bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–10–13
seventy papers selected by
Henver Brunetta, Karolinska Institutet
  1. Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes.
  2. A partial loss-of-function variant (Ile191Val) of the TAS1R2 glucose receptor is associated with enhanced responses to exercise training in older adults with obesity: A translational study.
  3. Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity.
  4. Loss of adipose ATF3 promotes adipose tissue lipolysis and the development of MASH.
  5. MicroRNA dynamics in irisin-mediated signaling pathways within adipose tissue.
  6. Effect of alternative oxidase (AOX) expression on mouse cerebral mitochondria bioenergetics.
  7. CEAM is a mitochondrial-localized, amyloid-like motif-containing microprotein expressed in human cardiomyocytes.
  8. ATF4-dependent and independent mitokine secretion from OPA1 deficient skeletal muscle in mice is sexually dimorphic.
  9. Protonophore treatment augments energy expenditure in mice housed at thermoneutrality.
  10. A combination of major histocompatibility complex (MHC) I overexpression and type I interferon induce mitochondrial dysfunction in human skeletal myoblasts.
  11. Sex differences in cardiac mitochondrial respiration and reactive oxygen species production may predispose Scn1a -/+ mice to cardiac arrhythmias and Sudden Unexpected Death in Epilepsy.
  12. Activity and phosphatidylcholine transfer protein interactions of skeletal muscle thioesterase Them2 enable hepatic steatosis and insulin resistance.
  13. DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.
  14. Glucocorticoid chrono-pharmacology promotes glucose metabolism in heart through a cardiomyocyte-autonomous transactivation program.
  15. Inhibition of the FOXO1-ROCK1 axis mitigates cardiomyocyte injury under chronic hypoxia in Tetralogy of Fallot by maintaining mitochondrial quality control.
  16. Chromium and Palmitic Acid Supplementation Modulate Adipose Tissue Insulin Sensitivity in Postpartum Dairy Cows.
  17. An optimized pipeline for high-throughput bulk RNA-Seq deconvolution illustrates the impact of obesity and weight loss on cell composition of human adipose tissue.
  18. Mitochondrial RNA maturation.
  19. Overexpression of CPT1A disrupts the maintenance and regenerative function of muscle stem cells.
  20. SGLT2 inhibitors protect against diabetic cardiomyopathy and atrial fibrillation through a CaMKII independent mechanism.
  21. Effect of mitochondrial translocator protein TSPO on LPS-induced cardiac dysfunction.
  22. Evidence for a hydrogen sulfide-sensing E3 ligase in yeast.
  23. Drp1 Promotes Macrophage M1 Polarization and Inflammatory Response in Autoimmune Myocarditis by Driving Mitochondrial Fission.
  24. Rab8a Is a Key Target That Melatonin Prevents Lipid Disorder from Atrazine.
  25. Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy.
  26. The high-fat diet and low-dose streptozotocin type-2 diabetes model induces hyperinsulinemia and insulin resistance in male but not female C57BL/6J mice.
  27. Mitochondrial apolipoprotein MIC26 is a metabolic rheostat regulating central cellular fuel pathways.
  28. Pericardiotomy as a novel treatment for heart failure with preserved ejection fraction.
  29. Characteristics of gene expression in epicardial adipose tissue and subcutaneous adipose tissue in patients at risk for heart failure undergoing coronary artery bypass grafting.
  30. Metabolic regulation of mitochondrial morphologies in pancreatic beta cells: coupling of bioenergetics and mitochondrial dynamics.
  31. Commonalities of platelet dysfunction in heart failure with preserved ejection fraction and underlying comorbidities.
  32. Mild burn amplifies the locomotive depression in demyelinated mice without muscle pathophysiological changes.
  33. Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation.
  34. Author Correction: Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice.
  35. SNRK regulates TGFβ levels in atria to control cardiac fibrosis.
  36. Mitochondrial MOF regulates energy metabolism in heart failure via ATP5B hyperacetylation.
  37. Sirtuin 7 ameliorates cuproptosis, myocardial remodeling and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling.
