and causes insulin resistance in L6 myotubes.
    CONCLUSIONS/INTERPRETATION: These data suggest that circulating oxidised phosphatidylcholine species promote ceramide accumulation and decrease insulin sensitivity in muscle, help explain localised sphingolipid accumulation and muscle inflammatory response, and highlight oxidised phosphatidylcholine species as potential targets to combat insulin resistance.
    Keywords:  Ceramide; Inflammation; Insulin resistance; Obesity; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s00125-024-06280-8
  3. Rev Cardiovasc Med. 2024 Sep;25(9): 311
    Potential Mechanisms of Epicardial Adipose Tissue Influencing Heart Failure with Preserved Ejection Fraction.
    Qiuxuan Li, Ur Rehman Muhib, Xiaoteng Ma, Zaiqiang Liu, Fei Gao, Zhijian Wang.
      Heart failure (HF) is the predominant terminal stage and the leading cause of mortality in cardiac disease. Heart failure with preserved ejection fraction (HFpEF) affects roughly 50% of HF patients globally. Due to the global aging population, the prevalence, morbidity, and mortality of HFpEF have gradually increased. Epicardial adipose tissue (EAT), as a key visceral adipose tissue around the heart, affects cardiac diastolic function and exercise reserve capacity. EAT closely adheres to the myocardium and can produce inflammatory factors, neurotransmitters, and other factors through autocrine or paracrine mechanisms, affecting the heart function by inflammatory response, cardiac metabolism and energy supply, cardiomyocyte structure and electrical activity, and pericardial vascular function. Currently, research on the mechanism and treatment methods of HFpEF is constantly improving. EAT may play a multi-level impact on the occurrence and development of HFpEF. This review also summarizes the potential impact of EAT on the heart in HFpEF combined with other metabolism-related diseases such as obesity or diabetes over other obesity-related measures, such as body mass index (BMI) or other adipose tissue. Above all, this review comprehensively summarizes the potential mechanisms by which EAT may affect HFpEF. The objective is to enhance our comprehension and management of HFpEF. Future research should delve into the mechanistic relationship between EAT and HFpEF, and investigate interventions aimed at EAT to improve the prognosis of patients with HFpEF.
    Keywords:  HF; HFpEF; epicardial adipose tissue; visceral adipose tissue
    DOI:  https://doi.org/10.31083/j.rcm2509311
  4. bioRxiv. 2024 Sep 18. pii: 2024.09.17.613531. [Epub ahead of print]
    Afterload-induced Decreases in Fatty Acid Oxidation Develop Independently of Increased Glucose Utilization.
    Hande C Piristine, Herman I May, Nan Jiang, Daniel Daou, Francisco Olivares-Silva, Abdallah Elnwasany, Pamela Szweda, Luke Szweda, Caroline Kinter, Michael Kinter, Gaurav Sharma, Xiaodong Wen, Craig R Malloy, Michael E Jessen, Thomas G Gillette, Joseph A Hill.
       Background: Metabolic substrate utilization in HFpEF (heart failure with preserved ejection fraction), the leading cause of heart failure worldwide, is pivotal to syndrome pathogenesis and yet remains ill defined. Under resting conditions, oxidation of free fatty acids (FFA) is the predominant energy source of the heart, supporting its unremitting contractile activity. In the context of disease-related stress, however, a shift toward greater reliance on glucose occurs. In the setting of obesity or diabetes, major contributors to HFpEF pathophysiology, the shift in metabolic substrate use toward glucose is impaired, sometimes attributed to the lower oxygen requirement of glucose oxidation versus fat metabolism. This notion, however, has never been tested conclusively. Furthermore, whereas oxygen demand increases in the setting of increased afterload, myocardial oxygen availability remains adequate for fatty acid oxidation (FAO). Therefore, a "preference" for glucose has been proposed.
    Methods and Results: Pyruvate dehydrogenase complex (PDC) is the rate-limiting enzyme linking glycolysis to the TCA cycle. As PDK4 (PDC kinase 4) is up-regulated in HFpEF, we over-expressed PDK4 in cardiomyocytes, ensuring that PDC is phosphorylated and thereby inhibited. This leads to diminished use of pyruvate as energy substrate, mimicking the decline in glucose oxidation in HFpEF. Importantly, distinct from HFpEF-associated obesity, this model positioned us to abrogate the load-induced shift to glucose utilization in the absence of systemic high fat conditions. As expected, PDK4 transgenic mice manifested normal cardiac performance at baseline. However, they manifested a rapid and severe decline in contractile performance when challenged with modest increases in afterload triggered either by L-NAME or surgical transverse aortic constriction (TAC). This decline in function was not accompanied by an exacerbation of the myocardial hypertrophic growth response. Surprisingly, metabolic flux analysis revealed that, after TAC, fractional FAO decreased, even when glucose/pyruvate utilization was clamped at very low levels. Additionally, proteins involved in the transport and oxidation of FFA were paradoxically downregulated after TAC regardless of genotype.
    Conclusions: These data demonstrate that cardiomyocytes in a setting in which glucose utilization is robustly diminished and prevented from increasing do not compensate for the deficit in glucose utilization by up-regulating FFA use.
    DOI:  https://doi.org/10.1101/2024.09.17.613531
  5. Biomolecules. 2024 Aug 25. pii: 1058. [Epub ahead of print]14(9):
    Cold Exposure Rejuvenates the Metabolic Phenotype of Panx1-/- Mice.
    Filippo Molica, Avigail Ehrlich, Graziano Pelli, Olga M Rusiecka, Christophe Montessuit, Marc Chanson, Brenda R Kwak.
      Pannexin1 (Panx1) ATP channels are important in adipocyte biology, potentially influencing energy storage and expenditure. We compared the metabolic phenotype of young (14 weeks old) and mature (20 weeks old) wild-type (WT) and Panx1-/- mice exposed or not to cold (6 °C) during 28 days, a condition promoting adipocyte browning. Young Panx1-/- mice weighed less and exhibited increased fat mass, improved glucose tolerance, and lower insulin sensitivity than WT mice. Their energy expenditure and respiratory exchange ratio (RER) were increased, and their fatty acid oxidation decreased. These metabolic effects were no longer observed in mature Panx1-/- mice. The exposure of mature mice to cold exacerbated their younger metabolic phenotype. The white adipose tissue (WAT) of cold-exposed Panx1-/- mice contained more small-sized adipocytes, but, in contrast to WT mice, white adipocytes did not increase their expression of Ucp1 nor of other markers of browning adipocytes. Interestingly, Glut4 expression was already enhanced in the WAT of young Panx1-/- mice kept at 22 °C as compared to WT mice. Thus, Panx1 deletion exerts overall beneficial metabolic effects in mice that are pre-adapted to chronic cold exposure. Panx1-/- mice show morphological characteristics of WAT browning, which are exacerbated upon cold exposure, an effect that appears to be associated with Ucp1-independent thermogenesis.
    Keywords:  Pannexin1; adipocytes; browning; cold; mitochondrial genes; thermogenesis
    DOI:  https://doi.org/10.3390/biom14091058
  6. Mol Cell Biochem. 2024 Oct 04.
    Improving effect of physical exercise on heart failure: Reducing oxidative stress-induced inflammation by restoring Ca2+ homeostasis.
    Shunling Yuan, Zhongkai Kuai, Fei Zhao, Diqun Xu, Weijia Wu.
      Heart failure (HF) is associated with the occurrence of mitochondrial dysfunction. ATP produced by mitochondria through the tricarboxylic acid cycle is the main source of energy for the heart. Excessive release of Ca2+ from myocardial sarcoplasmic reticulum (SR) in HF leads to excessive Ca2+ entering mitochondria, which leads to mitochondrial dysfunction and REDOX imbalance. Excessive accumulation of ROS leads to mitochondrial structure damage, which cannot produce and provide energy. In addition, the accumulation of a large number of ROS can activate NF-κB, leading to myocardial inflammation. Energy deficit in the myocardium has long been considered to be the main mechanism connecting mitochondrial dysfunction and systolic failure. However, exercise can improve the Ca2+ imbalance in HF and restore the Ca2+ disorder in mitochondria. Similarly, exercise activates mitochondrial dynamics to improve mitochondrial function and reshape intact mitochondrial structure, rebalance mitochondrial REDOX, reduce excessive release of ROS, and rescue cardiomyocyte energy failure in HF. In this review, we summarize recent evidence that exercise can improve Ca2+ homeostasis in the SR and activate mitochondrial dynamics, improve mitochondrial function, and reduce oxidative stress levels in HF patients, thereby reducing chronic inflammation in HF patients. The improvement of mitochondrial dynamics is beneficial for ameliorating metabolic flow bottlenecks, REDOX imbalance, ROS balance, impaired mitochondrial Ca2+ homeostasis, and inflammation. Interpretation of these findings will lead to new approaches to disease mechanisms and treatment.
    Keywords:  Ca2+ ; Exercise; Heart failure; Mitochondrial dynamics; ROS
    DOI:  https://doi.org/10.1007/s11010-024-05124-8
  7. Acta Physiol (Oxf). 2024 Oct 03. e14234
    p38α kinase governs muscle strength through PGC1α in mice.
    Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A Dumesic, Sarah E Wilensky, Elena Rodríguez, Luis Leiva-Vega, Ainoa Caballero, Marta León, Jesús Vázquez, Bruce M Spiegelman, Cintia Folgueira, Alfonso Mora, Guadalupe Sabio.
       AIMS: Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.
    METHODS: We conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.
    RESULTS: Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.
    CONCLUSIONS: This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; muscle strength; p38α; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.14234
  8. Nutrients. 2024 Sep 11. pii: 3063. [Epub ahead of print]16(18):
    Impact of Sex on the Therapeutic Efficacy of Rosiglitazone in Modulating White Adipose Tissue Function and Insulin Sensitivity.
    Marco Bauzá-Thorbrügge, Emilia Amengual-Cladera, Bel Maria Galmés-Pascual, Andrea Morán-Costoya, Magdalena Gianotti, Adamo Valle, Ana Maria Proenza, Isabel Lladó.
      Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction.
    Keywords:  high-fat diet; inflammation; mitochondria; obesity; rosiglitazone; white adipose tissue
    DOI:  https://doi.org/10.3390/nu16183063
  9. Physiol Genomics. 2024 Sep 30.
    A long-term high fat diet induces differential gene expression changes in spatially distinct adipose tissue of male mice.
    Malak Alradi, Hassan Askari, Mark Shaw, Jaysheel D Bhavsar, Brewster F Kingham, Shawn W Polson, Ibra S Fancher.
      The accumulation of visceral adipose tissue (VAT) is strongly associated with cardiovascular disease and diabetes. In contrast, individuals with increased subcutaneous adipose tissue (SAT) without corresponding increases in VAT are associated with a metabolic healthy obese phenotype. These observations implicate dysfunctional VAT as a driver of disease processes, warranting investigation into obesity-induced alterations of distinct adipose depots. To determine the effects of obesity on adipose gene expression, male mice (n=4) were fed a high fat diet to induce obesity or a normal laboratory diet (lean controls) for 12-14 months. Mesenteric VAT and inguinal SAT were isolated for bulk RNA-sequencing. AT from lean controls served as a reference to obesity-induced changes. The long-term high fat diet induced the expression of 169 and 814 unique genes in SAT and VAT, respectively. SAT from obese mice exhibited 308 differentially expressed genes (164 upregulated, 144 downregulated). VAT from obese mice exhibited 690 differentially expressed genes (262 genes upregulated, 428 downregulated). KEGG pathway and GO analyses revealed that metabolic pathways were upregulated in SAT vs. downregulated in VAT while inflammatory signaling was upregulated in VAT. We next determined common genes that were differentially regulated between SAT and VAT in response to obesity and identified four genes that exhibited this profile: elovl6 and kcnj15 were upregulated in SAT/downregulated in VAT while trdn and hspb7 were downregulated in SAT/ upregulated in VAT. We propose that these genes in particular should be further pursued to determine their roles in SAT vs. VAT with respect to obesity.
    Keywords:  RNA sequencing; adipose tissue; obesity; subcutaneous adipose; visceral adipose
    DOI:  https://doi.org/10.1152/physiolgenomics.00080.2024
  10. Lipids Health Dis. 2024 Sep 27. 23(1): 308
    Empagliflozin alleviates obesity-related cardiac dysfunction via the activation of SIRT3-mediated autophagosome formation.
    Youhong Luo, Tongtong Ye, Hongzhan Tian, Hongwei Song, Chengxia Kan, Fang Han, Ningning Hou, Xiaodong Sun, Jingwen Zhang.
       BACKGROUND: Empagliflozin (EMPA) has demonstrated efficacy in providing cardiovascular benefits in metabolic diseases. However, the direct effect of EMPA on autophagy in obesity-related cardiac dysfunction remains unclear. Therefore, this study aimed to determine changes in cardiac autophagy during diet-induced obesity and clarify the exact mechanism by which EMPA regulates autophagic pathways.
    METHODS: Male C57BL/6J mice were fed a 12-week high-fat diet (HFD) followed by 8 weeks of EMPA treatment. Body composition analysis and echocardiography were performed to evaluate metabolic alterations and cardiac function. Histological and immunofluorescence staining was used to evaluate potential enhancements in myocardial structure and biological function. Additionally, H9c2 cells were transfected with small interfering RNA targeting sirtuin 3 (SIRT3) and further treated with palmitic acid (PA) with or without EMPA. Autophagy-related targets were analyzed by western blotting and RT‒qPCR.
    RESULTS: EMPA administration effectively ameliorated metabolic disorders and cardiac diastolic dysfunction in HFD-fed mice. EMPA prevented obesity-induced myocardial hypertrophy, fibrosis, and inflammation through the activation of SIRT3-mediated autophagosome formation. The upregulation of SIRT3 triggered by EMPA promoted the initiation of autophagy by activating AMP-activated protein kinase (AMPK) and Beclin1. Furthermore, activated SIRT3 contributed to the elongation of autophagosomes through autophagy-related 4B cysteine peptidase (ATG4B) and autophagy-related 5 (ATG5).
    CONCLUSIONS: EMPA promotes SIRT3-mediated autophagosome formation to alleviate damage to the cardiac structure and function of obese mice. Activated SIRT3 initiates autophagy through AMPK/Beclin1 and further stimulates elongation of the autophagosome membrane via ATG4B/ATG5. These results provide a new explanation for the cardioprotective benefits of EMPA in obesity.
    Keywords:  Autophagy; Empagliflozin; Obesity-related cardiac dysfunction; SIRT3
    DOI:  https://doi.org/10.1186/s12944-024-02293-9
  11. Mol Metab. 2024 Sep 27. pii: S2212-8778(24)00170-4. [Epub ahead of print] 102039
    miR-10a regulates cell death and inflammation in adipose tissue of male mice with diet-induced obesity.
    Sumin Lee, Yoon Keun Cho, Heeseong Kim, Cheoljun Choi, Sangseob Kim, Yun-Hee Lee.
       OBJECTIVE: Adipose tissue remodeling plays a critical role in obesity-induced metabolic dysfunction, but the underlying molecular mechanisms remain incompletely understood. This study investigates the role of miR-10a-5p in adipose tissue inflammation and metabolic dysfunction induced by a high fat diet (HFD).
    METHODS: Male miR-10a knockout (KO) mice were fed a HFD to induce obesity for up to 16 weeks. RNA sequencing (RNA-seq) analysis was performed to profile mRNA expression and assess the effects of miR-10a-5p KO in gonadal white adipose tissue (gWAT). Additional analyses included immunoblotting, qPCR, histological examination, and validation of the miR-10a-5p target sequence using a dual-luciferase reporter assay.
    RESULTS: miR-10a-5p was highly expressed in gWAT but decreased after 8 weeks of HFD feeding. Over the 16-week HFD period, miR-10a KO mice exhibited greater weight gain and reduced energy expenditure compared to wild-type (WT) controls. gWAT of miR-10a KO mice on a HFD showed an increased population of proinflammatory macrophages, elevated inflammation, and increased cell death, characterized by upregulated apoptosis and necrosis markers. This was also associated with increased triglyceride accumulation in the liver. Mechanistically, the proapoptotic gene Bcl2l11 was identified as a direct target of miR-10a-5p. Loss of miR-10a-5p led to BIM-mediated adipocyte death and inflammation, contributing to mitochondrial metabolic dysregulation, increased fibrosis marker expression, and the onset of inflammation in adipose tissue.
    CONCLUSIONS: This study demonstrates the significant role of miR-10a-5p and its downstream target BIM in regulating adipocyte death during diet-induced obesity. This signaling pathway presents a potential therapeutic target for modulating obesity-induced inflammation and cell death in adipose tissue.
    Keywords:  Adipose tissue; Cell death; Inflammation; Obesity; microRNA
    DOI:  https://doi.org/10.1016/j.molmet.2024.102039
  12. Biomedicines. 2024 Sep 15. pii: 2107. [Epub ahead of print]12(9):
    Omega-3 Fatty Acids Modify Drp1 Expression and Activate the PINK1-Dependent Mitophagy Pathway in the Kidney and Heart of Adenine-Induced Uremic Rats.
    Dong Ho Choi, Su Mi Lee, Bin Na Park, Mi Hwa Lee, Dong Eun Yang, Young Ki Son, Seong Eun Kim, Won Suk An.
      Mitochondrial homeostasis is controlled by biogenesis, dynamics, and mitophagy. Mitochondrial dysfunction plays a central role in cardiovascular and renal disease and omega-3 fatty acids (FAs) are beneficial for cardiovascular disease. We investigated whether omega-3 fatty acids (FAs) regulate mitochondrial biogenesis, dynamics, and mitophagy in the kidney and heart of adenine-induced uremic rats. Eighteen male Sprague Dawley rats were divided into normal control, adenine control, and adenine with omega-3 FA groups. Using Western blot analysis, the kidney and heart expression of mitochondrial homeostasis-related molecules, including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), dynamin-related protein 1 (Drp1), and phosphatase and tensin homolog-induced putative kinase 1 (PINK1) were investigated. Compared to normal, serum creatinine and heart weight/body weight in adenine control were increased and slightly improved in the omega-3 FA group. Compared to the normal controls, the expression of PGC-1α and PINK1 in the kidney and heart of the adenine group was downregulated, which was reversed after omega-3 FA supplementation. Drp1 was upregulated in the kidney but downregulated in the heart in the adenine group. Drp1 expression in the heart recovered in the omega-3 FA group. Mitochondrial DNA (mtDNA) was decreased in the kidney and heart of the adenine control group but the mtDNA of the heart was recovered in the omega-3 FA group. Drp1, which is related to mitochondrial fission, may function oppositely in the uremic kidney and heart. Omega-3 FAs may be beneficial for mitochondrial homeostasis by activating mitochondrial biogenesis and PINK1-dependent mitophagy in the kidney and heart of uremic rats.
    Keywords:  biogenesis; chronic kidney disease; dynamics; fatty acid; mitochondria; omega-3
    DOI:  https://doi.org/10.3390/biomedicines12092107
  13. Nutrients. 2024 Sep 19. pii: 3163. [Epub ahead of print]16(18):
    1,2-Dicinnamoyl-sn-glycero-3-phosphocholine Improves Insulin Sensitivity and Upregulates mtDNA-Encoded Genes in Insulin-Resistant 3T3-L1 Adipocytes: A Preliminary Study.
    Aneta Cierzniak, Anna Gliszczyńska, Małgorzata Małodobra-Mazur.
       BACKGROUND: Insulin resistance is a condition characterized by a reduced biological response to insulin. It is one of the most common metabolic diseases in modern civilization. Numerous natural substances have a positive effect on metabolism and energy homeostasis including restoring the proper sensitivity to insulin. There may be several possible mechanisms of action. In the present study, we elucidated two natural compounds with an impact on insulin signaling in IR adipocytes involving mitochondria.
    METHODS: Mature 3T3-L1 adipocytes with artificially induced insulin resistance by palmitic acid (16:0) were used for the study. Cinnamic acid and 1,2-dicinnamoyl-sn-glycero-3-phosphocholin (1,2-diCA-PC) were tested at three concentrations: 25 μM, 50 μM, and 125 μM. The number of mitochondria and the expression of genes encoded by mtDNA were elucidated in control and experimental cells.
    RESULTS: Experimental cells treated with 1,2-diCA-PC displayed increased insulin-stimulated glucose uptake in a dose-dependent manner, accompanied by an increase in mtDNA copy number. Moreover, in experimental cells treated with 1,2-diCA-PC at a concentration of 125 μM, a significant increase in the expression level of all analyzed genes encoded by mtDNA compared to control cells was observed. Our study showed a relationship between improved cellular sensitivity to insulin by 1,2-diCA-PC and an increase in the number of mitochondria and expression levels of genes encoded by mtDNA.
    CONCLUSIONS: To summarize, the results suggest the therapeutic potential of cinnamic acid derivative 1,2-diCA-PC to enhance the insulin sensitivity of adipocytes.
    Keywords:  1,2-di-CA-PC; cinnamic acid; insulin resistance; phenolic acid; phospholipid derivative
    DOI:  https://doi.org/10.3390/nu16183163
  14. Sci Adv. 2024 Oct 04. 10(40): eadq6223
    SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
    Richard Seager, Nitheyaa Shree Ramesh, Stephen Cross, Chun Guo, Kevin A Wilkinson, Jeremy M Henley.
      Mitochondria undergo fragmentation in response to bioenergetic stress, mediated by dynamin-related protein 1 (DRP1) recruitment to the mitochondria. The major pro-fission DRP1 receptor is mitochondrial fission factor (MFF), and mitochondrial dynamics proteins of 49 and 51 kilodaltons (MiD49/51), which can sequester inactive DRP1. Together, they form a trimeric DRP1-MiD-MFF complex. Adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation of MFF is necessary for mitochondrial fragmentation, but the molecular mechanisms are unclear. Here, we identify MFF as a target of small ubiquitin-like modifier (SUMO) at Lys151, MFF SUMOylation is enhanced following AMPK-mediated phosphorylation and that MFF SUMOylation regulates the level of MiD binding to MFF. The mitochondrial stressor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) promotes MFF SUMOylation and mitochondrial fragmentation. However, CCCP-induced fragmentation is impaired in MFF-knockout mouse embryonic fibroblasts expressing non-SUMOylatable MFF K151R. These data suggest that the AMPK-MFF SUMOylation axis dynamically controls stress-induced mitochondrial fragmentation by regulating the levels of MiD in trimeric fission complexes.
    DOI:  https://doi.org/10.1126/sciadv.adq6223
  15. J Clin Med. 2024 Sep 18. pii: 5533. [Epub ahead of print]13(18):
    Epicardial Fat in Heart Failure with Preserved Ejection Fraction Compared with Reduced Ejection Fraction.
    Gurwinder S Sidhu, Simon W Rabkin.
      Background: The role of epicardial adipose tissue (EAT) in heart failure with preserved ejection fraction (HFpEF) remains to be defined. Methods: A consecutive series of outpatients with chronic heart failure-heart failure with reduced ejection fraction (HFrEF) and HFpEF and/or diastolic dysfunction-had EAT assessed by echocardiographic measurement and related to indices of cardiac structure and function. Results: Epicardial fat thickness was significantly (p < 0.05) greater in HFpEF (N = 141) with a mean of 6.7 ± 1.6 mm compared with a mean of 5.1 ± 1.0 mm in HFrEF (n = 40). After adjusting for the relationship with BMI, in HFpEF, epicardial fat was significantly (p < 0.05) negatively correlated with left ventricular internal diameter end diastole (LVIDd), left ventricular internal diameter end systole (LVIDs), left ventricular (LV) end-diastolic volume (EDV) index, lateral e', septal e', right atrial (RA) volume index, and hemoglobin (Hgb). The association with Hgb was no longer significant after adjusting for the effect of age. HFpEF was associated with smaller LVIDd, LVIDs, LV EDV indexes, and left atrial (LA) and RA volume indexes. Conclusions: Epicardial fat is significantly (p < 0.05) greater in HFpEF than HFrEF. Epicardial fat is associated with smaller cardiac chamber sizes in HFpEF suggesting that epicardial fat acts as a constraint to cardiac dilation.
    Keywords:  HFpEF; HFrEF; atrial size; epicardial fat; ventricular size
    DOI:  https://doi.org/10.3390/jcm13185533
  16. Cardiovasc Res. 2024 Oct 01. pii: cvae216. [Epub ahead of print]
    Leveraging metabolism for better outcomes in heart failure.
    Yann Huey Ng, Yen Chin Koay, Francine Z Marques, David M Kaye, John F O'Sullivan.
      Whilst metabolic inflexibility and substrate constraint have been observed in heart failure for many years, their exact causal role remains controversial. In parallel, many of our fundamental assumptions about cardiac fuel use are now being challenged like never before. For example, the emergence of sodium glucose cotransporter 2 inhibitor (SGLT2i) therapy as one of the four "pillars" of heart failure therapy is causing a revisit of metabolism as a key mechanism and therapeutic target in heart failure. Improvements in the field of cardiac metabolomics will lead to a far more granular understanding of the mechanisms underpinning normal and abnormal human cardiac fuel use, an appreciation of drug action, and novel therapeutic strategies. Technological advances and expanding biorepositories offer exciting opportunities to elucidate the novel aspects of these metabolic mechanisms. Methodologic advances include comprehensive and accurate substrate quantitation such as metabolomics and stable-isotope fluxomics, improved access to arterio-venous blood samples across the heart to determine fuel consumption and energy conversion, high quality cardiac tissue biopsies, biochemical analytics, and informatics. Pairing these technologies with recent discoveries in epigenetic regulation, mitochondrial dynamics, and organ-microbiome metabolic crosstalk will garner critical mechanistic insights in heart failure. In this state-of-the-art review, we focus on new metabolic insights, with an eye on emerging metabolic strategies for heart failure. Our synthesis of the field will be valuable for a diverse audience with an interest in cardiac metabolism.
    Keywords:  SGLT2i; cardiac metabolism; epigenetics; heart failure; microbiome; therapy
    DOI:  https://doi.org/10.1093/cvr/cvae216
  17. Biochem Biophys Res Commun. 2024 Sep 25. pii: S0006-291X(24)01275-0. [Epub ahead of print]734 150739
    Oct-B: A derivative of L-BAIBA significantly alleviating high-fat diet-induced obesity in mice.
    Jianhua Wang, Shanshan Wei, Jinxiu Guo, Xin Xie, Wenxue Sun, Shiyuan Zhao, Junjun Meng, Fang Wang, Jing Wang, Rong Rong, Pei Jiang.
      The rising prevalence of obesity is a global health concern. Supplementation with (S)-β-aminoisobutyric acid (L-BAIBA) has shown potential in preventing obesity and related metabolic disorders induced by high-fat diets. However, developing effective and low-toxicity BAIBA derivatives remains a challenging yet promising field. In this study, we introduce Oct-B, a novel BAIBA ester compound, which exhibits 80-fold greater efficacy than L-BAIBA in alleviating obesity in high-fat diet-fed mice. Our results demonstrate that Oct-B significantly reduces serum TG, TC, LDL-C, and the activities of ALT and AST, and also reduces TG and TC in liver, surpassing the effects of L-BAIBA. Histological analysis shows that Oct-B significantly decreases lipid accumulation in liver tissues, normalizes mast cells in white adipose tissue, and upregulates the expression of UCP1 protein in white adipose tissue. The qRT-PCR results indicated Oct-B alleviates obesity by downregulating lipogenic genes (PPARγ, ACC1, FAS), upregulating lipolysis related genes (PPARα, HSL) and thermogenic gene UCP1. Additionally, quantitative mass spectrometry reveals a marked increase in L-BAIBA levels in white fat, brown fat, serum, and muscle following Oct-B administration. These findings suggest that Oct-B is an efficient L-BAIBA substitute, offering a promising therapeutic approach for preventing and treating high-fat diet-induced obesity.
    Keywords:  Histological analysis; L-BAIBA; Obesity; Oct-B; Quantitative mass spectrometry
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150739
  18. bioRxiv. 2024 Sep 19. pii: 2024.09.16.613349. [Epub ahead of print]
    Reduced Hydrogen Sulfide Bioavailability Contributes to Cardiometabolic Heart Failure with Preserved Ejection Fraction.
    Jake E Doiron, Mahmoud H Elbatreek, Huijing Xia, Xiaoman Yu, W H Wilson Tang, Kyle B LaPenna, Thomas E Sharp, Traci T Goodchild, Ming Xian, Shi Xu, Heather Quiriarte, Timothy D Allerton, Alexia Zagouras, Jennifer Wilcox, Sanjiv J Shah, Josef Pfeilschifter, Karl-Friedrich Beck, Zhen Li, David J Lefer.
       Background: Heart failure with preserved ejection fraction (HFpEF) is a significant public health concern with limited treatment options. Dysregulated nitric oxide-mediated signaling has been implicated in HFpEF pathophysiology, however, little is known about the role of endogenous hydrogen sulfide (H2S).
    Objectives: This study evaluated H2S bioavailability in patients and two animal models of cardiometabolic HFpEF and assessed the impact of H2S on HFpEF severity through alterations in endogenous H2S production and pharmacological supplementation.
    Methods: HFpEF patients and two rodent models of HFpEF ("two-hit" L-NAME + HFD mouse and ZSF1 obese rat) were evaluated for H2S bioavailability. Two cohorts of two-hit mice were investigated for changes in HFpEF pathophysiology: (1) endothelial cell cystathionine-γ-lyase (EC-CSE) knockout; (2) H2S donor, JK-1, supplementation.
    Results: H2S levels were significantly reduced (i.e., 81%) in human HFpEF patients and in both preclinical HFpEF models. This depletion was associated with reduced CSE expression and activity, and increased SQR expression. Genetic knockout of H2S -generating enzyme, CSE, worsened HFpEF characteristics, including elevated E/e' ratio and LVEDP, impaired aortic vasorelaxation and increased mortality. Pharmacologic H2S supplementation restored H2S bioavailability, improved diastolic function and attenuated cardiac fibrosis corroborating an improved HFpEF phenotype.
    Conclusions: H2S deficiency is evident in HFpEF patients and conserved across multiple HFpEF models. Increasing H2S bioavailability improved cardiovascular function, while knockout of endogenous H2S production exacerbated HFpEF pathology and mortality. These results suggest H2S dysregulation contributes to HFpEF and increasing H2S bioavailability may represent a novel therapeutic strategy for HFpEF.
    Highlights: H2S deficiency is evident in both human HFpEF patients and two clinically relevant models.Reduced H2S production by CSE and increased metabolism by SQR impair H2S bioavailability in HFpEF.Pharmacological H2S supplementation improves diastolic function and reduces cardiac fibrosis in HFpEF models.Targeting H2S dysregulation presents a novel therapeutic strategy for managing HFpEF.
    DOI:  https://doi.org/10.1101/2024.09.16.613349
  19. bioRxiv. 2024 Sep 22. pii: 2024.09.18.612717. [Epub ahead of print]
    Increased cGMP improves microvascular exercise training adaptations independent of endothelial nitric oxide synthase.
    Nathan C Winn, David A Cappel, Ethan D Pollock, Louise Lantier, Jillian K Riveros, Payton Debrow, Deanna P Bracy, Joshua A Beckman, David H Wasserman.
      Impaired microvascular function is a hallmark of pre-diabetes. With development of atherosclerosis this impaired microvascular function can result in diminished capacity for ambulation and is a risk factor for Type 2 Diabetes. Dynamic changes in vascular tone are determined, in large part, by the eNOS/NO/cGMP axis. We used gain of function of the eNOS/NO/cGMP axis in diet-induced obese (DIO) mice and reduced function in lean mice to test the hypothesis that functionality of this vascular control mechanism parallels the benefits of an exercise training regimen. DIO mice have lower exercise capacity than lean mice and were used for pharmacological gain of function. The PDE-5a inhibitor - sildenafil - increases cGMP and was administered to DIO mice daily. In sedentary mice, we find that sildenafil does not improve exercise capacity. In contrast, it amplifies the microcirculatory effects of exercise training. Sildenafil synergizes with exercise training to improve performance during an incremental exercise test. Improved exercise performance was accompanied by increased skeletal muscle capillary flow velocity and capillary density measured via intravital microscopy. Loss of function was tested in lean mice hemizygous for endothelial cell (EC) specific eNOS creating an EC-eNOS knockdown (KD). EC-eNOS KD decreases capillary density and exercise tolerance in sedentary mice; however, it did not prevent exercise-training induced improvements in endurance capacity. These data show that 1) increasing cGMP with sildenafil enhances microcirculatory function and exercise work tolerance that results from training; 2) eNOS KD does not prevent the microcirculatory or improvements in exercise tolerance with training. PDE-5a inhibitors combined with physical exercise are a potential mechanism for improving ambulation in patients with circulatory limitations.
    DOI:  https://doi.org/10.1101/2024.09.18.612717
  20. Nat Cell Biol. 2024 Oct 02.
    The role of PINK1-Parkin in mitochondrial quality control.
    Derek P Narendra, Richard J Youle.
      Mitophagy mediated by the recessive Parkinson's disease genes PINK1 and Parkin responds to mitochondrial damage to preserve mitochondrial function. In the pathway, PINK1 is the damage sensor, probing the integrity of the mitochondrial import pathway, and activating Parkin when import is blocked. Parkin is the effector, selectively marking damaged mitochondria with ubiquitin for mitophagy and other quality-control processes. This selective mitochondrial quality-control pathway may be especially critical for dopamine neurons affected in Parkinson's disease, in which the mitochondrial network is widely distributed throughout a highly branched axonal arbor. Here we review the current understanding of the role of PINK1-Parkin in the quality control of mitophagy, including sensing of mitochondrial distress by PINK1, activation of Parkin by PINK1 to induce mitophagy, and the physiological relevance of the PINK1-Parkin pathway.
    DOI:  https://doi.org/10.1038/s41556-024-01513-9
  21. Heart Rhythm. 2024 Sep 26. pii: S1547-5271(24)03385-X. [Epub ahead of print]
    Changes in epicardial adipose tissue volume before and after cryoballoon ablation in patients with atrial fibrillation: supporting the "AF begets EAT" theory.
    Kazuki Shimojo, Itsuro Morishima, Yasuhiro Morita, Yasunori Kanzaki, Naoki Watanabe, Naoki Yoshioka, Naoki Shibata, Yoshihito Arao, Takuma Ohi, Hiroki Goto, Hoshito Karasawa, Yuta Nakagawa, Yuki Kawasaki, Tatsuki Yoshie.
       BACKGROUND: Epicardial adipose tissue (EAT) is closely associated with atrial fibrillation (AF), suggesting it may be one of the causes of AF progression. However, it is unclear whether atrial fibrillation affects EAT.
    OBJECTIVE: This study aimed to demonstrate that sinus rhythm restoration reduces EAT volume (EATV) through left atrial reverse remodeling (LARR).
    METHODS: We analyzed data from 247 patients who underwent cryoballoon ablation (CBA) for AF. EATV was assessed using contrast-enhanced computed tomography with three-dimensional analysis workstation, evaluating EATV surrounding the entire heart (Total-EATV) and left atrial EATV (LA-EATV) at baseline and 6 months post-CBA.
    RESULTS: At 6 months, all patients but one with persistent AF were in sinus rhythm. Total-EATV and LA-EATV were both significantly decreased in patients with persistent AF (n=33) (Total-EATV: 148.8±53.3 to 142.9±53.5 mL, p=0.01; LA-EATV: 26.8±11.3 to 25.2±10.7 mL, p=0.01). No changes were observed in patients with paroxysmal AF (n=214). Persistent AF was more strongly associated with LARR than paroxysmal AF (odds ratio [OR]: 2.34, 95% confidence interval [CI]: 1.01-5.44, p=0.05). LARR showed an independent correlation with both Total-EATV and LA-EATV reduction (OR: 1.78, p=0.04 and OR: 2.80, p<0.001, respectively).
    CONCLUSION: These findings suggest a novel "AF begets EAT" theory, complementing the previously accepted role of EAT as a cause of AF and supporting the "AF begets AF" mechanism.
    Keywords:  atrial fibrillation; atrial reverse remodeling; contrast-enhanced computed tomography; cryoballoon ablation; epicardial adipose tissue
    DOI:  https://doi.org/10.1016/j.hrthm.2024.09.054
  22. Cell Chem Biol. 2024 Sep 26. pii: S2451-9456(24)00393-3. [Epub ahead of print]
    Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation.
    Beste Mutlu, Kfir Sharabi, Jee Hyung Sohn, Bo Yuan, Pedro Latorre-Muro, Xin Qin, Jin-Seon Yook, Hua Lin, Deyang Yu, João Paulo G Camporez, Shingo Kajimura, Gerald I Shulman, Sheng Hui, Theodore M Kamenecka, Patrick R Griffin, Pere Puigserver.
      Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.09.001
  23. Free Radic Biol Med. 2024 Sep 26. pii: S0891-5849(24)00691-9. [Epub ahead of print]
    GTPBP8 mitigates nonalcoholic steatohepatitis (NASH) by depressing hepatic oxidative stress and mitochondrial dysfunction via PGC-1α signaling.
    Dongxiao Meng, Minghui Chang, Xianling Dai, Qin Kuang, Guangchuan Wang.
      Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of liver transplantation and hepatocellular carcinoma (HCC). Regrettably, its pathological mechanisms are still not fully comprehended. GTP-binding protein 8 (GTPBP8), belonging to the GTP-binding protein superfamily, assumes a crucial role in RNA metabolism, cell proliferation, differentiation, and signal transduction. Its aberrant expression is associated with oxidative stress and mitochondrial dysfunctions. Nevertheless, its specific functions and mechanisms of action, particularly in NASH, remain elusive. In our current study, we initially discovered that human hepatocytes L02 displayed evident mitochondrial respiratory anomaly, mitochondrial damage, and dysfunction upon treatment with palmitic acids and oleic acids (PO), accompanied by significantly reduced GTPBP8 expression levels through RNA-Seq, RT-qPCR, western blotting, and immunofluorescence assays. We then demonstrated that GTPBP8 overexpression mediated by adenovirus vector (Ad-GTPBP8) markedly attenuate lipid accumulation, inflammatory response, and mitochondrial impair and dysfunction in hepatocytes stimulated by PO. Conversely, adenovirus vector-mediated GTPBP8 knockdown (Ad-shGTPBP8) significantly accelerated lipid deposition, inflammation and mitochondrial damage in PO-treated hepatocytes in vitro. Furthermore, we constructed an in vivo NASH murine model by giving a 16-week high fat high cholesterol diet (HFHC) diet to hepatocyte specific GTPBP8-knockout (GTPBP8HKO) mice. We firstly found that HFHC feeding led to metabolic disorder in mice, including high body weight, blood glucose and insulin levels, and liver dysfunctions, which were accelerated in these NASH mice with GTPBP8 deficiency in hepatocytes. Consistently, GTPBP8HKO remarkably exacerbated the progression of NASH phenotypes induced by HFHC, as proved by the anabatic lipid accumulation, inflammation, fibrosis and reactive oxygen species (ROS) production in liver tissues, which could be largely attributed to the severe mitochondrial damage and dysfunction. Mechanistically, we further identified that GTPBP8 interacted with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in hepatocytes. Importantly, the hepaprotective effects of GTPBP8 against mitochondrial dysfunction, oxidative stress and inflammation was largely dependent on PGC-1α expression. Collectively, GTPBP8 may exert a protective role in the progression of NASH, and targeting the GTPBP8/PGC-1α axis may represent a potential strategy for NASH treatment by improving mitochondrial functions.