  38. Adipocyte metabolic state regulates glial phagocytic function.
  39. Sorafenib induces cachexia by impeding transcriptional signaling of the SET1/MLL complex on muscle-specific genes.
  40. Drug-induced increase in dispersion of ventricular repolarization in patients with heart failure with preserved ejection fraction.
  41. Utilization of Glucagon-Like Peptide-1 Receptor Agonist and Dipeptidyl Peptidase-4 Inhibitors at the Veterans Health Administration.
  42. Adipose tissue insulin resistance in young Japanese women is associated with metabolic abnormalities and dehydroepiandrosterone-sulfate.
  43. Effects of Exercise Training on Mitochondrial and Capillary Growth in Human Skeletal Muscle: A Systematic Review and Meta-Regression.
  44. FINEARTS Restoration: Revisiting the Role of Steroidal Mineralocorticoid Receptor Antagonists in Heart Failure with Mildly-Reduced or Preserved Ejection Fraction Following FINEARTS-HF.
  45. Crosstalk between macrophages and immunometabolism and their potential roles in tissue repair and regeneration.
  46. The expression of the formin Fhod3 in mouse tongue striated muscle.
  47. Cold Exposure Alleviates T2DM Through Plasma-Derived Extracellular Vesicles.
  48. Synergy between time-restricted feeding and time-restricted running is necessary to shift the muscle clock in male wistar rats.
  49. Association of BMI, lipid-lowering medication, and age with prevalence of type 2 diabetes in adults with heterozygous familial hypercholesterolaemia: a worldwide cross-sectional study.
  50. Hypoxanthine ameliorates diet-induced insulin resistance by improving hepatic lipid metabolism and gluconeogenesis via AMPK/mTOR/PPARα pathway.
  51. Regulation of cardiovascular diseases by histone deacetylases and NADPH oxidases.
  52. Fibroblast-specific TGF-β signaling mediates cardiac dysfunction, fibrosis, and hypertrophy in obese diabetic mice.
  53. Interleukin 11 therapy causes acute left ventricular dysfunction.
  54. Selection promotes age-dependent degeneration of the mitochondrial genome.
  55. BCKDH kinase promotes hepatic gluconeogenesis independent of BCKDHA.
  56. Aged gut microbiota promotes arrhythmia susceptibility via oxidative stress.
  57. Glibenclamide reverses cardiac damage and NLRP3 inflammasome activation associated with a high refined sugar diet.
  58. Antiarrhythmic potentials of irisin in ischemia/reperfusion injury of diabetic rats through modulating mitochondria-endoplasmic reticulum interaction and inhibiting pyroptosis.
  59. Artificial Intelligence Prediction of Cardiovascular Events Using Opportunistic Epicardial Adipose Tissue Assessments From Computed Tomography Calcium Score.
  60. Melatonin protects against sarcopenia in middle-aged mice.
  61. FDG Uptake in Brown Adipose Tissue Activated by a Long-Acting β2-Adrenergic Receptor Agonist Inhaler Prescribed for Bronchial Asthma.
  62. Histone-like transcription factor Hfl1p in Candida albicans harmonizes nuclear and mitochondrial genomic network in regulation of energy metabolism and filamentation development.
  63. Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.
  64. Bimagrumab: an investigational human monoclonal antibody against activin type II receptors for treating obesity.
  65. Salidroside rescues hypoxic cardiomyocytes by regulating the EGLN1/HIF‑1α pathway.
  66. CRISPR/Cas9 gene editing in induced pluripotent stem cells to investigate the feline hypertrophic cardiomyopathy causing MYBPC3/R820W mutation.
  67. Loss of mitochondrial Ca2+ response and CaMKII/ERK activation by LRRK2R1441G mutation correlate with impaired depolarization-induced mitophagy.
  68. Cardiomyocyte Reduction of Hybrid/Complex N-Glycosylation in the Adult Causes Heart Failure With Reduced Ejection Fraction in the Absence of Cellular Remodeling.
  69. [Taurine for Mitochondrial Diseases].
  70. Genomic and biochemical analysis of lipid biosynthesis in Cyanophora paradoxa: Limited role of chloroplast in fatty acid synthesis.
  1. Sci Transl Med. 2024 Oct 09. 16(768): eado3022
    Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes.
    David Rizo-Roca, Dimitrius Santiago P S F Guimarães, Logan A Pendergrast, Nicolas Di Leo, Alexander V Chibalin, Salwan Maqdasy, Mikael Rydén, Erik Näslund, Juleen R Zierath, Anna Krook.
      Increased plasma creatine concentrations are associated with the risk of type 2 diabetes, but whether this alteration is associated with or causal for impairments in metabolism remains unexplored. Because skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. In men with type 2 diabetes, plasma creatine concentrations were increased, and intramuscular phosphocreatine content was reduced. These alterations were coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 (CKMT2). In C57BL/6 mice fed a high-fat diet, neither supplementation with creatine for 2 weeks nor treatment with the creatine analog β-GPA for 1 week induced changes in glucose tolerance, suggesting that increased circulating creatine was associated with insulin resistance rather than causing it. In C2C12 myotubes, silencing Ckmt2 using small interfering RNA reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of Ckmt2 in skeletal muscle of high-fat diet-fed male mice increased mitochondrial respiration, independent of creatine availability. Given that overexpression of Ckmt2 improved mitochondrial function, we explored whether exercise regulates CKMT2 expression. Analysis of public data revealed that CKMT2 content was up-regulated by exercise training in both humans and mice. We reveal a previously underappreciated role of CKMT2 in mitochondrial homeostasis beyond its function for creatine phosphorylation, independent of insulin action. Collectively, our data provide functional evidence for how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes.
    DOI:  https://doi.org/10.1126/scitranslmed.ado3022
  2. Metabolism. 2024 Oct 09. pii: S0026-0495(24)00273-7. [Epub ahead of print] 156045
    A partial loss-of-function variant (Ile191Val) of the TAS1R2 glucose receptor is associated with enhanced responses to exercise training in older adults with obesity: A translational study.
    Joan Serrano, Saki Kondo, Grace M Link, Ian S Brown, Richard E Pratley, Kedryn K Baskin, Bret H Goodpaster, Paul M Coen, George A Kyriazis.
       BACKGROUND: The TAS1R2 receptor, known for its role in taste perception, has also emerged as a key regulator of muscle physiology. Previous studies have shown that genetic ablation of TAS1R2 in mice enhances muscle fitness mimicking responses to endurance exercise training. However, the translational relevance of these findings to humans remains uncertain.
    METHODS: We explored responses to endurance exercise training in mice and humans with genetic deficiency of TAS1R2. First, we assessed the effects of muscle-specific deletion of TAS1R2 in mice (mKO) or wild type controls (mWT) following 4 weeks of voluntary wheel running (VWR). Next, we investigated the effects of the TAS1R2-Ile191Val (rs35874116) partial loss-of-function variant on responses to a 6-month diet-induced weight loss with exercise training (WLEX), weight loss alone (WL), or education control (CON) interventions in older individuals with obesity. Participants were retrospectively genotyped for the TAS1R2-Ile191Val polymorphism and classified as conventional function (Ile/Ile) or partial loss-of-function (Val carriers: Ile/Val and Val/Val). Body composition, cardiorespiratory fitness, and skeletal muscle mitochondrial function were assessed before and after the intervention.
    RESULTS: In response to VWR, mKO mice demonstrated enhanced running endurance and mitochondrial protein content. Similarly, TAS1R2 Val carriers exhibited distinctive improvements in body composition, including increased muscle mass, along with enhanced cardiorespiratory fitness and mitochondrial function in skeletal muscle following the WLEX intervention compared to Ile/Ile counterparts. Notably, every Val carrier demonstrated substantial responses to exercise training and weight loss, surpassing all Ile/Ile participants in overall performance metrics.
    CONCLUSIONS: Our findings suggest that TAS1R2 partial loss-of-function confers beneficial effects on muscle function and metabolism in humans in response to exercise training, akin to observations in TAS1R2 muscle-deficient mice. Targeting TAS1R2 may help enhancing exercise training adaptations in individuals with compromised exercise tolerance or metabolic disorders, presenting a potential avenue for personalized exercise interventions.