    Keywords:  GTPBP8; Nonalcoholic steatohepatitis (NASH); PGC-1α; fibrosis and oxidative stress; lipid accumulation and inflammation; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.044
  24. Int J Mol Sci. 2024 Sep 22. pii: 10173. [Epub ahead of print]25(18):
    Advances in the Insulin-Heart Axis: Current Therapies and Future Directions.
    Alfredo Caturano, Erica Vetrano, Raffaele Galiero, Celestino Sardu, Luca Rinaldi, Vincenzo Russo, Marcellino Monda, Raffaele Marfella, Ferdinando Carlo Sasso.
      The insulin-heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) and other CVDs. This review was conducted by systematically searching PubMed, Scopus, and Web of Science databases for peer-reviewed studies published in the past decade, focusing on therapeutic interventions targeting the insulin-heart axis. Studies were selected based on their relevance to insulin resistance, cardiovascular outcomes, and the efficacy of pharmacologic treatments. Key findings from the review highlight the efficacy of lifestyle modifications, such as dietary changes and physical activity, which remain the cornerstone of managing insulin resistance and improving cardiovascular outcomes. Moreover, pharmacologic interventions, such as metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors, have shown efficacy in reducing cardiovascular risk by addressing metabolic dysfunction, reducing inflammation, and improving endothelial function. Furthermore, emerging treatments, such as angiotensin receptor-neprilysin inhibitors, and mechanical interventions like ventricular assist devices offer new avenues for managing HF in insulin-resistant patients. The potential of these therapies to improve left ventricular ejection fraction and reverse pathological cardiac remodeling highlights the importance of early intervention. However, challenges remain in optimizing treatment regimens and understanding the long-term cardiovascular effects of these agents. Future research should focus on personalized approaches that integrate lifestyle and pharmacologic therapies to effectively target the insulin-heart axis and mitigate the burden of cardiovascular complications in insulin-resistant populations.
    Keywords:  cardiovascular pharmacotherapy; heart failure management; insulin resistance; insulin sensitivity; insulin–heart axis
    DOI:  https://doi.org/10.3390/ijms251810173
  25. Arch Physiol Biochem. 2024 Oct 02. 1-9
    HM-chromanone attenuates obesity and adipose tissue inflammation by downregulating SREBP-1c and NF-κb pathway in high-fat diet-fed mice.
    Bo Ra Moon, Jae Eun Park, Ji Sook Han.
      Background: Obese adipose tissue produces various pro-inflammatory cytokines that are major contributors to adipose tissue inflammation.
    Objective: The present study aimed to determine the effects of HM-chromanone (HMC) against obesity and adipose tissue inflammation in high-fat diet-fed mice.
    Materials and methods: Twenty-four C57BL/6J male mice were divided into three groups: ND (normal diet), HFD (high-fat diet), and HFD + HMC. The ND group was fed a normal diet, whereas the HFD and HFD + HMC groups were fed a high-fat diet. After 10 weeks of feeding, the animals were orally administered the treatments daily for 9 weeks. The ND and HFD group received distilled water as treatment. The HFD+HMC group was treated with HM-chromaone (50 mg/kg).
    Results: HM-chromanone administration decreased body weight, fat mass, and adipocyte diameter. HM-chromanone also improved plasma lipid profiles, decreased leptin levels, and increased adiponectin levels. The inhibiting effect of HM-chromanone on SREBP-1c, PPARγ, C/EBPα, and FAS decreased adipogenesis, thereby alleviating lipid accumulation. Furthermore, HM-chromanone administration exhibited a reduction in macrophage infiltration and the expression of pro-inflammatory cytokines. HM-chromanone suppressed the phosphorylation of IκBα and NF-κB, leading to the inhibition of iNOS and COX2 expressions, resulting in decreased inflammation in adipose tissue.
    Discussion and conclusion: These results highlight the anti-obesity and anti-inflammatory properties of HM-chromanone, achieved through the downregulation of the SREBP-1c and NF-κB pathway in high-fat diet-fed mice.
    Keywords:  HM-chromanone; NF-κB; SREBP-1c; adipose tissue inflammation; obesity
    DOI:  https://doi.org/10.1080/13813455.2024.2399554
  26. Aging Cell. 2024 Sep 30. e14332
    Sirtuin 3 reinforces acylcarnitine metabolism and maintains thermogenesis in brown adipose tissue of aging mice.
    Kuiliang Zhang, Yucheng Wang, Yujie Sun, Lamei Xue, Yu Wang, Chenzhipeng Nie, Mingcong Fan, Haifeng Qian, Hao Ying, Li Wang, Yan Li.
      Acylcarnitine (ACar) is a novel fuel source for activating thermogenesis in brown adipose tissue (BAT). However, whether ACar metabolism underlies BAT thermogenesis decline with aging remain unclear. Here, the L-carnitine-treated young and aging mice were used to investigate the effects of activation of ACar metabolism on BAT thermogenesis during aging. We showed that long term L-carnitine feeding, which results in an elevation in circulating ACar levels, failed to improve cold sensitivity of aging mice, which still displayed impaired thermogenesis and ACar metabolism in interscapular BAT (iBAT). The RNA-sequencing was used to identify the key regulator for the response of aging mice to LCar induced activation of ACar metabolism in BAT, and we identified Sirt3 as a key regulator for the response of aging mice to L-carnitine induced activation of ACar metabolism in iBAT. Then the adipose-specific Sirt3 knockout (Sirt3 AKO) mice were used to investigate the role of Sirt3 in ACar metabolism and thermogenesis of BAT and explore the underlying mechanism, and the results showed that Sirt3 AKO mice displayed defective ACar metabolism and thermogenesis in iBAT. Mechanically, Sirt3 regulated ACar metabolism via HIF1α-PPARα signaling pathway to promote iBAT thermogenesis, and knockdown or inhibition of HIF1α ameliorated impaired ACar metabolism and thermogenesis of iBAT in the absence of Sirt3. Collectively, we propose that Sirt3 regulated ACar metabolism is critical in maintaining thermogenesis in BAT of aging mice, which can promote the development of anti-aging intervention strategy.
    Keywords:  Sirt3; acylcarnitine metabolism; aging; brown adipose tissue; thermogenesis
    DOI:  https://doi.org/10.1111/acel.14332
  27. Diabetes Res Clin Pract. 2024 Oct 02. pii: S0168-8227(24)00788-5. [Epub ahead of print] 111878
    Role of epicardial adipose tissue in cardiac remodeling.
    Rongjun Zou, Miao Zhang, Weihui Lv, Jun Ren, Xiaoping Fan.
      Epicardial adipose tissue, or epicardial fat, is a type of visceral fat located between the heart and the pericardium. Due to its anatomical proximity to the heart, EAT plays a significant role in both cardiac physiology and pathologies, including cardiac remodeling and cardiovascular diseases (CVD). However, our understanding of how EAT pathology is influenced by risk factors such as obesity and type 2 diabetes mellitus and how altered EAT can drive cardiac remodeling and CVD, remains limited. Herein, we aimed to summarize and discuss the latest findings on EAT and its role in cardiac remodeling, highlighting the outcomes of clinical and observational studies, provide mechanistic insights, and finally introduce emerging therapeutic agents and nutritional guidelines aimed at preventing these conditions.
    Keywords:  And adipocytokines; Cardiac remodeling; Cardiovascular diseases; Diabetes; Epicardial fat/adipose tissue; Leptin; Obesity
    DOI:  https://doi.org/10.1016/j.diabres.2024.111878
  28. Biomedicines. 2024 Sep 11. pii: 2071. [Epub ahead of print]12(9):
    The ABA/LANCL1-2 Hormone/Receptors System Controls ROS Production in Cardiomyocytes through ERRα.
    Sonia Spinelli, Lucrezia Guida, Mario Passalacqua, Mirko Magnone, Bujar Caushi, Elena Zocchi, Laura Sturla.
      Rat H9c2 cardiomyocytes overexpressing the abscisic acid (ABA) hormone receptors LANCL1 and LANCL2 have an increased mitochondrial proton gradient, respiration, and vitality after hypoxia/reoxygenation. Our aim was to investigate the role of the ABA/LANCL1-2 system in ROS turnover in H9c2 cells. H9c2 cells were retrovirally infected to induce the overexpression or silencing of LANCL1 and LANCL2, without or with the concomitant silencing of the transcription factor ERRα. Enzymes involved in radical production or scavenging were studied by qRT-PCR and Western blot. The mitochondrial proton gradient and ROS were measured with specific fluorescent probes. ROS-generating enzymes decreased, ROS-scavenging enzymes increased, and mitochondrial ROS were reduced in LANCL1/2-overexpressing vs. control cells infected with the empty vector, while the opposite occurred in LANCL1/2-silenced cells. The knockdown of ERRα abrogated all beneficial effects on ROS turnover in LANCL1/2 overexpressing cells. Taken together, these results indicate that the ABA/LANCL1-2 system controls ROS turnover in H9c2 via ERRα. The ABA/LANCL system emerges as a promising target to improve cardiomyocyte mitochondrial function and resilience to oxidative stress.
    Keywords:  COX2; ERRα; GPX4; NOX4; ROS-producing enzymes; ROS-scavenging enzymes; SOD2; XO; mitochondrial proton gradient
    DOI:  https://doi.org/10.3390/biomedicines12092071
  29. Endocrinol Diabetes Metab. 2024 Nov;7(6): e70002
    Adalimumab Treatment Effects on Inflammation and Adipose Tissue Mitochondrial Respiration in Hidradenitis Suppurativa.
    Ronni Eg Sahl, Axel Illeris Poggi, Valdemar Wendelboe Nielsen, Yiqiu Yao, Ioanna Patsi, Steen Seier Poulsen, Flemming Dela, Steen Larsen, Simon Francis Thomsen, Jørn Wulff Helge.
       OBJECTIVE: Tumour necrosis factor (TNF)-α is a proinflammatory marker and has been shown to affect mitochondrial function in different tissues. We investigated the effect on adipose tissue (AT) inflammation and mitochondrial respiration in patients with hidradenitis suppurativa (HS) after 12 weeks of treatment with adalimumab, a TNF-α inhibitor.
    METHODS: We sampled blood and an AT biopsy from 13 patients with HS and 10 control subjects after an overnight fast. The patients were retested after at least 12 weeks of treatment with adalimumab (40 mg/week). We measured macrophage content and mitochondrial respiration in the AT and interleukin (IL)-1β, IL-6, IL-10, high-sensitivity C-reactive protein (hsCRP), interferon-γ, TNF-α, adiponectin and leptin in plasma. Clinical scores and Dermatology Quality of Life Index (DLQI) were assessed.
    RESULTS: We found a higher anti-inflammatory macrophage content (CD206+) in the patient group compared with the control group, but no differences between before and after the intervention. No difference in mitochondrial respiration was observed. We observed higher plasma IL-6 and hsCRP concentrations in patients with HS compared to controls, with no differences before and after the intervention. The difference between controls and HS patients was abolished after the intervention. HS patients improved their DLQI after the intervention with no change in clinical scores.
    CONCLUSION: Treatment with adalimumab in patients with HS does not alter AT inflammation or mitochondrial respiratory capacity; however, we did see a higher content of anti-inflammatory macrophages in the patient group compared with the control group.
    Keywords:  adalimumab; adipose tissue; hidradenitis suppurativa; inflammation; low‐grade inflammation; macrophages; mitochondrial respiration
    DOI:  https://doi.org/10.1002/edm2.70002
  30. Nutr Metab Cardiovasc Dis. 2023 Jul 13. pii: S0939-4753(23)00276-4. [Epub ahead of print]
    Cannabidiol treatment changes myocardial lipid profile in spontaneously hypertensive rats.
    Ewa Harasim-Symbor, Patrycja Bielawiec, Anna Pedzinska-Betiuk, Jolanta Weresa, Barbara Malinowska, Karolina Konstantynowicz-Nowicka, Adrian Chabowski.
       BACKGROUND AND AIMS: Hypertension is a potent risk factor for cardiovascular diseases, which are the leading worldwide cause of death. Within time increased blood pressure (BP) induces cardiac contractile dysfunction, metabolic alternations, and eventually, heart failure, which makes hypertension an area for seeking safe therapies such as phytocannabinoids.
    METHODS AND RESULTS: In the present study spontaneously hypertensive rats (SHRs) were used as an experimental model of genetically induced hypertension, where cannabidiol (CBD) was applied as a potential treatment (intraperitoneally administered for 2 weeks, 10 mg/kg) for elevated BP and related metabolic disturbances. Langendorff working heart system, Western blotting as well as gas-liquid chromatography were applied to determine radiolabeled 3H-palmitate uptake, incorporation, and oxidation, protein expression, as well as the content and fatty acid composition of different lipid fractions in the left ventricle and plasma, respectively. Most importantly, we noticed that 2-week CBD treatment was effective in upregulating ex vivo3H-palmitate uptake, oxidation, and its incorporation into triacylglycerol and cholesterol fractions with concomitant lowering free fatty acid, diacylglycerol, and phospholipid fractions, which was in agreement with in vivo studies and alternations in protein expressions of lipoprotein lipase, carnitine palmitoyltransferase I, 3-hydroxyacyl-CoA dehydrogenase, diacylglycerol acyltransferase 1, and adipose triglyceride lipase as well as proteins associated with eicosanoid signaling pathways and extracellular matrix remodeling in the heart of hypertensive rats.
    CONCLUSION: Our study reveals that 2-week CBD administration substantially affects the energetic substrate milieu in cardiac muscle regarding fatty acids uptake and their further utilization without parallel significant alternations in cardiovascular parameters.
    Keywords:  Cannabidiol; Fatty acid transporters; Fatty acid uptake; Lipids; Spontaneously hypertensive rats
    DOI:  https://doi.org/10.1016/j.numecd.2023.07.007
  31. Sci Rep. 2024 10 03. 14(1): 22965
    Molecular composition of skeletal muscle in infants and adults: a comparative proteomic and transcriptomic study.
    Alexander Schaiter, Andreas Hentschel, Felix Kleefeld, Julia Schuld, Vincent Umathum, Tara Procida-Kowalski, Christopher Nelke, Angela Roth, Andreas Hahn, Heidrun H Krämer, Tobias Ruck, Rita Horvath, Peter F M van der Ven, Marek Bartkuhn, Andreas Roos, Anne Schänzer.
      To gain a deeper understanding of skeletal muscle function in younger age and aging in elderly, identification of molecular signatures regulating these functions under physiological conditions is needed. Although molecular studies of healthy muscle have been conducted on adults and older subjects, there is a lack of research on infant muscle in terms of combined morphological, transcriptomic and proteomic profiles. To address this gap of knowledge, we performed RNA sequencing (RNA-seq), tandem mass spectrometry (LC-MS/MS), morphometric analysis and assays for mitochondrial maintenance in skeletal muscle biopsies from both, infants aged 4-28 months and adults aged 19-65 years. We identified differently expressed genes (DEGs) and differentially expressed proteins (DEPs) in adults compared to infants. The down-regulated genes in adults were associated with functional terms primarily related to sarcomeres, cellular maintenance, and metabolic, immunological and developmental processes. Thus, our study indicates age-related differences in the molecular signatures and associated functions of healthy skeletal muscle. Moreover, the findings assert that processes previously associated solely with aging are indeed part of development and healthy aging. Hence, combined findings of this study also indicate that age-dependent controls are crucial in muscle disease studies, as otherwise the comparative results may not be reliable.
    Keywords:  Bioinformatics in omics; Mitochondria in aging; Muscle proteomics; Muscle transcriptomics
    DOI:  https://doi.org/10.1038/s41598-024-74913-4
  32. Nat Commun. 2024 Oct 02. 15(1): 8533
    Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors.
    Sanil Patel, Khatanzul Ganbold, Chung Hwan Cho, Juwairriyyah Siddiqui, Ramazan Yildiz, Njeri Sparman, Shani Sadeh, Christy M Nguyen, Jiexin Wang, Julian P Whitelegge, Susan K Fried, Hironori Waki, Claudio J Villanueva, Marcus M Seldin, Shinya Sakaguchi, Wilfried Ellmeier, Peter Tontonoz, Prashant Rajbhandari.
      White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1's function during differentiation. These findings underscore PATZ1's regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.
    DOI:  https://doi.org/10.1038/s41467-024-52917-y
  33. Chem Pharm Bull (Tokyo). 2024 ;72(10): 845-855
    Diosgenin Alleviates Obesity-Induced Insulin Resistance by Modulating PI3K/Akt Signaling Pathway in Mice Fed a High-Fat Diet.
    Seung-Hyun Oh, Min-Seong Lee, Byung-Cheol Lee.
      Obesity is a global medical issue that can be effectively treated by relieving adipose inflammation and subsequent insulin resistance. Diosgenin (DIOS) has various effects as a steroidal saponin in inflammatory disorders. This study explored the effects and mechanism of DIOS on adipose inflammation and insulin sensitivity, both in silico and in vivo. The high-fat diet-induced obesity model in C57BL/6 mice was divided into five groups: normal chow (NC), high-fat diet (HFD), HFD with atorvastatin 10 mg/kg (AT), HFD with DIOS 100 mg/kg (DIOS 100), and HFD with DIOS 200 mg/kg (DIOS 200). Each group underwent an oral intervention for seven weeks. DIOS significantly suppressed weight gain in the body, liver, and epididymal fat pads. Additionally, it significantly improved fasting glucose and insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), and oral glucose tolerance test results, and reduced the proportion of total and M1 adipose tissue macrophages. Significant changes were shown in mRNA expression of janus kinase 2 (JAK2), insulin receptor (INRS), insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt), all of which exhibited high binding affinity in the in silico. Safety indices, including aspartate aminotransferase (AST), alanine transaminase (ALT), and creatinine level indicated the preventive effects of DIOS. In conclusion, DIOS improves insulin resistance and obesity-associated inflammation via the PI3K/Akt signaling pathway.
    Keywords:  diosgenin; inflammation; insulin resistance; obesity; phosphatidylinositol 3-kinase; protein kinase B
    DOI:  https://doi.org/10.1248/cpb.c24-00313
  34. Eur J Endocrinol. 2024 Oct 01. pii: lvae123. [Epub ahead of print]
    Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.
    Felix A Westcott, Shilpa R Nagarajan, Sion A Parry, Dragana Savic, Charlotte J Green, Thomas Marjot, Elspeth Johnson, Thomas Cornfield, Ferenc E Mózes, Paige O'Rourke, Jessica Mendall, David Dearlove, Barbara Fielding, Kieran Smith, Jeremy W Tomlinson, Leanne Hodson.
       OBJECTIVE: Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR; defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans.
    DESIGN: Cross-sectional study in men and women across a range of adiposity.
    METHODS: Medication-free participants (n=177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast.
    RESULTS: Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups.
    CONCLUSIONS: Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF and these pathways should be considered for therapeutic targeting.
    Keywords:   de novo lipogenesis; Insulin resistance; gluconeogenesis; hyperinsulinemia; liver fat
    DOI:  https://doi.org/10.1093/ejendo/lvae123
  35. Am J Physiol Cell Physiol. 2024 Sep 30.
    Mitochondrial antioxidant SkQ1 attenuates C26 cancer-induced muscle wasting in males and improves muscle contractility in female tumor-bearing mice.