    Keywords:  Aging; Exercise; Genetics; HbA1c; Mitochondria; Muscle mass; Muscle metabolism; NAD; Obesity; PDE; Polymorphism; Running; Sweet taste receptor; TAS1R2; Weight loss; rs35874116
    DOI:  https://doi.org/10.1016/j.metabol.2024.156045
  3. Sci Adv. 2024 Oct 11. 10(41): eadl4374
    Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity.
    Deborah Carper, Marlène Lac, Marine Coue, Axel Labour, Andre Märtens, Jorge Alberto Ayala Banda, Laurène Mazeyrie, Mie Mechta, Lars Roed Ingerslev, Mohamed Elhadad, Justine Vily Petit, Claire Maslo, Laurent Monbrun, Peggy Del Carmine, Yannis Sainte-Marie, Virginie Bourlier, Claire Laurens, Gilles Mithieux, Denis R Joanisse, Charles Coudray, Christine Feillet-Coudray, Emilie Montastier, Nathalie Viguerie, Geneviève Tavernier, Melanie Waldenberger, Annette Peters, Rui Wang-Sattler, Jerzy Adamski, Karsten Suhre, Christian Gieger, Gabi Kastenmüller, Thomas Illig, Ralf Lichtinghagen, Jochen Seissler, Remy Mounier, Karsten Hiller, Jens Jordan, Romain Barrès, Michaela Kuhn, Dominik Pesta, Cedric Moro.
      Type 2 diabetes (T2D) and obesity are strongly associated with low natriuretic peptide (NP) plasma levels and a down-regulation of NP guanylyl cyclase receptor-A (GCA) in skeletal muscle and adipose tissue. However, no study has so far provided evidence for a causal link between atrial NP (ANP)/GCA deficiency and T2D pathogenesis. Here, we show that both systemic and skeletal muscle ANP/GCA deficiencies in mice promote metabolic disturbances and prediabetes. Skeletal muscle insulin resistance is further associated with altered mitochondrial function and impaired endurance running capacity. ANP/GCA-deficient mice exhibit increased proton leak and reduced content of mitochondrial oxidative phosphorylation proteins. We further show that GCA is related to several metabolic traits in T2D and positively correlates with markers of oxidative capacity in human skeletal muscle. Together, these results indicate that ANP/GCA signaling controls muscle mitochondrial integrity and oxidative capacity in vivo and plays a causal role in the development of prediabetes.
    DOI:  https://doi.org/10.1126/sciadv.adl4374
  4. Commun Biol. 2024 Oct 10. 7(1): 1300
    Loss of adipose ATF3 promotes adipose tissue lipolysis and the development of MASH.
    Shuwei Hu, Fathima N Cassim Bawa, Yingdong Zhu, Xiaoli Pan, Hui Wang, Raja Gopoju, Yanyong Xu, Yanqiao Zhang.
      The crosstalk between adipose tissue and the liver is finely controlled to maintain metabolic health. Yet, how adipose tissue controls toxic free fatty acid overflow into the liver remains incompletely understood. Here, we show that adipocyte activating transcription factor 3 (ATF3) was induced in human or mouse obesity. Adipocyte Atf3-/- (Atf3Adi-/-) mice developed obesity, glucose intolerance, and metabolic dysfunction-associated steatohepatitis (MASH) in chow diet, high-fat diet, or Western diet-fed mice. Blocking fatty acid flux by inhibiting hepatocyte CD36, but not the restoration of hepatic AMPK signaling, prevented the aggravation of MASH in Atf3Adi-/- mice. Further studies show that the loss of adipocyte ATF3 increased lipolysis via inducing adipose triglyceride lipase, which in turn induced lipogenesis and inflammation in hepatocytes. Moreover, Atf3Adi-/- mice had reduced energy expenditure and increased adipose lipogenesis and inflammation. Our data demonstrate that adipocyte ATF3 is a gatekeeper in counteracting MASH development under physiological and pathological conditions.
    DOI:  https://doi.org/10.1038/s42003-024-06915-x
  5. J Biosci. 2024 ;pii: 89. [Epub ahead of print]49
    MicroRNA dynamics in irisin-mediated signaling pathways within adipose tissue.
    Ming-Yun Ho, Kai-Pin Chiu, Ming-Lung Tsai, Jih-Kai Yeh, Yi-Chun Huang, Yan-Rong Li, Horng-Dar Wang, I-Chang Hsieh, Ming-Shien Wen, Chao-Yung Wang.
      The regulation of adipose tissue metabolism by irisin involves modulating gene expressions related to energy metabolism and insulin sensitivity via miRNA-mediated signaling pathways within adipose tissue. Understanding the molecular mechanisms behind the role of irisin is vital for addressing obesity and related metabolic complications. In this study, we undertook an extensive miRNA transcriptomic approach to identify differentially expressed miRNAs following irisin exposure in adipocytes and murine white adipose tissue. Our findings spotlighted two miRNAs, miRNA-758 and miRNA-668, as being influenced by irisin. To understand the impact of the modulations of these miRNAs by irisin, we performed a signaling pathway and network analysis. After irisin exposure, both, miRNA-758 and miRNA-668, emerged as key regulators in leptin and CDK5 signaling pathways. Leptin, a hormone originating from adipose tissue, is primarily produced by adipocytes, and its effects are known to be mediated by CDK5. In essence, this study identifies pivotal genes and miRNAs in irisin-driven mechanisms in adipose tissue, offering valuable insights for crafting novel therapeutic strategies for metabolic and associated disorders.
  6. Redox Biol. 2024 Oct 01. pii: S2213-2317(24)00356-2. [Epub ahead of print]77 103378
    Effect of alternative oxidase (AOX) expression on mouse cerebral mitochondria bioenergetics.
    Belem Yoval-Sánchez, Ivan Guerrero, Fariha Ansari, Zoya Niatsetskaya, Max Siragusa, Jordi Magrane, Vadim Ten, Csaba Konrad, Marten Szibor, Alexander Galkin.
      Alternative oxidase (AOX) is an enzyme that transfers electrons from reduced quinone directly to oxygen without proton translocation. When AOX from Ciona intestinalis is xenotopically expressed in mice, it can substitute the combined electron-transferring activity of mitochondrial complexes III/IV. Here, we used brain mitochondria from AOX-expressing mice with such a chimeric respiratory chain to study respiratory control bioenergetic mechanisms. AOX expression did not compromise the function of the mammalian respiratory chain at physiological conditions, however the complex IV inhibitor cyanide only partially blocked respiration by AOX-containing mitochondria. The relative fraction of cyanide-insensitive respiration increased at lower temperatures, indicative of a temperature-controlled attenuation of mammalian respiratory enzyme activity. As AOX does not translocate protons, the mitochondrial transmembrane potential in AOX-containing mitochondria was more sensitive to cyanide during succinate oxidation than during malate/pyruvate-supported respiration. High concentrations of cyanide fully collapsed membrane potential during oxidation of either succinate or glycerol 3-phosphate, but not during malate/pyruvate-supported respiration. This confirms AOX's electroneutral redox activity and indicates differences in the proton-translocating capacity of dehydrogenases upstream of the ubiquinone pool. Our respiration data refutes previous proposals for quinone partitioning within the supercomplexes of the respiratory chain, instead supporting the concept of a single homogeneous, freely diffusing quinone pool. Respiration with either succinate or glycerol 3-phosphate promotes reverse electron transfer (RET) towards complex I. AOX expression significantly decreased RET-induced ROS generation, with the effect more pronounced at low temperatures. Inhibitor-sensitivity analysis showed that the AOX-induced decrease in H2O2 release is due to the lower contribution of complex I to net ROS production during RET. Overall, our findings provide new insights into the role of temperature as a mechanism to control respiration and highlight the utility of AOX as a genetic tool to characterize both the distinct pathways of oxygen reduction and the role of redox control in RET.