    Stavroula Tsitkanou, Francielly Morena da Silva, Ana Regina Cabrera, Eleanor R Schrems, Ruqaiza Muhyudin, Pieter J Koopmans, Sabin Khadgi, Seongkyun Lim, Luca J Delfinis, Tyrone A Washington, Kevin A Murach, Christopher G R Perry, Nicholas P Greene.
      Mitochondrial dysfunction is a hallmark of cancer cachexia (CC). Mitochondrial reactive oxygen species (ROS) are elevated in muscle shortly after tumor onset. Targeting mitochondrial ROS may be a viable option to prevent CC. The aim of this study was to evaluate the efficacy of a mitochondria-targeted antioxidant, SkQ1, to mitigate CC in both biological sexes. Male and female Balb/c mice were injected bilaterally with colon 26 adenocarcinoma (C26) cells (total 1x106 cells) or PBS (equal volume control). SkQ1 was dissolved in drinking water (~250 nmol/kg body weight/day) and administered to mice beginning seven days following tumor induction, while control groups consumed normal drinking water. In vivo muscle contractility of dorsiflexors, deuterium oxide-based protein synthesis, mitochondrial respiration and mRNA content of mitochondrial, protein turnover and calcium channel-related markers were assessed at endpoint (25 days following tumor induction). Two-way ANOVAs, followed by Tukey's post-hoc test when interactions were significant (p≤0.05), were performed. SkQ1 attenuated cancer-induced atrophy, promoted protein synthesis and abated Redd1 and Atrogin induction in gastrocnemius of C26 male mice. In female mice, SkQ1 decreased muscle mass and increased catabolic signaling in the plantaris of tumor-bearing mice, as well as reduced mitochondrial oxygen consumption, regardless of tumor. However, in females SkQ1 enhanced muscle contractility of the dorsiflexors with concurrent induction of Ryr1, Serca1 and Serca2a in TA. In conclusion, the mitochondria-targeted antioxidant SkQ1 may attenuate CC-induced muscle loss in males, while improving muscle contractile function in tumor-bearing female mice, suggesting sexual dimorphism in the effects of this mitochondrial therapy in CC.
    Keywords:  cancer cachexia; protein turnover; reactive oxygen species; sexual dimorphism; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00497.2024
  36. J Dairy Sci. 2024 Sep 27. pii: S0022-0302(24)01176-7. [Epub ahead of print]
    Longitudinal characterization of the muscle metabolome in dairy cows during the transition from lactation cessation to lactation resumption.
    H Sadri, M H Ghaffari, H Sauerwein, S Schuchardt, J Martín-Tereso, John Doelman, J B Daniel.
      Skeletal muscle is vital in maintaining metabolic homeostasis and adapting to the physiological needs of pregnancy and lactation. Despite advancements in understanding metabolic changes in dairy cows around calving and early lactation, there are still gaps in our knowledge, especially concerning muscle metabolism and the changes associated with drying off. This study aimed to characterize the skeletal muscle metabolome in the context of the dietary and metabolic changes occurring during the transition from the cessation of lactation to the resumption of lactation in dairy cows. Twelve Holstein dairy cows housed in tie stalls were dried off 6 weeks (wk) before the expected calving date. Cows were individually fed ad libitum total mixed rations composed of grass silage, corn silage, and concentrate during lactation and of corn silage, barley straw, and concentrate during the dry period. The metabolome was characterized in skeletal muscle samples (M. longissimus dorsi) collected on wk -7 (9 d before dry-off), -5 (6 d after dry-off), and wk -1, and 1 relative to calving. The targeted metabolomics approach was conducted using the MxP Quant 500 kit (Biocrates Life Sciences AG) with liquid chromatography, flow injection, and electrospray ionization triple quadrupole mass spectrometry. Statistical analysis on the muscle metabolite data was performed using MetaboAnalyst 5.0, which allowed us to conduct various multivariate analyses such as principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), informative heat map generation, and hierarchical clustering. The statistical analysis revealed a clear separation between pregnancy (wk -7, -5, and -1) and post-calving (wk 1). Starting 5 wk before calving and continuing through the first wk thereafter, the concentration of 3-methylhistidine (3-MH) in the muscle increased. This coincided with an increase in the concentrations of 11 AA (Phe, His, Tyr, Trp, Arg, Asn, Leu, Ile, Gly, Ser, and Thr) in the first wk after calving, whereas Gln decreased. l-arginine pathway metabolites (homoarginine, ornithine, citrulline, and asymmetric dimethylarginine), betaine, and sarcosine followed a similar pattern, increasing from wk -7 to -5, but decreasing from wk -1 to 1. The transition from pregnancy to lactation was associated with an increase in concentrations of the long-chain acylcarnitine species C16, C16:1, C18, and C18:1 in the muscle, whereas the concentrations of phosphatidylcholine and sphingomyelin in the muscle remained stable. The significant changes observed in the metabolome mainly concerned the AA and AA-related metabolites, indicating muscle protein breakdown in the first wk after calving. The metabolites produced by the L-Arg pathway might contribute to regulating skeletal muscle mass and function in periparturient dairy cows. The elevated concentrations of long-chain acylcarnitine species in the muscle in the first wk after calving suggest incomplete fatty acid oxidation, likely due to insufficient metabolic adaptation in response to the fatty acid load around the time of calving.
    Keywords:  dairy cow; muscle; targeted metabolomics; transition
    DOI:  https://doi.org/10.3168/jds.2024-25324
  37. J Cachexia Sarcopenia Muscle. 2024 Oct 02.
    Prenatal and progressive coenzyme Q10 administration to mitigate muscle dysfunction in mitochondrial disease.
    Juan Diego Hernández-Camacho, Cristina Vicente-García, Lorena Ardila-García, Ana Padilla-Campos, Guillermo López-Lluch, Carlos Santos-Ocaña, Peter S Zammit, Jaime J Carvajal, Plácido Navas, Daniel J M Fernández-Ayala.
       BACKGROUND: ADCK genes encode aarF domain-containing mitochondrial kinases involved in coenzyme Q (CoQ) biosynthesis and regulation. Haploinsufficiency of ADCK2 in humans leads to adult-onset physical incapacity with reduced mitochondrial CoQ levels in skeletal muscle, resulting in mitochondrial myopathy and alterations in fatty acid β-oxidation. The sole current treatment for CoQ deficiencies is oral administration of CoQ10, which causes only partial recovery with postnatal treatment, underscoring the importance of early diagnosis for successful intervention.
    METHODS: We used Adck2 heterozygous mice to examine the influence of this gene on muscle structure, function and regeneration throughout development, growth and ageing. This investigation involved techniques including immunohistochemistry, analysis of CoQ levels, mitochondrial respiratory content, muscle transcriptome analysis and functional tests.
    RESULTS: We demonstrated that Adck2 heterozygous mice exhibit defects from embryonic development, particularly in skeletal muscle (1102 genes deregulated). Adck2 heterozygous embryos were 7% smaller in size and displayed signs of delayed development. Prenatal administration of CoQ10 could mitigate these embryonic defects. Heterozygous Adck2 mice also showed a decrease in myogenic cell differentiation, with more severe consequences in 'aged' mice (41.63% smaller) (P < 0.01). Consequently, heterozygous Adck2 mice displayed accelerated muscle wasting associated with ageing in muscle structure (P < 0.05), muscle function (less grip strength capacity) (P < 0.001) and muscle mitochondrial respiration (P < 0.001). Furthermore, progressive CoQ10 administration conferred protective effects on mitochondrial function (P < 0.0001) and skeletal muscle (P < 0.05).
    CONCLUSIONS: Our work uncovered novel aspects of CoQ deficiencies, revealing defects during embryonic development in mammals for the first time. Additionally, we identified the gradual establishment and progression of the deleterious Adck2 mouse phenotype. Importantly, CoQ10 supplementation demonstrated a protective effect when initiated during development.
    Keywords:  ageing; coenzyme Q; development; mitochondria; satellite cell; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13574
  38. bioRxiv. 2024 Sep 21. pii: 2024.09.17.613577. [Epub ahead of print]
    Integration of metabolomic and transcriptomic analyses reveals novel regulatory functions of the ChREBP transcription factor in energy metabolism.
    Jie An, Inna Astapova, Guofang Zhang, Andrew L Cangelosi, Olga Ilkayeva, Hannah Marchuk, Michael J Muehlbauer, Tabitha George, Joseph Brozinick, Mark A Herman, Christopher B Newgard.
      Carbohydrate Response Element-Binding Protein (ChREBP) is a transcription factor that activates key genes involved in glucose, fructose, and lipid metabolism in response to carbohydrate feeding, but its other potential roles in metabolic homeostasis have not been as well studied. We used liver-selective GalNAc-siRNA technology to suppress expression of ChREBP in rats fed a high fat/high sucrose diet and characterized hepatic and systemic responses by integrating transcriptomic and metabolomic analyses. GalNAc-siChREBP-treated rats had lower levels of multiple short-chain acyl CoA metabolites compared to rats treated with GalNAc-siCtrl containing a non-targeting siRNA sequence. These changes were related to a sharp decrease in free CoA levels in GalNAc-siChREBP treated-rats, accompanied by lower expression of transcripts encoding enzymes and transporters involved in CoA biosynthesis. These activities of ChREBP likely contribute to its complex effects on hepatic lipid and energy metabolism. While core enzymes of fatty acid (FA) oxidation are induced by ChREBP knockdown, accumulation of liver acylcarnitines and circulating ketones indicate diversion of acetyl CoA to ketone production rather than complete oxidation in the TCA cycle. Despite strong suppression of pyruvate kinase and activation of pyruvate dehydrogenase, pyruvate levels were maintained, likely via increased expression of pyruvate transporters, and decreased expression of lactate dehydrogenase and alanine transaminase. GalNAc-siChREBP treatment increased hepatic citrate and isocitrate levels while decreasing levels of distal TCA cycle intermediates. The drop in free CoA levels, needed for the 2-ketoglutarate dehydrogenase reaction, as well as a decrease in transcripts encoding the anaplerotic enzymes pyruvate carboxylase, glutamate dehydrogenase, and aspartate transaminase likely contributed to these effects. GalNAc-siChREBP treatment caused striking increases in PRPP and ZMP/AICAR levels, and decreases in GMP, IMP, AMP, NaNM, NAD(P), and NAD(P)H levels, accompanied by reduced expression of enzymes that catalyze late steps in purine and NAD synthesis. ChREBP suppression also increased expression of a set of plasma membrane amino acid transporters, possibly as an attempt to replenish TCA cycle intermediates. In sum, combining transcriptomic and metabolomic analyses has revealed regulatory functions of ChREBP that go well beyond its canonical roles in control of carbohydrate and lipid metabolism to now include mitochondrial metabolism and cellular energy balance.
    DOI:  https://doi.org/10.1101/2024.09.17.613577
  39. Sci Rep. 2024 09 27. 14(1): 22147
    Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling.
    Takeru Akabane, Hiromori Sagae, Koen van Wijk, Shinichi Saitoh, Tomohiro Kimura, Satoshi Okano, Ken Kodama, Kiwamu Takahashi, Motowo Nakajima, Tohru Tanaka, Michiaki Takagi, Osamu Nakajima.
      Heme serves as a prosthetic group in hemoproteins, including subunits of the mammalian mitochondrial electron transfer chain. The first enzyme in vertebrate heme biosynthesis, 5-aminolevulinic acid synthase 1 (ALAS1), is ubiquitously expressed and essential for producing 5-aminolevulinic acid (ALA). We previously showed that Alas1 heterozygous mice at 20-35 weeks (aged-A1+/-s) manifested impaired glucose metabolism, mitochondrial malformation in skeletal muscle, and reduced exercise tolerance, potentially linked to autophagy dysfunction. In this study, we investigated autophagy in A1+/-s and a sarcopenic phenotype in A1+/-s at 75-95 weeks (senile-A1+/-s). Senile-A1+/-s exhibited significantly reduced body and gastrocnemius muscle weight, and muscle strength, indicating an accelerated sarcopenic phenotype. Decreases in total LC3 and LC3-II protein and Map1lc3a mRNA levels were observed in aged-A1+/-s under fasting conditions and in Alas1 knockdown myocyte-differentiated C2C12 cells (A1KD-C2C12s) cultured in high- or low-glucose medium. ALA treatment largely reversed these declines. Reduced AMP-activated protein kinase (AMPK) signaling was associated with decreased autophagy in aged-A1+/-s and A1KD-C2C12s. AMPK modulation using AICAR (activator) and dorsomorphin (inhibitor) affected LC3 protein levels in an AMPK-dependent manner. Our findings suggest that heme deficiency contributes to accelerated sarcopenia-like defects and reduced autophagy in skeletal muscle, primarily due to decreased AMPK signaling.
    Keywords:  5-aminolevulinic acid; 5-aminolevulinic acid synthase 1 (ALAS1); Autophagy; Heme; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-024-73049-9
  40. Nutr Metab (Lond). 2024 Sep 30. 21(1): 77
    Construction of a metabolism-malnutrition-inflammation prognostic risk score in patients with heart failure with preserved ejection fraction: a machine learning based Lasso-Cox model.
    Jiayu Feng, Liyan Huang, Xuemei Zhao, Xinqing Li, Anran Xin, Chengyi Wang, Yuhui Zhang, Jian Zhang.
       BACKGROUND: Metabolic disorder, malnutrition and inflammation are involved and interplayed in the mechanisms of heart failure with preserved ejection fraction (HFpEF). We aimed to construct a Metabolism-malnutrition-inflammation score (MIS) to predict the risk of death in patients with HFpEF.
    METHODS: We included patients diagnosed with HFpEF and without infective or systemic disease. 20 biomarkers were filtered by the Least absolute shrinkage and selection operator (Lasso)-Cox regression. 1000 times bootstrapping datasets were generated to select biomarkers that appeared above 95% frequency in repetitions to construct the MIS.
    RESULTS: Among 1083 patients diagnosed with HFpEF, 342 patients (31.6%) died during a median follow-up period of 2.5 years. The MIS was finally constructed based on 6 biomarkers, they were albumin (ALB), red blood cell distribution width-standard deviation (RDW-SD), high-sensitivity C-reactive protein (hs-CRP), lymphocytes, triiodothyronine (T3) and uric acid (UA). Incorporating MIS into the basic predictive model significantly increased both discrimination (∆C-index = 0.034, 95% CI 0.013-0.050) and reclassification (IDI, 6.6%, 95% CI 4.0%-9.5%; NRI, 22.2% 95% CI 14.4%-30.2%) in predicting all-cause mortality. In the time-dependent receiver operating characteristic (ROC) analysis, the mean area under the curve (AUC) for the MIS was 0.778, 0.782 and 0.772 at 1, 3, and 5 years after discharge in the cross-validation sets. The MIS was independently associated with all-cause mortality (hazard ratio: 1.98, 95% CI [1.70-2.31], P < 0.001).
    CONCLUSIONS: A risk score derived from 6 commonly used inflammatory, nutritional, thyroid and uric acid metabolic biomarkers can effectively identify high-risk patients with HFpEF, providing potential individualized management strategies for patients with HFpEF.
    Keywords:  Biomarker; Heart failure with preserved ejection fraction; Machine learning; Malnutrition-inflammation complex
    DOI:  https://doi.org/10.1186/s12986-024-00856-2
  41. Scand J Med Sci Sports. 2024 Oct;34(10): e14737
    The Rate of Leg Fat Oxidation Is Not Attenuated During Incremental Intensity One-Leg Knee Extensor Exercise.
    J W Helge, C E Shannon, B Stallknecht, F B Stephens, P L Greenhaff, F Dela.
      It is not clear if fat oxidation is attenuated at higher exercise intensities, when exercising with a small muscle mass, and therefore, we studied leg fat oxidation during graded one-leg exercise. Ten males (age: 27 ± 2 years, body mass: 82 ± 3 kg, BMI: 24 ± 1 kg m-2, V̇O2max: 49 ± 2 mL min-1 kg-1) performed one-leg exercise at 25% of maximal workload (Wmax) for 30 min, followed by 120-min exercise at 55% Wmax with the contralateral leg, and finally 30-min exercise at 85% Wmax with the first leg. Blood was sampled from an artery and both femoral veins, and blood flow was determined using Doppler ultrasound. Muscle biopsies were obtained before and after 30 min at each workload. One-way RM ANOVA was applied to determine the impact of exercise intensity. Data are expressed as mean ± SEM. From rest through exercise average blood flow (0.4 ± 0.1, 2.1 ± 0.1, 2.6 ± 0.2, 3.7 ± 0.2 L min-1) and oxygen uptake across the leg (0.03 ± 0.01, 0.23 ± 0.02, 0.35 ± 0.03, 0.53 ± 0.04 L min-1) increased with exercise intensity (p < 0.001). Leg RQ (0.76 ± 0.04, 0.86 ± 0.02,0.87 ± 0.01, 0.92 ± 0.01, p < 0.001), leg plasma FA uptake (2 ± 2, 46 ± 8,83 ± 9, 114 ± 16 μmol min-1; p < 0.001) and rate of leg fat oxidation (0.016 ± 0.005, 0.062 ± 0.012, 0.075 ± 0.011, 0.084 ± 0.018 g min-1, p < 0.007) increased with exercise intensity. Muscle-free carnitine content was unchanged from rest at 25% Wmax and decreased after 30 min exercise at 55% and 85% Wmax (17.4 ± 1.6, 16.6 ± 0.7, 14.5 ± 1.2, 10.5 ± 1.0 mmol/kg dry muscle, respectively; p < 0.006). During incremental one-leg exercise, the rate of leg fat oxidation was not attenuated with increasing exercise intensity, probably due to an insufficient muscle metabolic stress response.
    Keywords:  carnitine; exercise; metabolism; muscle; one‐leg exercise
    DOI:  https://doi.org/10.1111/sms.14737
  42. Pediatr Res. 2024 Oct 02.
    Elevated plasma bile acids coincide with cardiac stress and inflammation in young Cyp2c70-/- mice.
    Hilde D de Vries, Tim R Eijgenraam, Vincent W Bloks, Niels L Mulder, Tim van Zutphen, Herman H W Silljé, Folkert Kuipers, Jan Freark de Boer.
       BACKGROUND: High plasma bile acids (BAs), for instance due to intrahepatic cholestasis of pregnancy or neonatal cholestasis, are associated with cardiac abnormalities. Here, we exploited the variability in plasma BA levels in Cyp2c70-/- mice with a human-like BA composition to investigate the acute effects of elevated circulating BAs on the heart.
    METHODS: RNA sequencing was performed on hearts of 3-week-old Cyp2c70-/- mice lacking mouse-specific BA species that show features of neonatal cholestasis. Cardiac transcriptomes were compared between wild-type pups, Cyp2c70-/- pups with low or high plasma BAs, and Cyp2c70-/- pups from dams that were perinatally treated with ursodeoxycholic acid (UDCA).
    RESULTS: We identified 1355 genes that were differentially expressed in hearts of Cyp2c70-/- mice with high versus low plasma BAs with enrichment of inflammatory processes. Strikingly, expression of 1053 (78%) of those genes was normalized in hearts of pups of UDCA-treated dams. Moreover, 645 cardiac genes strongly correlated to plasma BAs, of which 172 genes were associated with cardiovascular disease.
    CONCLUSIONS: Elevated plasma BAs alter gene expression profiles of hearts of mice with a human-like BA profile, revealing cardiac stress and inflammation. Our findings support the notion that high plasma BAs induce cardiac complications in early life.
    IMPACT: Cyp2c70-/- mice with a human-like bile acid composition show features of neonatal cholestasis but the extrahepatic consequences hereof have so far hardly been addressed Elevated plasma bile acids in Cyp2c70-/- pups coincide with cardiac stress and inflammation Perinatal treatment with UDCA prevents dysregulated cardiac gene expression patterns in Cyp2c70-/- pups.
    DOI:  https://doi.org/10.1038/s41390-024-03596-4
  43. Eur J Endocrinol. 2024 Sep 30. pii: lvae128. [Epub ahead of print]
    Mechanisms in Endocrinology: Hypogonadism and metabolic health in men - novel insights into pathophysiology.
    Clare Miller, Lauren Madden-Doyle, Channa Jayasena, Marie McIlroy, Mark Sherlock, Michael W O'Reilly.
      Hypogonadism in men is associated with an adverse metabolic phenotype and increased mortality. Reciprocally, obesity and insulin resistance can suppress the hypothalamic-pituitary-gonadal axis in the absence of structural organic disease, further perpetuating a cycle of metabolic dysfunction and low testosterone. The mechanisms underpinning this bidirectional association are complex as hypogonadism is a heterogenous syndrome, and obesity is associated with metabolic perturbations in glucose and lipid metabolism even in the presence of normal testicular function. However, distinct molecular defects specific to testosterone deficiency have been identified in pathways relating to glucose and lipid metabolism in target metabolic depots such as adipose tissue and skeletal muscle. This review discusses the aetiology and prevalence of metabolic disease in male hypogonadism, with a specific focus on both disease mechanisms and novel potential approaches to enhance our understanding.
    Keywords:  Hypogonadism; androgens; insulin resistance; metabolism; obesity
    DOI:  https://doi.org/10.1093/ejendo/lvae128
  44. Circulation. 2024 Oct 02.
    Essential Role of the RIα Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development.
    Ibrahim Bedioune, Marine Gandon-Renard, Matthieu Dessillons, Aurélien Barthou, Audrey Varin, Delphine Mika, Saïd Bichali, Joffrey Cellier, Patrick Lechène, Sarah Karam, Maya Dia, Susana Gomez, Walma Pereira de Vasconcelos, Françoise Mercier-Nomé, Philippe Mateo, Audrey Dubourg, Constantine A Stratakis, Jean-Jacques Mercadier, Jean-Pierre Benitah, Vincent Algalarrondo, Jérôme Leroy, Rodolphe Fischmeister, Ana-Maria Gomez, Grégoire Vandecasteele.
       BACKGROUND: The heart expresses 2 main subtypes of cAMP-dependent protein kinase (PKA; type I and II) that differ in their regulatory subunits, RIα and RIIα. Embryonic lethality of RIα knockout mice limits the current understanding of type I PKA function in the myocardium. The objective of this study was to test the role of RIα in adult heart contractility and pathological remodeling.
    METHODS: We measured PKA subunit expression in human heart and developed a conditional mouse model with cardiomyocyte-specific knockout of RIα (RIα-icKO). Myocardial structure and function were evaluated by echocardiography, histology, and ECG and in Langendorff-perfused hearts. PKA activity and cAMP levels were determined by immunoassay, and phosphorylation of PKA targets was assessed by Western blot. L-type Ca2+ current (ICa,L), sarcomere shortening, Ca2+ transients, Ca2+ sparks and waves, and subcellular cAMP were recorded in isolated ventricular myocytes (VMs).
    RESULTS: RIα protein was decreased by 50% in failing human heart with ischemic cardiomyopathy and by 75% in the ventricles and in VMs from RIα-icKO mice but not in atria or sinoatrial node. Basal PKA activity was increased ≈3-fold in RIα-icKO VMs. In young RIα-icKO mice, left ventricular ejection fraction was increased and the negative inotropic effect of propranolol was prevented, whereas heart rate and the negative chronotropic effect of propranolol were not modified. Phosphorylation of phospholamban, ryanodine receptor, troponin I, and cardiac myosin-binding protein C at PKA sites was increased in propranolol-treated RIα-icKO mice. Hearts from RIα-icKO mice were hypercontractile, associated with increased ICa,L, and [Ca2+]i transients and sarcomere shortening in VMs. These effects were suppressed by the PKA inhibitor, H89. Global cAMP content was decreased in RIα-icKO hearts, whereas local cAMP at the phospholamban/sarcoplasmic reticulum Ca2+ ATPase complex was unchanged in RIα-icKO VMs. RIα-icKO VMs had an increased frequency of Ca2+ sparks and proarrhythmic Ca2+ waves, and RIα-icKO mice had an increased susceptibility to ventricular tachycardia. On aging, RIα-icKO mice showed progressive contractile dysfunction, cardiac hypertrophy, and fibrosis, culminating in congestive heart failure with reduced ejection fraction that caused 50% mortality at 1 year.
    CONCLUSIONS: These results identify RIα as a key negative regulator of cardiac contractile function, arrhythmia, and pathological remodeling.
    Keywords:  arrhythmias, cardiac; calcium; cyclic AMP-dependent protein kinases; excitation contraction coupling; heart; protein kinases
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.068858
  45. Am J Physiol Heart Circ Physiol. 2024 Oct 04.
    Usp20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality.
    Pierre-Yves Jean-Charles, Bipradas Roy, Samuel Mon-Wei Yu, Gianluigi Pironti, Karim Nagi, Lan Mao, Suneet Kaur, Dennis M Abraham, Stuart Maudsley, Howard A Rockman, Sudha K Shenoy.
      Left ventricular hypertrophy (LVH) caused by chronic pressure overload with subsequent pathological remodeling is a major cardiovascular risk factor for heart failure and mortality. The role of deubiquitinases in LVH has not been well-characterized. To define if the deubiquitinase ubiquitin-specific peptidase 20 (USP20) regulates LVH, we subjected USP20 knockout (KO) and cognate wild type (WT) mice to chronic pressure overload by transverse aortic constriction (TAC) and measured changes in cardiac function by serial echocardiography followed by histological and biochemical evaluations. USP20-KO mice showed severe deterioration of systolic function within 4-weeks of TAC compared to WT cohorts. Both USP20-TAC and WT-TAC cohorts presented cardiac hypertrophy following pressure overload. However, USP20-KO-TAC mice showed an increase in cardiomyocyte length and developed maladaptive eccentric hypertrophy, a phenotype generally observed with volume-overload states and decompensated heart failure. In contrast, WT-TAC mice displayed increase in cardiomyocyte width, producing concentric remodeling that is characteristic of pressure overload. In addition, cardiomyocyte apoptosis, interstitial fibrosis and mouse mortality were augmented in USP20-KO-TAC compared to WT-TAC mice. Quantitative mass spectrometry of LV tissue revealed that the expression of sarcomeric myosin heavy chain 7 (MYH7), a fetal gene normally upregulated during cardiac remodeling was significantly reduced in USP20-KO after TAC. Mechanistically, we identified increased degradative lysine-48 polyubiquitination of MYH7 in USP20-KO hearts indicating that USP20-mediated deubiquitination likely prevents protein degradation of MYH7 during pressure overload. Our findings suggest that USP20-dependent signaling pathways regulate the layering pattern of sarcomeres to suppress maladaptive remodeling during chronic pressure overload and prevent cardiac failure.
    Keywords:  apoptosis; cardiac hypertrophy; deubiquitinase; eccentric hypertrophy; heart failure
    DOI:  https://doi.org/10.1152/ajpheart.00329.2024
  46. Int J Mol Sci. 2024 Sep 22. pii: 10179. [Epub ahead of print]25(18):
    Aerobic Exercise Training Protects Against Insulin Resistance, Despite Low-Sodium Diet-Induced Increased Inflammation and Visceral Adiposity.
    Vanessa Del Bianco, Guilherme da Silva Ferreira, Ana Paula Garcia Bochi, Paula Ramos Pinto, Letícia Gomes Rodrigues, Luzia Naoko Shinohara Furukawa, Maristela Mitiko Okamoto, Jaíne Alves Almeida, Lizandre Keren Ramos da Silveira, Aritania Sousa Santos, Kely Cristina Soares Bispo, Vera Luiza Capelozzi, Maria Lucia Correa-Giannella, Alexandre Alves da Silva, Ana Paula Pereira Velosa, Edna Regina Nakandakare, Ubiratan Fabres Machado, Walcy Paganelli Rosolia Teodoro, Marisa Passarelli, Sergio Catanozi.
      Dietary sodium restriction increases plasma triglycerides (TG) and total cholesterol (TC) concentrations as well as causing insulin resistance and stimulation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. Stimulation of the angiotensin II type-1 receptor (AT1) is associated with insulin resistance, inflammation, and the inhibition of adipogenesis. The current study investigated whether aerobic exercise training (AET) mitigates or inhibits the adverse effects of dietary sodium restriction on adiposity, inflammation, and insulin sensitivity in periepididymal adipose tissue. LDL receptor knockout mice were fed either a normal-sodium (NS; 1.27% NaCl) or a low-sodium (LS; 0.15% NaCl) diet and were either subjected to AET for 90 days or kept sedentary. Body mass, blood pressure (BP), hematocrit, plasma TC, TG, glucose and 24-hour urinary sodium (UNa) concentrations, insulin sensitivity, lipoprotein profile, histopathological analyses, and gene and protein expression were determined. The results were evaluated using two-way ANOVA. Differences were not observed in BP, hematocrit, diet consumption, and TC. The LS diet was found to enhance body mass, insulin resistance, plasma glucose, TG, LDL-C, and VLDL-TG and reduce UNa, HDL-C, and HDL-TG, showing a pro-atherogenic lipid profile. In periepididymal adipose tissue, the LS diet increased tissue mass, TG, TC, AT1 receptor, pro-inflammatory macro-phages contents, and the area of adipocytes; contrarily, the LS diet decreased anti-inflammatory macrophages, protein contents and the transcription of genes related to insulin sensitivity. The AET prevented insulin resistance, but did not protect against dyslipidemia, adipose tissue pro-inflammatory profile, increased tissue mass, AT1 receptor expression, TG, and TC induced by the LS diet.
    Keywords:  adipose tissue; aerobic exercise training; dietary sodium restriction; dyslipidemia; insulin resistance
    DOI:  https://doi.org/10.3390/ijms251810179
  47. Biomolecules. 2024 Sep 14. pii: 1158. [Epub ahead of print]14(9):
    Insights into Transient Dimerisation of Carnitine/Acylcarnitine Carrier (SLC25A20) from Sarkosyl/PAGE, Cross-Linking Reagents, and Comparative Modelling Analysis.
    Nicola Giangregorio, Annamaria Tonazzi, Ciro Leonardo Pierri, Cesare Indiveri.
      The carnitine/acylcarnitine carrier (CAC) is a crucial protein for cellular energy metabolism, facilitating the exchange of acylcarnitines and free carnitine across the mitochondrial membrane, thereby enabling fatty acid β-oxidation and oxidative phosphorylation (OXPHOS). Although CAC has not been crystallised, structural insights are derived from the mitochondrial ADP/ATP carrier (AAC) structures in both cytosolic and matrix conformations. These structures underpin a single binding centre-gated pore mechanism, a common feature among mitochondrial carrier (MC) family members. The functional implications of this mechanism are well-supported, yet the structural organization of the CAC, particularly the formation of dimeric or oligomeric assemblies, remains contentious. Recent investigations employing biochemical techniques on purified and reconstituted CAC, alongside molecular modelling based on crystallographic AAC dimeric structures, suggest that CAC can indeed form dimers. Importantly, this dimerization does not alter the transport mechanism, a phenomenon observed in various other membrane transporters across different protein families. This observation aligns with the ping-pong kinetic model, where the dimeric form potentially facilitates efficient substrate translocation without necessitating mechanistic alterations. The presented findings thus contribute to a deeper understanding of CAC's functional dynamics and its structural parallels with other MC family members.
    Keywords:  SLC25A20; Sarkosyl-PAGE; cardiolipin; carnitine/acylcarnitine carrier (CAC); heterobifunctional reagents; homodimer; mitochondrial carriers; oligomeric structure; ping–pong kinetic mechanism; purification–reconstitution–transport; site-directed mutagenesis
    DOI:  https://doi.org/10.3390/biom14091158
  48. ESC Heart Fail. 2024 Sep 30.
    Association between appendicular skeletal muscle mass and myocardial glucose uptake measured by 18F-FDG PET.
    Young-Eun Kim, Dongwoo Kim, Jiwon Kim, Mijin Yun, Eun Seok Kang.
       BACKGROUND: Low muscle mass is associated with high insulin resistance and an increased risk of cardiovascular disease. This study aims to determine whether low muscle mass affects the alterations in myocardial substrate metabolism that are associated with the development of cardiovascular disease.
    METHOD: The study included 299 individuals (182 men and 117 women) who underwent examination at the Severance Health Check-up Center between January 2018 and February 2019. Myocardial glucose uptake was assessed using [18F]-fluorodeoxyglucose-positron emission tomography (18F-FDG PET/CT) scanning. Direct segmental bioimpedance analysis was used to measure appendicular skeletal muscle mass (ASM).
    RESULTS: We analysed men and women separately owing to sex-related body composition differences. ASM/Ht2 was significantly positively correlated with myocardial glucose uptake measured by 18F-FDG PET/CT [ln (SUVheart/liver)] only in men (r = 0.154, P = 0.038 in men; r = -0.042, P = 0.652 in women, respectively). In men, myocardial glucose uptake was significantly associated with ASM/Ht2 even after adjusting for multiple confounders in a multivariable linear regression model (standardized β = 0.397, P = 0.004, in men; β = - 0.051, P = 0.698, in women). In women, age (β = -0.424 P = 0.029) was independent determinants of myocardial glucose uptake.
    CONCLUSIONS: In men, ASM was strongly associated with myocardial glucose uptake as measured by 18F-FDG PET/CT. In women, age was significantly correlated with myocardial substrate utilization, but not with ASM.
    Keywords:  PET; glucose metabolism; physiology; sarcopenia
    DOI:  https://doi.org/10.1002/ehf2.15086
  49. Nutrients. 2024 Sep 20. pii: 3183. [Epub ahead of print]16(18):
    Capsinoids Increase Antioxidative Enzyme Activity and Prevent Obesity-Induced Cardiac Injury without Positively Modulating Body Fat Accumulation and Cardiac Oxidative Biomarkers.
    Késsia Cristina Carvalho Santos, Lucas Furtado Domingos, Fabiane Merigueti Nunes, Luisa Martins Simmer, Evellyn Rodrigues Cordeiro, Filipe Martinuzo Filetti, Danilo Sales Bocalini, Camila Renata Corrêa, Ana Paula Lima-Leopoldo, André Soares Leopoldo.
       BACKGROUND/OBJECTIVES: Capsinoids are potential antioxidant agents capable of reducing oxidative damage and the resulting complications triggered by obesity. Thus, this study aimed to investigate the effects of capsinoids on adiposity and biomarkers of cardiac oxidative stress in obese rats induced by a high-fat diet.
    METHODS: Male Wistar rats were exposed to a high-fat diet for 27 consecutive weeks. After the characterization of obesity (week 19), some of the obese animals began to receive capsinoids (10 mg/kg/day) by orogastric gavage. Adiposity and comorbidities were assessed. In the heart, remodeling, injury, and biomarkers of oxidative stress were determined.
    RESULTS: The treatment did not reduce obesity-induced adiposity but was efficient in reducing cholesterol levels. Capsinoid treatment did not cause a difference in heart and LV mass, despite having reduced troponin I concentrations. Furthermore, capsinoids did not reduce the increase in the advanced oxidation of protein products and carbonylated proteins caused by obesity in cardiac tissue. In addition, obese rats treated with capsinoids presented high levels of malondialdehyde and greater antioxidant enzyme activity compared to untreated obese rats.
    CONCLUSIONS: In conclusion, treatment with capsinoids increases antioxidative enzyme activity and prevents obesity-induced cardiac injury without positively modulating body fat accumulation and cardiac oxidative biomarkers.
    Keywords:  antioxidant capacity; capsinoids; cardiac remodeling; obesity; oxidative stress
    DOI:  https://doi.org/10.3390/nu16183183
  50. Biomolecules. 2024 Sep 01. pii: 1096. [Epub ahead of print]14(9):
    Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs).
    Kumudesh Mishra, Or Kakhlon.
      Glycogen storage disorders (GSDs) are a group of inherited metabolic disorders characterized by defects in enzymes involved in glycogen metabolism. Deficiencies in enzymes responsible for glycogen breakdown and synthesis can impair mitochondrial function. For instance, in GSD type II (Pompe disease), acid alpha-glucosidase deficiency leads to lysosomal glycogen accumulation, which secondarily impacts mitochondrial function through dysfunctional mitophagy, which disrupts mitochondrial quality control, generating oxidative stress. In GSD type III (Cori disease), the lack of the debranching enzyme causes glycogen accumulation and affects mitochondrial dynamics and biogenesis by disrupting the integrity of muscle fibers. Malfunctional glycogen metabolism can disrupt various cascades, thus causing mitochondrial and cell metabolic dysfunction through various mechanisms. These dysfunctions include altered mitochondrial morphology, impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and defective mitophagy. The oxidative burden typical of GSDs compromises mitochondrial integrity and exacerbates the metabolic derangements observed in GSDs. The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications. GSD patients often present with multisystem manifestations, including hepatomegaly, hypoglycemia, and muscle weakness, which can be exacerbated by mitochondrial impairment. Moreover, mitochondrial dysfunction may contribute to the progression of GSD-related complications, such as cardiomyopathy and neurocognitive deficits. Targeting mitochondrial dysfunction thus represents a promising therapeutic avenue in GSDs. Potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies. Mitochondrial dysfunction plays a critical role in the pathophysiology of GSDs. Recognizing and addressing this aspect can lead to more comprehensive and effective treatments, improving the quality of life of GSD patients. This review aims to elaborate on the intricate relationship between mitochondrial dysfunction and various types of GSDs. The review presents challenges and treatment options for several GSDs.
    Keywords:  autophagy and mitophagy; glycogen storage disorders; mitochondrial dysfunction; myopathy; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.3390/biom14091096
  51. Biomedicines. 2024 Sep 02. pii: 1980. [Epub ahead of print]12(9):
    Effects of Polyunsaturated Fatty Acid/Saturated Fatty Acid Ratio and Different Amounts of Monounsaturated Fatty Acids on Adipogenesis in 3T3-L1 Cells.
    Sim Yee Lim, Yi-Wen Chien.
      (1) Background: Adipose tissue serves as a central repository for energy storage and is an endocrine organ capable of secreting various adipokines, including leptin and adiponectin. These adipokines exert profound influences on diverse physiological processes such as insulin sensitivity, appetite regulation, lipid metabolism, energy homeostasis, and body weight. Given the integral role of adipose tissue in metabolic regulation, it is imperative to investigate the effects of varying proportions and types of dietary fats on adipocyte function. In addition, our previous study showed that P/S = 5 and MUFA = 60% appeared to be beneficial in preventing white adipose tissue accumulation by decreasing plasma insulin levels and increasing hepatic lipolytic enzyme activities involved in β-oxidation. Therefore, the objective of this study was to explore the effects of a polyunsaturated fatty acid (PUFA) to saturated fatty acid (SFA) ratio of 5 and varying levels of monounsaturated fatty acids (MUFA = 30% or 60%) on lipogenesis. (2) Methods: We cultured 3T3-L1 mouse embryo fibroblasts in Dulbecco's modified Eagle's medium (DMEM) containing 10% bovine calf serum until confluent. Varying ratios of palmitic acid (PA), oleic acid (OA), and linoleic acid (LA) were first bound with bovine serum albumin (BSA) before being applied to 3T3-L1 adipocytes in low doses and in high doses. (3) Results: Low doses of P/S ratio = 5, MUFA = 60% (M60) fatty acids decreased the accumulation of triglycerides in mature adipocytes by decreasing the mRNA expression of adipogenic factors, such as peroxisome proliferator-activated receptors (PPARs), lipoprotein lipase (LPL), and glucose transporter-4 (GLUT-4), while increasing lipolytic enzyme (hormone-sensitive lipase, HSL) expression when compared to high doses of P/S ratio = 5, MUFA = 60% (M60), low and high doses of P/S ratio = 5, MUFA = 30% (M30). Furthermore, the treatment of M60 in low doses also decreased the secretion of leptin and increased the secretion of adiponectin in adipocytes. (4) Conclusions: The composition of P/S = 5, MUFA = 60% fatty acid in low doses appeared to result in anti-adipogenic effects on 3T3-L1 adipocytes due to the down-regulation of adipogenic effects and the transcription factor.