    Keywords:  Alternative quinol oxidase; Complex I; Mitochondria; Mitochondrial membrane potential; ROS generation; Reverse electron transfer
    DOI:  https://doi.org/10.1016/j.redox.2024.103378
  7. Biochem Biophys Res Commun. 2024 Oct 05. pii: S0006-291X(24)01273-7. [Epub ahead of print]734 150737
    CEAM is a mitochondrial-localized, amyloid-like motif-containing microprotein expressed in human cardiomyocytes.
    Ruobing Li, Ti Qin, Yabo Guo, Shan Zhang, Xiaogang Guo.
      Microproteins synthesized through non-canonical translation pathways are frequently found within mitochondria. However, the functional significance of these mitochondria-localized microproteins in energy-intensive organs such as the heart remains largely unexplored. In this study, we demonstrate that the long non-coding RNA CD63-AS1 encodes a mitochondrial microprotein. Notably, in ribosome profiling data of human hearts, there is a positive correlation between the expression of CD63-AS1 and genes associated with cardiomyopathy. We have termed this microprotein CEAM (CD63-AS1 encoded amyloid-like motif containing microprotein), reflecting its sequence characteristics. Our biochemical assays show that CEAM forms protease-resistant aggregates within mitochondria, whereas deletion of the amyloid-like motif transforms CEAM into a soluble cytosolic protein. Overexpression of CEAM triggers mitochondrial stress responses and adversely affect mitochondrial bioenergetics in cultured cardiomyocytes. In turn, the expression of CEAM is reciprocally inhibited by the activation of mitochondrial stresses induced by oligomycin. When expressed in mouse hearts via adeno-associated virus, CEAM impairs cardiac function. However, under conditions of pressure overload-induced cardiac hypertrophy, CEAM expression appears to offer a protective benefit and mitigates the expression of genes associated with cardiac remodeling, presumably through a mechanism that suppresses stress-induced translation reprogramming. Collectively, our study uncovers a hitherto unexplored amyloid-like microprotein expressed in the human cardiomyocytes, offering novel insights into myocardial hypertrophy pathophysiology.
    Keywords:  CD63-AS1; Microprotein; Mitochondrial unfolded protein response; Pressure overload-induced cardiac hypertrophy; Transverse aortic constriction
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150737
  8. Front Endocrinol (Lausanne). 2024 ;15 1325286
    ATF4-dependent and independent mitokine secretion from OPA1 deficient skeletal muscle in mice is sexually dimorphic.
    Jennifer Streeter, Luis Persaud, Jason Gao, Deeraj Manika, Will Fairman, Luis Miguel García-Peña, Alex Marti, Chethan Manika, Shreya Gaddi, Brandon Schickling, Renata O Pereira, E Dale Abel.
       Introduction: Reducing Optic Atrophy 1 (OPA1) expression in skeletal muscle in male mice induces Activation Transcription Factor 4 (ATF4) and the integrated stress response (ISR). Additionally, skeletal muscle secretion of Fibroblast Growth Factor 21 (FGF21) is increased, which mediates metabolic adaptations including resistance to diet-induced obesity (DIO) and glucose intolerance in these mice. Although FGF21 induction in this model can be reversed with pharmacological attenuation of ER stress, it remains to be determined if ATF4 is responsible for FGF21 induction and its metabolic benefits in this model.
    Methods: We generated mice with homozygous floxed Opa1 and Atf4 alleles and a tamoxifen-inducible Cre transgene controlled by the human skeletal actin promoter to enable simultaneous depletion of OPA1 and ATF4 in skeletal muscle (mAO DKO). Mice were fed high fat (HFD) or control diet and evaluated for ISR activation, body mass, fat mass, glucose tolerance, insulin tolerance and circulating concentrations of FGF21 and growth differentiation factor 15 (GDF15).