    Keywords:  adipocytes; adipogenesis; monounsaturated fatty acids; polyunsaturated to saturated fatty acid ratio
    DOI:  https://doi.org/10.3390/biomedicines12091980
  52. Eur J Prev Cardiol. 2024 Sep 28. pii: zwae314. [Epub ahead of print]
    Fontan hemodynamics in adults with obesity compared to overweight and normal body mass index: a retrospective invasive exercise study.
    Derek N Opp, C Charles Jain, Alexander C Egbe, Barry A Borlaug, Yogesh V Reddy, Heidi M Connolly, Kyla M Lara-Breitinger, Rachael Cordina, William R Miranda.
       AIMS: The effects of obesity on Fontan hemodynamics are poorly understood. Accordingly, we assessed its impact on exercise invasive hemodynamics and exercise capacity.
    METHODS: Seventy-seven adults post-Fontan undergoing exercise cardiac catheterization (supine cycle protocol) were retrospectively identified using an institutional database and categorized according to the presence of obesity (body mass index [BMI] >30 kg/m2) and overweight/normal BMI (BMI≤30 kg/m2).
    RESULTS: There were 18 individuals with obesity (BMI 36.4±3 kg/m2) and 59 (BMI 24.1±3.6 kg/m2) with overweight/normal BMI. Peak oxygen consumption (VO2) on noninvasive cardiopulmonary exercise testing was lower in patients with obesity (15.6±3.5 vs 19.6±5.8 ml/kg/min, p=0.04). At rest, systemic flow (Qs) (7.0 [4.8; 8.3] vs 4.8 [3.9; 5.8] l/min, p=0.001), pulmonary artery (PA) pressure (16.3±3.5 vs 13.1±3.5 mmHg, p=0.002), and PA wedge pressure (PAWP) (11.7±4.4 vs 8.9±3.1 mmHg, p=0.01) were higher, while arterial O2 saturation was lower (89.5% [86.5; 92.3] vs 93% [90; 95]) in obesity compared to overweight/normal BMI. Similarly, patients with obesity had higher exercise PA pressure (29.7±6.5 vs 24.7±6.8 mmHg, p=0.01) and PAWP (23.0±6.5 vs 19.8±7.3 mmHg, p=0.047), but lower arterial O2 saturation (82.4±7.0% vs 89% [85; 92], p=0.003).
    CONCLUSION: Adults post-Fontan with obesity have worse aerobic capacity, increased Qs, higher filling pressures, and decreased arterial O2 saturation compared to those with overweight/normal BMI, both at rest and during exercise, mirroring the findings observed in the obesity phenotype of heart failure with preserved ejection fraction. Whether treating obesity and its cardiometabolic sequelae in Fontan patients will improve hemodynamics and outcomes requires further study.
    Keywords:  Fontan; exercise; hemodynamics; obesity
    DOI:  https://doi.org/10.1093/eurjpc/zwae314
  53. ESC Heart Fail. 2024 Oct 01.
    Diagnostic and therapeutic practice for HFpEF across continents and regions: An international survey.
    Inga J Ingimarsdóttir, Julie K K Vishram-Nielsen, Hafsteinn Einarsson, Sidney Goldfeder, Nathan Mewton, Anders Barasa, Carmen Basic, Marish I F J Oerlemans, David Niederseer, Anastasia Shchendrygina, Finn Gustafsson, Frank Ruschitzka, Keisuke Kida, Dania Mohty, Rolland R Rakotonoel, Han Naung Tun, Thórdís J Hrafnkelsdóttir, Clara Saldarriaga.
       AIMS: This study aims to evaluate the worldwide variations in the diagnosis and treatment of heart failure with preserved ejection fraction (HFpEF), using an HF survey distributed internationally to physicians, including both cardiologists and non-cardiologists.
    METHODS AND RESULTS: A group of HF specialists designed an independent, academic web-based survey focusing on HFpEF care and diagnosis, which was distributed via scientific societies and various social networks between 1 May 2023 and 1 July 2023. The survey included 1459 physicians (1242 cardiologists and 217 non-cardiologists) from 91 countries, with a mean age of 42 (34-49) years and 61% male. Most physicians (89.2%) defined HFpEF as left ventricular ejection fraction ≥50%. Significant regional variations were observed in HFpEF management (P < 0.001 for all comparisons unless stated otherwise). Cardiologists managed 63.1% of HFpEF patients overall, with significant variability across regions (P < 0.001). The estimated HFpEF prevalence was highest in Eastern Asia and Western Europe and lowest in Africa and South America. Diagnostic practices varied: natriuretic peptide use ranged from 70%-74% in Africa to 95%-97% in Southern/Western Europe. Echocardiographic parameters showed regional differences, with diastolic stress testing used most in South-Eastern Asia (47% vs. 13-36% elsewhere). HFpEF scoring systems were most common in South-Eastern Asia (78%) and least in Africa (30.1%). Coronary artery disease screening approaches differed, with Eastern Asian physicians more likely to always perform routine angiograms (52%) compared with Northern Europeans (12%). Treatment preferences also varied regionally. Sodium glucose co-transporter-2 inhibitors (SGLT2i) was the preferred first-line treatment (45%-70% across regions), followed by diuretics. In an ideal setting, 52% would primarily use SGLT2i, 33% loop diuretics, and 22% beta-blockers. Drug availability differed significantly: SGLT2i was most available (88% overall), while ARNI was least available (61%). South America and Middle Eastern/Northern Africa reported lower availability of guideline-directed therapies. Multidisciplinary HF programmes were most common in Asia (70%) and least in Africa (24%). The perceived benefit of atrial flow regulator devices also showed significant regional differences.
    CONCLUSIONS: There are considerable global variations in the diagnosis and management of HFpEF. Most physicians favour SGLT2i despite regional disparities in health care resources and guideline adherence. Harmonized practices and improved access to comprehensive care can enhance outcomes of HFpEF patients worldwide.
    Keywords:  Global differences; Heart failure with preserved ejection fraction; Management; Risk factors; Survey
    DOI:  https://doi.org/10.1002/ehf2.15084
  54. J Biol Chem. 2024 Sep 27. pii: S0021-9258(24)02322-6. [Epub ahead of print] 107820
    Nonfunctional coq10 mutants maintain the ERMES complex and reveal true phenotypes associated with the loss of the coenzyme Q chaperone protein Coq10.
    Noelle Alexa Novales, Kelsey J Feustel, Kevin L He, Guillaume F Chanfreau, Catherine F Clarke.
      Coenzyme Q (CoQ) is a redox-active lipid molecule that acts as an electron carrier in the mitochondrial electron transport chain. In Saccharomyces cerevisiae, CoQ is synthesized in the mitochondrial matrix by a multi-subunit protein-lipid complex termed the CoQ synthome, the spatial positioning of which is coordinated by the Endoplasmic Reticulum-Mitochondria Encounter Structure (ERMES). The MDM12 gene encoding the cytosolic subunit of ERMES, is co-expressed with COQ10, which encodes the putative CoQ chaperone Coq10, via a shared bidirectional promoter. Deletion of COQ10 results in respiratory deficiency, impaired CoQ biosynthesis, and reduced spatial coordination between ERMES and the CoQ Synthome. While Coq10 protein content is maintained upon deletion of MDM12, we show that deletion of COQ10 by replacement with a HIS3 marker results in diminished Mdm12 protein content. Since deletion of individual ERMES subunits prevents ERMES formation, we asked whether some or all of the phenotypes associated with COQ10 deletion result from ERMES dysfunction. To identify the phenotypes resulting solely due to the loss of Coq10, we constructed strains expressing a functionally impaired (coq10-L96S) or truncated (coq10-R147*) Coq10 isoform using CRISPR-Cas9. We show that both coq10 mutants preserve Mdm12 protein content and exhibit impaired respiratory capacity like the coq10Δ mutant, indicating that Coq10's function is vital for respiration regardless of ERMES integrity. Moreover, the maintenance of CoQ synthome stability and efficient CoQ biosynthesis observed for the coq10-R147* mutant suggests these deleterious phenotypes in the coq10Δ mutant result from ERMES disruption. Overall, this study clarifies the role of Coq10 in modulating CoQ biosynthesis.
    Keywords:  CoQ synthome; Coq10; Endoplasmic Reticulum-Mitochondria Encounter Structure; Mdm12; START domain; Saccharomyces cerevisiae; coenzyme Q; lipid; mitochondrial metabolism; ubiquinone
    DOI:  https://doi.org/10.1016/j.jbc.2024.107820
  55. Commun Biol. 2024 Oct 03. 7(1): 1250
    Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy.
    Lili Salinas, Claire B Montgomery, Francisco Figueroa, Phung N Thai, Nipavan Chiamvimonvat, Gino Cortopassi, Elena N Dedkova.
      Friedreich's ataxia (FA) is an autosomal recessive disorder caused by reduced frataxin (FXN) expression in mitochondria, where the lethal component is cardiomyopathy. Using the conditional Fxnflox/null::MCK-Cre knock-out (Fxn-cKO) mouse model, we discovered significant sex differences in the progression towards heart failure, with Fxn-cKO males exhibiting a worse cardiac phenotype, low survival rate, kidney and reproductive organ deficiencies. These differences are likely due to a decline in testosterone in Fxn-cKO males. The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.
    DOI:  https://doi.org/10.1038/s42003-024-06962-4
  56. Antioxidants (Basel). 2024 Aug 26. pii: 1036. [Epub ahead of print]13(9):
    Downregulation of Iron-Sulfur Cluster Biogenesis May Contribute to Hyperglycemia-Mediated Diabetic Peripheral Neuropathy in Murine Models.
    Lin Wu, Fei Huang, Zichen Sun, Jinghua Zhang, Siyu Xia, Hongting Zhao, Yutong Liu, Lu Yang, Yibing Ding, Dezhi Bian, Kuanyu Li, Yu Sun.
       BACKGROUND: Diabetic peripheral neuropathy (DPN) is considered one of the most common chronic complications of diabetes. Impairment of mitochondrial function is regarded as one of the causes. Iron-sulfur clusters are essential cofactors for numerous iron-sulfur (Fe-S)-containing proteins/enzymes, including mitochondrial electron transport chain complex I, II, and III and aconitase.
    METHODS: To determine the impact of hyperglycemia on peripheral nerves, we used Schwann-like RSC96 cells and classical db/db mice to detect the expression of Fe-S-related proteins, mitochondrially enzymatic activities, and iron metabolism. Subsequently, we treated high-glucose-induced RSC96 cells and db/db mice with pioglitazone (PGZ), respectively, to evaluate the effects on Fe-S cluster biogenesis, mitochondrial function, and animal behavior.
    RESULTS: We found that the core components of Fe-S biogenesis machinery, such as frataxin (Fxn) and scaffold protein IscU, significantly decreased in high-glucose-induced RSC96 cells and db/db mice, accompanied by compromised mitochondrial Fe-S-containing enzymatic activities, such as complex I and II and aconitase. Consequently, oxidative stress and inflammation increased. PGZ not only has antidiabetic effects but also increases the expression of Fxn and IscU to enhance mitochondrial function in RSC96 cells and db/db mice. Meanwhile, PGZ significantly alleviated sciatic nerve injury and improved peripheral neuronal behavior, accompanied by suppressed oxidative stress and inflammation in the sciatic nerve of the db/db mice.
    CONCLUSIONS: Iron-sulfur cluster deficiency may contribute to hyperglycemia-mediated DPN.
    Keywords:  DPN; IscU; frataxin; inflammation; iron–sulfur cluster biogenesis
    DOI:  https://doi.org/10.3390/antiox13091036
  57. bioRxiv. 2024 Sep 22. pii: 2024.09.20.614152. [Epub ahead of print]
    Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific and individualized regulatory mechanisms.
    Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.
      Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have high and others low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic activities in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mtDNA density were correlated between tissues (median r = -0.01-0.16), indicating that animals with high mitochondrial capacity in one tissue can have low capacity in other tissues. Similarly, the multi-tissue correlation structure of RNAseq-based indices of mitochondrial gene expression across 45 tissues from 948 women and men (GTEx) showed small to moderate coherence between only some tissues (regions of the same brain), but not between brain-body tissue pairs in the same person (median r = 0.01). Mitochondrial DNA copy number (mtDNAcn) also lacked coherence across organs and tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were attributable in part to i) tissue-specific activation of canonical energy sensing pathways including the transcriptional coactivator PGC-111 and the integrated stress response (ISR), and ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with high mitochondrial gene expression in some tissues (e.g., heart) but low expression in others (e.g., skeletal muscle) who display different clinical phenotypic patterns. Taken together, these data raise the possibility that tissue-specific energy sensing pathways may contribute to the idiosyncratic mitochondrial distribution patterns associated with the inter-organ heterogeneity and phenotypic diversity among individuals.
    DOI:  https://doi.org/10.1101/2024.09.20.614152
  58. Int J Mol Sci. 2024 Sep 20. pii: 10116. [Epub ahead of print]25(18):
    Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.
    Chong Zhao, Yonghao Wu, Shuaiqi Zhu, Haiying Liu, Shuai Xu.
      Irisin, a myokine derived from fibronectin type III domain-containing 5 (FNDC5), is increasingly recognized for its protective role in musculoskeletal health through the modulation of mitochondrial quality control. This review synthesizes the current understanding of irisin's impact on mitochondrial biogenesis, dynamics, and autophagy in skeletal muscle, elucidating its capacity to bolster muscle strength, endurance, and resilience against oxidative-stress-induced muscle atrophy. The multifunctional nature of irisin extends to bone metabolism, where it promotes osteoblast proliferation and differentiation, offering a potential intervention for osteoporosis and other musculoskeletal disorders. Mitochondrial quality control is vital for cellular metabolism, particularly in energy-demanding tissues. Irisin's influence on this process is highlighted, suggesting its integral role in maintaining cellular homeostasis. The review also touches upon the regulatory mechanisms of irisin secretion, predominantly induced by exercise, and its systemic effects as an endocrine factor. While the therapeutic potential of irisin is promising, the need for standardized measurement techniques and further elucidation of its mechanisms in humans is acknowledged. The collective findings underscore the burgeoning interest in irisin as a keystone in musculoskeletal health and a candidate for future therapeutic strategies.
    Keywords:  irisin; mitochondrial quality control; musculoskeletal health; myokine; osteoporosis; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms251810116
  59. Int J Mol Sci. 2024 Sep 11. pii: 9802. [Epub ahead of print]25(18):
    Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.
    Maria Mirabelli, Roberta Misiti, Luciana Sicilia, Francesco S Brunetti, Eusebio Chiefari, Antonio Brunetti, Daniela P Foti.
      Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.
    Keywords:  adipokine; adipose tissue; hypoxia; inflammation; insulin resistance; micro-RNA
    DOI:  https://doi.org/10.3390/ijms25189802
  60. Biomolecules. 2024 Sep 15. pii: 1160. [Epub ahead of print]14(9):
    Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner.
    Alexandra V Schmidt, Sivakama S Bharathi, Keaton J Solo, Joanna Bons, Jacob P Rose, Birgit Schilling, Eric S Goetzman.
      Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that Sirt2-/- males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed glucose handling during exercise compared to wild type controls. Conversion of injected lactate, pyruvate, and glycerol boluses into glucose via gluconeogenesis was impaired, but only in males. Primary Sirt2-/- male hepatocytes exhibited reduced glycolysis and reduced mitochondrial respiration. RNAseq and proteomics were used to interrogate the mechanisms behind this liver phenotype. Loss of Sirt2 did not lead to transcriptional dysregulation, as very few genes were altered in the transcriptome. In keeping with this, there were also negligible changes to protein abundance. Site-specific quantification of the hepatic acetylome, however, showed that 13% of all detected acetylated peptides were significantly increased in Sirt2-/- male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in Sirt2-/- female liver. The target sites in the male liver were distributed across mitochondria (44%), cytoplasm (32%), nucleus (8%), and other compartments (16%). Despite the high number of putative mitochondrial Sirt2 targets, Sirt2 antigen was not detected in purified wild type liver mitochondria, suggesting that Sirt2's regulation of mitochondrial function occurs from outside the organelle. We conclude that Sirt2 regulates hepatic protein acetylation and metabolism in a sex-specific manner.
    Keywords:  gluconeogenesis; glucose; liver; metabolism; sirt-2; sirtuin
    DOI:  https://doi.org/10.3390/biom14091160
  61. Pharmaceuticals (Basel). 2024 Sep 12. pii: 1202. [Epub ahead of print]17(9):
    Bixin Combined with Metformin Ameliorates Insulin Resistance and Antioxidant Defenses in Obese Mice.
    Camila Graça Pinheiro, Bruno Pereira Motta, Juliana Oriel Oliveira, Felipe Nunes Cardoso, Ingrid Delbone Figueiredo, Rachel Temperani Amaral Machado, Patrícia Bento da Silva, Marlus Chorilli, Iguatemy Lourenço Brunetti, Amanda Martins Baviera.
      Bixin (C25H30O4; 394.51 g/mol) is the main apocarotenoid found in annatto seeds. It has a 25-carbon open chain structure with a methyl ester group and carboxylic acid. Bixin increases the expression of antioxidant enzymes, which may be interesting for counteracting oxidative stress. This study investigated whether bixin-rich annatto extract combined with metformin was able to improve the disturbances observed in high-fat diet (HFD)-induced obesity in mice, with an emphasis on markers of oxidative damage and antioxidant defenses. HFD-fed mice were treated for 8 weeks with metformin (50 mg/kg) plus bixin-rich annatto extract (5.5 and 11 mg/kg). This study assessed glucose tolerance, insulin sensitivity, lipid profile and paraoxonase 1 (PON-1) activity in plasma, fluorescent AGEs (advanced glycation end products), TBARSs (thiobarbituric acid-reactive substances), and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver and kidneys. Treatment with bixin plus metformin decreased body weight gain, improved insulin sensitivity, and decreased AGEs and TBARSs in the plasma, liver, and kidneys. Bixin plus metformin increased the activities of PON-1, SOD, CAT, and GSH-Px. Bixin combined with metformin improved the endogenous antioxidant defenses in the obese mice, showing that this combined therapy may have the potential to contrast the metabolic complications resulting from oxidative stress.
    Keywords:  advanced glycation end products; antioxidant enzymes; carotenoids; glycoxidative stress; natural bioactives
    DOI:  https://doi.org/10.3390/ph17091202
  62. bioRxiv. 2024 Sep 21. pii: 2024.09.21.613572. [Epub ahead of print]
    Diet induced mitochondrial DNA replication instability in Rad51c mutant mice drives sex-bias in anemia of inflammation.
    Karl-Heinz Tomaszowski, Yue Chen, Sunetra Roy, Momo Harris, Jianhua Zhang, Chi-Lin Tsai, Katharina Schlacher.