    Results: In mAO DKO mice, ATF4 induction is absent. Other indices of ISR activation, including XBP1s, ATF6, and CHOP were induced in mAO DKO males, but not in mOPA1 or mAO DKO females. Resistance to diet-induced obesity was not reversed in mAO DKO mice of both sexes. Circulating FGF21 and GDF15 illustrated sexually dimorphic patterns. Loss of OPA1 in skeletal muscle increases circulating FGF21 in mOPA1 males, but not in mOPA1 females. Additional loss of ATF4 decreased circulating FGF21 in mAO DKO male mice, but increased circulating FGF21 in female mAO DKO mice. Conversely, circulating GDF15 was increased in mAO DKO males and mOPA1 females, but not in mAO DKO females.
    Conclusion: Sex differences exist in the transcriptional outputs of the ISR following OPA deletion in skeletal muscle. Deletion of ATF4 in male and female OPA1 KO mice does not reverse the resistance to DIO. Induction of circulating FGF21 is ATF4 dependent in males, whereas induction of circulating GDF15 is ATF4 dependent in females. Elevated GDF15 in males and FGF21 in females could reflect activation by other transcriptional outputs of the ISR, that maintain mitokine-dependent metabolic protection in an ATF4-independent manner.
    Keywords:  FGF21; insulin resistance; integrated stress response; mitochondria; obesity
    DOI:  https://doi.org/10.3389/fendo.2024.1325286
  9. Front Physiol. 2024 ;15 1452986
    Protonophore treatment augments energy expenditure in mice housed at thermoneutrality.
    Daniel G Sadler, Reid D Landes, Lillie Treas, James Sikes, Craig Porter.
       Background: Sub-thermoneutral housing increases facultative thermogenesis in mice, which may mask the pre-clinical efficacy of anti-obesity strategies that target energy expenditure (EE). Here, we quantified the impact of protonophore treatment on whole-body energetics in mice housed at 30°C.
    Methods: C57BL/6J mice (n = 48, 24M/24F) were housed at 24°C for 2 weeks; 32 (16M/16F) were then transitioned to 30°C for a further 4 weeks. Following 2 weeks acclimation at 30°C, mice (n = 16 per group, 8M/8F) received either normal (0 mg/L; Control) or supplemented (400 mg/L; 2,4-Dinitrophenol [DNP]) drinking water. Mice were singly housed in metabolic cages to determine total EE (TEE) and its components via respiratory gas exchange. Mitochondrial respiratory function of permeabilized liver tissue was determined by high-resolution respirometry.
    Results: Transitioning mice from 24°C to 30°C reduced TEE and basal EE (BEE) by 16% and 41%, respectively (both P < 0.001). Compared to 30°C controls, TEE was 2.6 kcal/day greater in DNP-treated mice (95% CI: 1.6-3.6 kcal/day, P < 0.001), which was partly due to a 1.2 kcal/day higher BEE in DNP-treated mice (95% CI: 0.6-1.7 kcal/day, P < 0.001). The absolute TEE of 30°C DNP-treated mice was lower than that of mice housed at 24°C in the absence of DNP (DNP: 9.4 ± 0.7 kcal/day vs. 24°C control: 10.4 ± 1.5 kcal/day). DNP treatment reduced overall body fat of females by 2.9 percentage points versus sex-matched controls (95% CI: 1.3%-4.5%, P < 0.001), which was at least partly due to a reduction in inguinal white fat mass.
    Conclusion: Protonophore treatment markedly increases EE in mice housed at 30°C. The magnitude of change in TEE of mice receiving protonophore treatment at 30°C was smaller than that brought about by transitioning mice from 24°C to 30°C, emphasizing that housing temperature must be considered when assessing anti-obesity strategies that target EE in mice.
    Keywords:  energy expenditure; mitochondria; mouse models; protonophores; thermoneutral
    DOI:  https://doi.org/10.3389/fphys.2024.1452986
  10. J Cell Physiol. 2024 Oct 09. e31458
    A combination of major histocompatibility complex (MHC) I overexpression and type I interferon induce mitochondrial dysfunction in human skeletal myoblasts.
    Anastasia Thoma, Razan Alomosh, Holly L Bond, Tania Akter-Miah, Nasser Al-Shanti, Hans Degens, Vanja Pekovic-Vaughan, Adam P Lightfoot.