      Anemia of inflammation (AI) is a common comorbidity associated with obesity, diabetes, cardiac disease, aging, and during anti-cancer therapies. Mounting evidence illustrates that males are disproportionally affected by AI, but not why. Here we demonstrate a molecular cause for a sex-bias in inflammation. The data shows that mitochondrial DNA (mtDNA) instability induced by dietary stress causes anemia associated with inflamed macrophages and improper iron recycling in mice. These phenotypes are enhanced in mice with mutations in Fanco/Rad51c , which predisposes to the progeroid disease Fanconi Anemia. The data reveals a striking sex-bias whereby females are protected. We find that estrogen acts as a mitochondrial antioxidant that reduces diet-induced oxidative stress, mtDNA replication instability and the distinctively mtDNA-dependent unphosphorylated STAT1 response. Consequently, treatment of male Rad51c mutant mice with estrogen or mitochondrial antioxidants suppresses the inflammation-induced anemia. Collectively, this study uncovers estrogen-responsive mtDNA replication instability as a cause for sex-specific inflammatory responses and molecular driver for AI.
    DOI:  https://doi.org/10.1101/2024.09.21.613572
  63. Front Med (Lausanne). 2024 ;11 1387195
    A multimodal approach identifies lactate as a central feature of right ventricular failure that is detectable in human plasma.
    Anna Hemnes, Niki Fortune, Katie Simon, Irina A Trenary, Sheila Shay, Eric Austin, Jamey D Young, Evan Britain, James West, Megha Talati.
       Background: In PAH metabolic abnormalities in multiple pathways are well-recognized features of right ventricular dysfunction, however, prior work has focused mainly on the use of a single "omic" modality to describe a single deranged pathway. We integrated metabolomic and epigenomic data using transcriptomics in failing and non-failing RVs from a rodent model to provide novel mechanistic insight and translated these findings to accessible human specimens by correlation with plasma from PAH patients.
    Methods: Study was conducted in a doxycycline-inducible BMPR2 mutant mouse model of RV failure. Plasma was collected from controls and PAH patients. Transcriptomic and metabolomic analyses were done on mouse RV tissue and human plasma. For mouse RV, we layered metabolomic and transcriptomic data for multiple metabolic pathways and compared our findings with metabolomic and transcriptomic data obtained for human plasma. We confirmed our key findings in cultured cardiomyocyte cells with BMPR2 mutation.
    Results: In failing mouse RVs, (1) in the glycolysis pathway, glucose is converted to lactate via aerobic glycolysis, but may also be utilized for glycogen, fatty acid, and nucleic acid synthesis, (2) in the fatty acid pathway, FAs are accumulated in the cytoplasm because the transfer of FAs to mitochondria is reduced, however, the ß-oxidation pathway is likely to be functional. (3) the TCA cycle is altered at multiple checkpoints and accumulates citrate, and the glutaminolysis pathway is not activated. In PAH patients, plasma metabolic and transcriptomic data indicated that unlike in the failing BMPR2 mutant RV, expression of genes and metabolites measured for the glycolysis pathway, FA pathway, TCA cycle, and glutaminolysis pathway were increased. Lactate was the only metabolite that was increased both in RV and circulation. We confirmed using a stable isotope of lactate that cultured cardiomyocytes with mutant BMPR2 show a modest increase in endogenous lactate, suggesting a possibility of an increase in lactate production by cardiomyocytes in failing BMPR2 mutant RV.
    Conclusion: In the failing RV with mutant BMPR2, lactate is produced by RV cardiomyocytes and may be secreted out, thereby increasing lactate in circulation. Lactate can potentially serve as a marker of RV dysfunction in PAH, which warrants investigation.
    Keywords:  BMPR2 mutation; H9c2 cultured cardiomyocyte; metabolic pathways; multi-omics; pulmonary arterial hypertension; right ventricular dysfunction and lipotoxicity
    DOI:  https://doi.org/10.3389/fmed.2024.1387195
  64. Biomedicines. 2024 Sep 19. pii: 2129. [Epub ahead of print]12(9):
    Adipokines in the Crosstalk between Adipose Tissues and Other Organs: Implications in Cardiometabolic Diseases.
    Shaghayegh Hemat Jouy, Sukrutha Mohan, Giorgia Scichilone, Amro Mostafa, Abeer M Mahmoud.
      Adipose tissue was previously regarded as a dormant organ for lipid storage until the identification of adiponectin and leptin in the early 1990s. This revelation unveiled the dynamic endocrine function of adipose tissue, which has expanded further. Adipose tissue has emerged in recent decades as a multifunctional organ that plays a significant role in energy metabolism and homeostasis. Currently, it is evident that adipose tissue primarily performs its function by secreting a diverse array of signaling molecules known as adipokines. Apart from their pivotal function in energy expenditure and metabolism regulation, these adipokines exert significant influence over a multitude of biological processes, including but not limited to inflammation, thermoregulation, immune response, vascular function, and insulin sensitivity. Adipokines are pivotal in regulating numerous biological processes within adipose tissue and facilitating communication between adipose tissue and various organs, including the brain, gut, pancreas, endothelial cells, liver, muscle, and more. Dysregulated adipokines have been implicated in several metabolic diseases, like obesity and diabetes, as well as cardiovascular diseases. In this article, we attempted to describe the significance of adipokines in developing metabolic and cardiovascular diseases and highlight their role in the crosstalk between adipose tissues and other tissues and organs.
    Keywords:  adipokines; adipose tissue; cardiovascular; crosstalk; diabetes; inflammation; insulin resistance; metabolism; obesity
    DOI:  https://doi.org/10.3390/biomedicines12092129
  65. Int J Mol Med. 2024 Dec;pii: 112. [Epub ahead of print]54(6):
    New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis.
    Lie Xiong, Huilin Hu, Fuxiang Zhu, Hanqiang Shi, Xiaoliang Fan, Sunfeng Pan, Feiye Zhu, Junyong Zhang, Zhongwei Yu, Yanbo Shi.
      SS‑31 is a mitochondria‑targeting antioxidant that exhibits promising therapeutic potential for various diseases; however, its protective effect on diabetic cardiomyopathy (DCM) remains to be elucidated. At present, SS‑31 is considered not only to mitigate cardiolipin oxidative damage, but also to alleviate ferroptosis. The present study aimed to explore SS‑31 as a potential therapeutic strategy for improving DCM by alleviating mitochondria‑dependent ferroptosis. In vitro, H9C2 cells were exposed to 35 mM glucose for 24 h to induce high glucose damage, then were simultaneously treated with 10, 20 or 50 µM SS‑31. In addition, in vivo studies were conducted on diabeticC57BL/6J mice, which were induced to develop DCM over 4 weeks, followed by intraperitoneal injections with 2.5 mg/kg/day SS‑31 for a further 4 weeks. The elevation of serum lactate dehydrogenase and creatine kinase isoenzymes, the reduction of fractional shortening and ejection fraction, the rupture of myocardial fibers and the deposition of collagen indicated the establishment of the DCM mouse model. The results of the present study indicated that SS‑31 effectively alleviated these pathological changes and exhibited significant efficacy in ameliorating mitochondrial dysfunction, such as by promoting adenosine triphosphate generation, improving mitochondrial membrane potential and restoring the mitochondrial ultrastructure. Further experiments suggested that activation of the mitochondrial glutathione (mitoGSH)/mitochondrial glutathione peroxidase 4 (mitoGPX4) pathway and the elimination of mitochondrial ferrous ions may constitute the mechanisms by which SS‑31 treats DCM. Therefore, the present study revealed that mitochondria‑dependent ferroptosis could serve as a pathogenic mechanism of DCM and highlighted that the cardioprotective effects of SS‑31 against DCM involves activation of the mitoGSH/mitoGPX4 pathway. Due to the safety profile and cardiac protective effects of SS‑31, SS‑31 was considered a promising strategy for treating DCM.
    Keywords:  SS‑31; diabetic cardiomyopathy; ferroptosis; glutathione peroxidase 4; lipid peroxidation; mitochondrial glutathione peroxidase 4; mitochondria‑­dependent ferroptosis
    DOI:  https://doi.org/10.3892/ijmm.2024.5436
  66. Redox Biol. 2024 Sep 24. pii: S2213-2317(24)00349-5. [Epub ahead of print]77 103371
    Interplay of ROS, mitochondrial quality, and exercise in aging: Potential role of spatially discrete signaling.
    Siobhan M Craige, Rebecca K Mammel, Niloufar Amiri, Orion S Willoughby, Joshua C Drake.
      
    Keywords:  Energetic stress; Mitochondrial adaptation to exercise; Mitochondrial quality control and aging; Reactive oxygen species (ROS); Spatially discrete signaling; Stress resilience
    DOI:  https://doi.org/10.1016/j.redox.2024.103371
  67. J Physiol. 2024 Oct 02.
    The yellow brick road to understanding the RyR2 signalosome.
    Shanna Hamilton, Dmitry Terentyev.
      
    Keywords:  arrhythmia; calcium signalling; cardiac electrophysiology; phosphorylation; ryanodine receptor
    DOI:  https://doi.org/10.1113/JP287538
  68. Antioxidants (Basel). 2024 Aug 30. pii: 1057. [Epub ahead of print]13(9):
    Sodium Houttuybonate Promotes the Browning of White Adipose Tissue by Inhibiting Ferroptosis via the AMPK-NRF2-HO1 Pathway.
    Wenhui Liu, Huren Zou, Danming You, Huijie Zhang, Lingling Xu.
      The rising prevalence of obesity has resulted in an increased demand for innovative and effective treatment strategies. Houttuynia cordata Thunb. (H. cordata) has demonstrated promising potential in preventing obesity. However, the mechanism underlying the anti-obesity effects of H. cordata and its bioactive component, sodium houttuybonate (SH), remains unclear. Our study reveals that SH treatment promotes the browning of inguinal white adipose tissue (iWAT) and prevents the obesity induced by a high-fat diet. SH significantly mitigates ferroptosis by upregulating glutathione peroxidase 4 (Gpx4) and decreasing malondialdehyde (MDA) levels, while also enhancing superoxide dismutase (SOD) levels. Furthermore, SH promotes the phosphorylation of AMP-activated protein kinase (AMPK), which subsequently increases the expression of nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) in the iWAT. However, the effects of SH were attenuated by ML385, an Nrf2 inhibitor. Collectively, our findings suggest that SH induces iWAT browning and prevents diet-induced obesity primarily through the AMPK/NRF2/HO-1 pathway by inhibiting ferroptosis.
    Keywords:  browning; ferroptosis; houttuynia cordata; iWAT; obesity; sodium houttuyfonate
    DOI:  https://doi.org/10.3390/antiox13091057
  69. Curr Nutr Rep. 2024 Oct 01.
    Ziziphus jujuba (Jujube) in Metabolic Syndrome: From Traditional Medicine to Scientific Validation.
    Mahboobeh Ghasemzadeh Rahbardar, Homa Fazeli Kakhki, Hossein Hosseinzadeh.
       PURPOSE OF REVIEW: This review evaluates the therapeutic potential of Ziziphus jujuba and its main components in managing complications of metabolic syndrome, including diabetes, dyslipidemia, obesity, and hypertension.
    RECENT FINDINGS: The reviewed studies provide evidence supporting the use of Z. jujuba and its main components (lupeol and betulinic acid) as natural treatments for complications of metabolic syndrome. These substances enhance glucose uptake through the activation of signaling pathways such as phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), reduce hepatic glucose synthesis, and increase glucose uptake by adipocytes and skeletal muscle cells. They also improve insulin sensitivity by modulating AMP-activated protein kinase (AMPK) activity and regulating insulin signaling proteins and glucose transporters. In the field of dyslipidemia, they inhibit triglyceride synthesis, lipid accumulation, and adipogenic enzymes, while influencing key signaling pathways involved in adipogenesis. Z. jujuba and its constituents demonstrate anti-adipogenic effects, inhibiting lipid accumulation and modulating adipogenic enzymes and transcription factors. They also exhibit positive effects on endothelial function and vascular health by enhancing endothelial nitric oxide synthase (eNOS) expression, NO production, and antioxidant enzyme activity. Z. jujuba, lupeol, and betulinic acid hold promise as natural treatments for complications of metabolic syndrome. They improve glucose metabolism, insulin sensitivity, and lipid profiles while exerting anti-adipogenic effects and enhancing endothelial function. However, further research is needed to elucidate the mechanisms and confirm their efficacy in clinical trials. These natural compounds offer potential as alternative therapies for metabolic disorders and contribute to the growing body of evidence supporting the use of natural medicines in their management.
    Keywords:  Anti-Inflammatory Agents; Antioxidants; Betulinic Acid; Hypoglycemic Agents; Lupeol; Phytochemicals
    DOI:  https://doi.org/10.1007/s13668-024-00581-5
  70. Pharmaceutics. 2024 Aug 28. pii: 1139. [Epub ahead of print]16(9):
    Contractile Effects of Semaglutide in the Human Atrium.
    Joachim Neumann, Katarína Hadová, Jan Klimas, Britt Hofmann, Ulrich Gergs.
      Semaglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist. GLP-1R agonists are used to treat type 2 diabetes and obesity. It is currently unknown whether semaglutide can directly increase force of contraction (FOC) in the human heart. We tested the hypothesis that semaglutide might increase the FOC in the isolated human atrium. To this end, we conducted contraction experiments in isolated human right atrial muscle preparations (HAP). HAP were obtained during open-heart surgery. We detected a concentration- and time-dependent positive inotropic effect (PIE) of semaglutide in HAP. These PIEs were accompanied by increases in the rates of tension development and tension relaxation and a reduction in muscle relaxation time. The PIE of semaglutide in HAP was attenuated by H89, an inhibitor of the cyclic AMP-dependent protein kinase and by ryanodine, an inhibitor of sarcoplasmic Ca2+ release. Semaglutide up to 100 nM failed to exert a PIE in isolated electrically paced (1 Hz) wild-type mouse left atrial preparations studied for comparison. Our data suggest that semaglutide can increase the FOC in the atria of patients at therapeutic drug concentrations.
    Keywords:  GLP-1 receptor; human atrium; inotropy; semaglutide
    DOI:  https://doi.org/10.3390/pharmaceutics16091139
  71. J Ethnopharmacol. 2024 Sep 26. pii: S0378-8741(24)01158-9. [Epub ahead of print] 118859
    Study on the Role of Dihuang Yinzi in Regulating the AMPK/SIRT1/PGC-1α Pathway to Promote Mitochondrial Biogenesis and Improve Alzheimer's Disease.
    Chao Zhu, Zheng Zhang, Yousong Zhu, Yuzhong Du, Cheng Han, Qiong Zhao, Qinqing Li, Jiangqi Hou, Junlong Zhang, Wenbin He, Yali Qin.
       ETHNOPHARMACOLOGICAL RELEVANCE: Dihuang Yinzi (DHYZ) is a classic prescription in traditional Chinese medicine. Its therapeutic effect on Alzheimer's disease (AD) has been widely validated. However, the underlying molecular mechanisms of DHYZ in AD treatment remain unclear and require further research.
    AIM OF THE STUDY: Elucidating DHYZ's promotion of mitochondrial biogenesis through the AMPK/SIRT1/PGC-1α pathway improves neuronal loss, mitochondrial damage, and memory deficits in AD.
    MATERIALS AND METHODS: Administering DHYZ by gavage to SAMP8 mice, after completing behavioral tests, the effects of DHYZ on hippocampal neuron loss and mitochondrial structural damage in AD model mice were assessed using Nissl staining and transmission electron microscopy. Western blot was used to detect the expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, mitochondrial fusion protein MFN2, and mitochondrial fission proteins DRP1 and FIS1. At the same time, immunofluorescence(IF) was employed to measure the relative fluorescence intensity of mitochondrial fusion protein MFN1. After determining the optimal dose of DYHZ for treating AD, we conducted mechanistic studies. By intraperitoneally injecting SAMP8 mice with the AMPK inhibitor (Compound C) to inhibit AMPK protein expression and subsequently treating them with DHYZ, the impact of DHYZ on hippocampal neurons in AD model mice was evaluated using Nissl and hematoxylin-eosin staining. Western blot was used to detect the protein expression of AMPK, p-AMPK, SIRT1, PGC-1α, NRF1, and TFAM. In contrast, IF was used to measure the relative fluorescence intensity of PGC-1α, NRF1, and TFAM proteins in the hippocampal CA1 region.
    RESULTS: DHYZ significantly improved AD model mice's cognitive impairment and memory deficits and mitigated hippocampal neuron loss and degeneration. Additionally, it ameliorated mitochondrial morphological structures. DHYZ upregulated the protein expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, and mitochondrial fusion proteins MFN1 and MFN2 while inhibiting the expression of mitochondrial fission proteins DRP1 and FIS1. Further studies revealed that DHYZ could upregulate the expression of the AMPK/SIRT1/PGC-1α pathway proteins and their downstream proteins NRF1 and TFAM.
    CONCLUSION: DHYZ promotes mitochondrial biogenesis by activating the AMPK/SIRT1/PGC-1α signaling pathway, thereby improving memory deficits, neuronal loss, and mitochondrial dysfunction in AD.
    Keywords:  Alzheimer's disease; Dihuang Yinzi; Mitochondria; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.jep.2024.118859
  72. Biochem Pharmacol. 2024 Sep 27. pii: S0006-2952(24)00560-4. [Epub ahead of print] 116560
    Curcumol effectively improves obesity through GDF15 induction via activation of endoplasmic reticulum stress response.
    Lin Wang, Jia-Jia Huang, Wei-Jia Zhu, Zhao-Kun Zhai, Chan Lin, Xiao Guan, Hai-Ping Liu, Tong Dou, Yi-Zhun Zhu, Xu Chen.
      The escalating prevalence of obesity presents a formidable global health challenge, underscoring the imperative for efficacious pharmacotherapeutic interventions. However, current anti-obesity medications often exhibit limited efficacy and adverse effects, necessitating the exploration of alternative therapeutic approaches. Growth differentiation factor 15 (GDF15) has emerged as a promising target for obesity management, given its crucial role in appetite control and metabolic regulation. In this study, we aimed to investigate the efficacy of curcumol, a sesquiterpene compound derived from plants of the Zingiberaceae family, in obesity treatment. Our findings demonstrate that curcumol effectively induces the expression of GDF15 through the activation of the endoplasmic reticulum stress pathway. To confirm the role of GDF15 as a critical target for curcumol's function, we compared the effects of curcumol in wild-type mice and Gdf15-knockout mice. Using a high-fat diet-induced obese murine model, we observed that curcumol led to reduced appetite and altered dietary preferences mediated by GDF15. Furthermore, chronic curcumol intervention resulted in promising anti-obesity effects. Additionally, curcumol administration improved glucose tolerance and lipid metabolism in the obese mice. These findings highlight the potential of curcumol as a GDF15 inducer and suggest innovative strategies for managing obesity and its associated metabolic disorders. In conclusion, our study provides evidence for the efficacy of curcumol in obesity treatment by inducing GDF15 expression. The identified effects of curcumol on appetite regulation, dietary preferences, glucose tolerance, and lipid metabolism emphasize its potential as a therapeutic agent for combating obesity and related metabolic disorders.
    Keywords:  Curcumol; Endoplasmic reticulum stress; GDF15; High-fat diet; Metabolic disorders; Obesity
    DOI:  https://doi.org/10.1016/j.bcp.2024.116560
  73. Pak J Pharm Sci. 2024 May;37(3): 669-679
    KLF6 aggravates myocardial fibrosis by promoting mitochondrial division.
    Tingting Zhang, Hongyao Ge, Qiuhang Song, Gaoshan Yang, Aiying Li.
      The dysregulation of mitochondrial dynamics in cardiac fibroblasts (CFs) is closely linked to myocardial fibrosis, which can induce cardiac dysfunction and even lead to heart failure. As an essential multifunctional zinc-finger transcriptional factor of cardiovascular remodeling, the role of KLF6 mediating the link between mitochondrial fission and myocardial fibrosis remains unclear. Next, we want to explore whether the effect of KLF6 on mitochondrial fission might influence cardiac fibroblasts, we established a model of Transforming growth factor β1 (TGF-β1) and Isoprenaline (ISO)-induced myocardial fibrosis. Here, we found that KLF6 up-regulation in CFs is correlated with myocardial fibrosis. While knockdown of KLF6 suppresses mitochondrial fission and the Keap1/Nrf2 pathway molecules, which alleviates myocardial fibrosis induced by TGF-β1. Our findings not only clarified the regulation mechanism of mitochondrial fission by KLF6 but also provided a potential therapeutic target for cardiovascular disease.
  74. Nutrients. 2024 Sep 13. pii: 3086. [Epub ahead of print]16(18):
    Generational Diet-Induced Obesity Remodels the Omental Adipose Proteome in Female Mice.
    Naviya Schuster-Little, Morgan McCabe, Kayla Nenninger, Reihaneh Safavi-Sohi, Rebecca J Whelan, Tyvette S Hilliard.
      Obesity, a complex condition that involves genetic, environmental, and behavioral factors, is a non-infectious pandemic that affects over 650 million adults worldwide with a rapidly growing prevalence. A major contributor is the consumption of high-fat diets, an increasingly common feature of modern diets. Maternal obesity results in an increased risk of offspring developing obesity and related health problems; however, the impact of maternal diet on the adipose tissue composition of offspring has not been evaluated. Here, we designed a generational diet-induced obesity study in female C57BL/6 mice that included maternal cohorts and their female offspring fed either a control diet (10% fat) or a high-fat diet (45% fat) and examined the visceral adipose proteome. Solubilizing proteins from adipose tissue is challenging due to the need for high concentrations of detergents; however, the use of a detergent-compatible sample preparation strategy based on suspension trapping (S-Trap) enabled label-free quantitative bottom-up analysis of the adipose proteome. We identified differentially expressed proteins related to lipid metabolism, inflammatory disease, immune response, and cancer, providing valuable molecular-level insight into how maternal obesity impacts the health of offspring. Data are available via ProteomeXchange with the identifier PXD042092.
    Keywords:  S-Trap; adipose tissue; diet; generational obesity; obesity; omental tissue; proteomics; suspension trapping
    DOI:  https://doi.org/10.3390/nu16183086
  75. Front Endocrinol (Lausanne). 2024 ;15 1383131
    Inspiratory muscle strength training to improve cardiometabolic health in patients with type 2 diabetes mellitus: protocol for the diabetes inspiratory training clinical trial.
    Baylee L Reed, Dallin Tavoian, E Fiona Bailey, Janet L Funk, Dawn K Coletta.
      Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic disease that carries with it a high prevalence of comorbid conditions, making T2DM one of the leading causes of death in the U.S. Traditional lifestyle interventions (e.g., diet, exercise) can counter some adverse effects of T2DM, however, participation in these activities is low with reasons ranging from physical discomfort to lack of time. Thus, there is a critical need to develop novel management strategies that effectively reduce cardiometabolic disease risk and address barriers to adherence. High-resistance inspiratory muscle strength training (IMST) is a time-efficient and simple breathing exercise that significantly reduces systolic and diastolic BP and improves vascular endothelial function in adults with above-normal blood pressure. Herein we describe the study protocol for a randomized clinical trial to determine the effects of a 6-week IMST regimen on glycemic control and insulin sensitivity in adults with T2DM. Our primary outcome measures include fasting plasma glucose, fasting serum insulin, and insulin resistance utilizing homeostatic model assessment for insulin resistance (HOMA-IR). Secondary outcome measures include resting systolic BP and endothelium-dependent dilation. Further, we will collect plasma for exploratory proteomic analyses. This trial seeks to establish the cardiometabolic effects of 6 weeks of high-resistance IMST in patients with T2DM.
    Keywords:  endothelial function; glycemic control; inspiratory muscle strength training; insulin sensitivity; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3389/fendo.2024.1383131
  76. Rinsho Ketsueki. 2024 ;65(9): 961-966
    [Mitochondrial metabolism in AML cells].
    Yoko Tabe.
      Mitochondrial metabolic dependencies characteristic of acute myeloid leukemia (AML) have recently been identified, demonstrating that metabolic enzymes regulate AML gene expression and control cell differentiation and stemness. These mitochondrial metabolic adaptations occur independently of underlying genomic abnormalities and contribute to chemotherapy resistance and relapse. Mitochondrial alterations also lead to metabolic vulnerability of AML cells, whose metabolism is characterized by dependence on oxidative phosphorylation, fatty acid oxidation, reactive oxygen species (ROS) production, and mitochondrial dynamics. Currently, mitochondrial properties of AML cells and leukemia stem cells are being investigated, focusing on metabolism, signal transduction, mitochondrial respiration, ROS generation, and mitophagy. In addition, mitochondria-targeted agents have shown promising results in clinical trials. This paper outlines recent findings from preclinical and clinical trials on the utility of agents targeting mitochondria-related molecules and metabolic pathways and their efficacy in combination with existing chemotherapies.
    Keywords:  Acute myeloid leukemia; Metabolism; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.11406/rinketsu.65.961
  77. Stem Cell Res Ther. 2024 Sep 27. 15(1): 321
    The effect of exogenous mitochondria in enhancing the survival and volume retention of transplanted fat tissue in a nude mice model.
    Haoran Li, Zhengyao Li, Xiaoyu Zhang, Yan Lin, Tongtong Zhang, Leijuan Gan, Dali Mu.
       BACKGROUND: Despite the pivotal role of fat grafting in plastic, reconstructive, and aesthetic surgery, inconsistent survival rates of transplanted adipose tissue, primarily due to early ischemic and hypoxic insults, remain a significant challenge. The infusion of healthy mitochondria has emerged as a promising intervention to support tissue recovery from ischemic, hypoxic, and other types of damages across various organ systems.
    OBJECTIVES: This study aims to evaluate the impact of supplementing human adipose tissue grafts with healthy exogenous mitochondria on their volume and mass retention rates when transplanted into the subcutaneous layers of nude mice. This approach seeks to improve and optimize fat grafting techniques.
    METHODS: Human adipose tissues were preconditioned with exogenous mitochondria (10 µg/mL), a combination of exogenous mitochondria and the inhibitor Dyngo-4a, Dyngo-4a alone, or PBS, and then transplanted into the subcutaneous tissue of 24 nude mice. Samples were harvested at 1 and 3 months post-transplantation for analysis of mass and volume retention. The structural morphology and integrity of the adipose tissues were assessed using Hematoxylin and Eosin (H&E) staining.
    RESULTS: Mitochondrial preconditioning significantly enhanced the retention of mass and volume in fat grafts, demonstrating superior structural morphology and integrity compared to the control group.
    CONCLUSIONS: This study highlights the potential of exogenous mitochondrial augmentation in fat transplantation to significantly improve fat graft survival, thereby optimizing the success of fat grafting procedures.
    Keywords:  Exogenous mitochondria; Fat grafting; Hypoxic injury; Mitochondria transplantation
    DOI:  https://doi.org/10.1186/s13287-024-03938-3
  78. Diabetes Metab Syndr Obes. 2024 ;17 3593-3601
    Insulin Resistance Surrogates May Predict HTN-HUA in Young, Non-Obese Individuals.
    Yu-Qiang Zuo, Zhi-Hong Gao, Yu-Ling Yin, Xu Yang, Xing Guan, Ping-Yong Feng.
       Objective: To compare the associations of three surrogate markers of insulin resistance (IR) [glucose and triglycerides (TyG index), TyG index with BMI (TyG-BMI), and the ratio of triglycerides divided by HDL-C (TG/HDL-C)] with hypertensive patients (HTN) plus hyperuricemia (HUA) (HTN-HUA) in young, non-obese individuals.
    Methods: Data from a cross-sectional epidemiological study of an annual health check-up population aged younger than 66 years were used to calculate the three IR surrogate indexes. The association with HTN-HUA and insulin resistance surrogates was examined with multinomial logistic regression and a receiver operating characteristic (ROC) curve.
    Results: A total of 6952 participants were included, including 671 (9.65%) participants with HTN alone, 272 (3.91%) participants with HUA alone, and 62 (0.90%) participants with HTN and HUA. Binary multiple-logistic regression results showed that TG/HDL-C was significantly correlated with HTN, HUA, and HTN-HUA. Compared with the lowest quartile, the odds ratios (95% CI) of the highest quartile of TG/HDL-C for HTN-HUA were 3.462 (1.138~10.530). TG/HDL-C and TyG-BMI had moderate discriminative abilities for HTN-HUA, and the area under the curve was 0.748 (0.682~0.815), 0.746 (0.694~0.798).
    Conclusion: Our study suggests that TG/HDL-C had a significant correlation with HTN-HUA and that TG/HDL-C had moderate discriminative abilities for HTN-HUA.
    Keywords:  HTN-HUA; TG/HDL-C ratio; TyG index; insulin resistance
    DOI:  https://doi.org/10.2147/DMSO.S482184
  79. Int J Mol Sci. 2024 Sep 13. pii: 9892. [Epub ahead of print]25(18):
    Reduction of Mitochondrial Calcium Overload via MKT077-Induced Inhibition of Glucose-Regulated Protein 75 Alleviates Skeletal Muscle Pathology in Dystrophin-Deficient mdx Mice.
    Mikhail V Dubinin, Anastasia E Stepanova, Irina B Mikheeva, Anastasia D Igoshkina, Alena A Cherepanova, Eugeny Yu Talanov, Ekaterina I Khoroshavina, Konstantin N Belosludtsev.
      Duchenne muscular dystrophy is secondarily accompanied by Ca2+ excess in muscle fibers. Part of the Ca2+ accumulates in the mitochondria, contributing to the development of mitochondrial dysfunction and degeneration of muscles. In this work, we assessed the effect of intraperitoneal administration of rhodacyanine MKT077 (5 mg/kg/day), which is able to suppress glucose-regulated protein 75 (GRP75)-mediated Ca2+ transfer from the sarcoplasmic reticulum (SR) to mitochondria, on the Ca2+ overload of skeletal muscle mitochondria in dystrophin-deficient mdx mice and the concomitant mitochondrial dysfunction contributing to muscle pathology. MKT077 prevented Ca2+ overload of quadriceps mitochondria in mdx mice, reduced the intensity of oxidative stress, and improved mitochondrial ultrastructure, but had no effect on impaired oxidative phosphorylation. MKT077 eliminated quadriceps calcification and reduced the intensity of muscle fiber degeneration, fibrosis level, and normalized grip strength in mdx mice. However, we noted a negative effect of MKT077 on wild-type mice, expressed as a decrease in the efficiency of mitochondrial oxidative phosphorylation, SR stress development, ultrastructural disturbances in the quadriceps, and a reduction in animal endurance in the wire-hanging test. This paper discusses the impact of MKT077 modulation of mitochondrial dysfunction on the development of skeletal muscle pathology in mdx mice.
    Keywords:  Duchenne muscular dystrophy; GRP75; MKT077; UPR; calcium; mdx mice; skeletal muscle mitochondria
    DOI:  https://doi.org/10.3390/ijms25189892
  80. J Am Coll Cardiol. 2024 Sep 25. pii: S0735-1097(24)08519-X. [Epub ahead of print]
    Cardiac Myosin Inhibitors: Is the Emperor Wearing Any Clothes, or Is it Placebo?
    Torsten B Rasmussen, Anne M Dybro, Morten Kvistholm Jensen.
      
    Keywords:  hypertrophic cardiomyopathy; metoprolol; myosin inhibitor; outflow tract gradient; placebo
    DOI:  https://doi.org/10.1016/j.jacc.2024.09.021
  81. bioRxiv. 2024 Sep 19. pii: 2024.09.13.612924. [Epub ahead of print]
    M2 Macrophage Exosomes Reverse Cardiac Functional Decline in Mice with Diet-Induced Myocardial Infarction by Suppressing Type 1 Interferon Signaling in Myeloid Cells.
    Martin Ng, Alex S Gao, Tuan Anh Phu, Ngan K Vu, Robert L Raffai.
      Effective treatment strategies to alleviate heart failure that develops as a consequence of myocardial infarction (MI) remain an unmet need in cardiovascular medicine. In this study, we uncovered that exosomes produced by human THP-1 macrophages cultured with the cytokine IL-4 (THP1-IL4-exo), reverse cardiac functional decline in mice that develop MI as a consequence of diet-induced occlusive coronary atherosclerosis. Therapeutic benefits of THP1-IL4-exo stem from their ability to reprogram circulating Ly-6C hi monocytes into an M2-like phenotype and suppress Type 1 Interferon signaling in myeloid cells within the bone marrow, the circulation, and cardiac tissue. Collectively, these benefits suppress myelopoiesis, myeloid cell recruitment to cardiac tissue, and preserve populations of resident cardiac macrophages that together mitigate cardiac inflammation, adverse ventricular remodeling, and heart failure. Our findings introduce THP1-IL4-exo, one form of M2-macrophage exosomes, as novel therapeutics to preserve cardiac function subsequent to MI.
    DOI:  https://doi.org/10.1101/2024.09.13.612924
  82. Cell Death Dis. 2024 Sep 30. 15(9): 707
    Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.
    Su Hyeon Wang, Duk-Shin Lee, Tae-Hyun Kim, Ji-Eun Kim, Tae-Cheon Kang.
      Loss of parvalbumin (PV) expressing neurons (PV neurons) is relevant to the underlying mechanisms of the pathogenesis of neurological and psychiatric diseases associated with the dysregulation of neuronal excitatory networks and brain metabolism. Although PV modulates mitochondrial morphology, volume and dynamics, it is largely unknown whether mitochondrial dynamics affect PV expression and what the molecular events are responsible for PV neuronal degeneration. In the present study, L-buthionine sulfoximine (BSO, an inhibitor of glutathione synthesis) did not degenerate PV neurons under physiological condition. However, BSO-induced oxidative stress decreased PV expression and facilitated cyclin-dependent kinase 5 (CDK5) tyrosine (Y) 15 phosphorylation, dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and glutathione peroxidase-1 (GPx1) downregulation in PV neurons. Co-treatment of roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission) attenuated BSO-induced PV downregulation. WY14643 (an inducer of mitochondrial fission) reduced PV expression without affecting CDK5 Y15 phosphorylation. Following status epilepticus (SE), CDK5 Y15 phosphorylation and mitochondrial fission were augmented in PV neurons. These were accompanied by reduced GPx1-mediated inhibition of NF-κB p65 serine (S) 536 phosphorylation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.
    DOI:  https://doi.org/10.1038/s41419-024-07050-5
  83. Nutrients. 2024 Sep 19. pii: 3177. [Epub ahead of print]16(18):
    Filbertone Reduces Senescence in C2C12 Myotubes Treated with Doxorubicin or H2O2 through MuRF1 and Myogenin.
    Sumin Jung, Byungyong Ahn.
      It has been demonstrated that filbertone, the principal flavor compound of hazelnuts, exhibits preventive effects against hypothalamic inflammation, obesity, neurodegenerative diseases, and muscle lipid accumulation. However, its influence on muscle aging has yet to be elucidated. The objective of this study was to investigate the effects of filbertone on muscle aging in C2C12 myotubes subjected to senescence induction by either doxorubicin or hydrogen peroxide. To ascertain the mechanisms by which filbertone exerts its effects, we conducted a series of experiments, including Western blot analysis, reverse transcription quantitative polymerase chain reaction (qRT-PCR), and senescence-associated β-galactosidase (SA-β-gal) staining. Filbertone was markedly observed to decrease not only the protein levels of p53 (p < 0.01) in senescence-induced skeletal muscle cells, but also the gene expression levels of p21 (p < 0.05), a direct target of p53. The expression of muscle-related genes, including myogenin and muscle RING-finger protein-1 (MuRF1), was found to be significantly enhanced in senescent muscle cells following treatment with filbertone (p < 0.05). In addition, the number of senescent skeletal muscle cells exhibiting β-galactosidase activity was found to be markedly reduced in the presence of filbertone (p < 0.01). Collectively, these findings suggest that filbertone plays a pivotal role in the regulation of muscle aging.
    Keywords:  filbertone; muscle aging; p53; senescence
    DOI:  https://doi.org/10.3390/nu16183177
  84. Sci Rep. 2024 09 28. 14(1): 22505
    Differential impacts of body composition on oxygen kinetics and exercise tolerance of HFrEF and HFpEF patients.
    Gerson Cipriano, Cássia da Luz Goulart, Gaspar R Chiappa, Marianne Lucena da Silva, Natália Turri Silva, Amanda Oliveira do Vale Lira, Edson Marcio Negrão, Luciana Bartolomei Orru DÁvila, Sergio Henrique Rodolpho Ramalho, Fausto Stauffer Junqueira de Souza, Graziella França Bernardelli Cipriano, Daniel Hirai, Dominique Hansen, Lawrence Patrick Cahalin.
      This study aims to (1) compare the kinetics of pulmonary oxygen uptake (VO2p), skeletal muscle deoxygenation ([HHb]), and microvascular O2 delivery (QO2mv) between heart failure (HF) patients with reduced ejection fraction (HFrEF) and those with preserved ejection fraction (HFpEF), and (2) explore the correlation between body composition, kinetic parameters, and exercise performance. Twenty-one patients (10 HFpEF and 11 HFrEF) underwent cardiopulmonary exercise testing to assess VO2 kinetics, with near-infrared spectroscopy (NIRS) employed to measure [HHb]. Microvascular O2 delivery (QO2mv) was calculated using the Fick principle. Dual-energy X-ray absorptiometry (DEXA) was performed to evaluate body composition. HFrEF patients exhibited significantly slower VO2 kinetics (time constant [t]: 63 ± 10.8 s vs. 45.4 ± 7.9 s; P < 0.05) and quicker [HHb] response (t: 12.4 ± 9.9 s vs. 25 ± 11.6 s; P < 0.05). Microvascular O2 delivery (QO2mv) was higher in HFrEF patients (3.6 ± 1.2 vs. 1.7 ± 0.8; P < 0.05), who also experienced shorter time to exercise intolerance (281.6 ± 84 s vs. 405.3 ± 96 s; P < 0.05). Correlation analyses revealed a significant negative relationship between time to exercise and both QO2mv (ρ= -0.51; P < 0.05) and VO2 kinetics (ρ= -0.63). Body adiposity was negatively correlated with [HHb] amplitude (ρ= -0.78) and peak VO2 (ρ= -0.54), while a positive correlation was observed between lean muscle percentage, [HHb] amplitude, and tau (ρ= 0.74 and 0.57; P < 0.05), respectively. HFrEF patients demonstrate more severely impaired VO2p kinetics, skeletal muscle deoxygenation, and microvascular O2 delivery compared to HFpEF patients, indicating compromised peripheral function. Additionally, increased adiposity and reduced lean mass are linked to decreased oxygen diffusion capacity and impaired oxygen uptake kinetics in HFrEF patients.
    Keywords:  Exercise Test [Mesh]; Exercise Tolerance [Mesh]; Heart failure [Mesh]; Oxygen consumption [Mesh]; Oxygen uptake kinetics [All fields]; Tissue oxygenation index [All fields]
    DOI:  https://doi.org/10.1038/s41598-024-72965-0
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