      The overexpression of major histocompatibility complex (MHC) I on the surface of muscle fibers is a characteristic hallmark of the idiopathic inflammatory myopathies (IIMs), collectively termed myositis. Alongside MHC-I overexpression, subtypes of myositis, display a distinct type I interferon (IFN) signature. This study examined the combinational effects of elevated MHC-I and type I IFNs (IFNα/β) on mitochondrial function, as mitochondrial dysfunction is often seen in IIMs. Human skeletal muscle myoblasts were transfected with an MHC-I isoform using the mammalian HLA-A2/Kb vector. Mitochondrial respiration, mitochondrial membrane potential, and reactive oxygen/nitrogen species generation were assessed with or without IFNα and IFNβ. We show that MHC-I overexpression in human skeletal muscle myoblasts led to decreased basal glycolysis and mitochondrial respiration, cellular spare respiratory capacity, adenosine triphosphate-linked respiration, and an increased proton leak, which were all exaggerated by type I IFNs. Mitochondrial membrane depolarization was induced by MHC-I overexpression both in absence and presence of type I IFNs. Human myoblasts overexpressing MHC-I showed elevated nitric oxide generation that was abolished when combined with IFN. MHC-I on its own did not result in an increased reactive oxygen species (ROS) production, but IFN on their own, or combined with MHC-I overexpression did induce elevated ROS generation. Surprisingly, we observed no gross changes in mitochondrial reticular structure or markers of mitochondrial dynamics. We present new evidence that MHC-I overexpression and type I IFNs aggravate the effects each has on mitochondrial function in human skeletal muscle cells, providing novel insights into their mechanisms of action and suggesting important implications in the further study of myositis pathogenesis.
    Keywords:  idiopathic inflammatory myopathies; major histocompatibility complex I; mitochondria; myositis; reactive and nitric oxygen species; type I interferon
    DOI:  https://doi.org/10.1002/jcp.31458
  11. J Mol Cell Cardiol Plus. 2024 Sep;pii: 100090. [Epub ahead of print]9
    Sex differences in cardiac mitochondrial respiration and reactive oxygen species production may predispose Scn1a -/+ mice to cardiac arrhythmias and Sudden Unexpected Death in Epilepsy.
    Jessa L Aldridge, Emily Davis Alexander, Allison A Franklin, Elizabeth Harrington, Farah Al-Ghzawi, Chad R Frasier.
      Dravet Syndrome (DS) is a pediatric-onset epilepsy with an elevated risk of Sudden Unexpected Death in Epilepsy (SUDEP). Most individuals with DS possess mutations in the voltage-gated sodium channel gene Scn1a, expressed in both the brain and heart. Previously, mutations in Scn1a have been linked to arrhythmia. We used a Scn1a -/+ DS mouse model to investigate changes to cardiac mitochondrial function that may underlie arrhythmias and SUDEP. We detected significant alterations in mitochondrial bioenergetics that were sex-specific. Mitochondria from male Scn1a -/+ hearts had deficits in maximal (p = 0.02) and Complex II-linked respiration (p = 0.03). Male Scn1a -/+ mice were also more susceptible to cardiac arrhythmias under increased workload. When isolated cardiomyocytes were subjected to diamide, cardiomyocytes from male Scn1a -/+ hearts were less resistant to thiol oxidation. They had decreased survivability compared to Scn1a +/+ (p = 0.02) despite no whole-heart differences. Lastly, there were no changes in mitochondrial ROS production between DS and wild-type mitochondria at basal conditions, but Scn1a -/+ mitochondria accumulated more ROS during hypoxia/reperfusion. This study determines novel sex-linked differences in mitochondrial and antioxidant function in Scn1a-linked DS. Importantly, we found that male Scn1a -/+ mice are more susceptible to cardiac arrhythmias than female Scn1a -/+ mice. When developing new therapeutics to address SUDEP risk in DS, sex should be considered.
    Keywords:  Arrhythmia; Dravet; Glutathione; Hypoxia; SUDEP; Sex differences
    DOI:  https://doi.org/10.1016/j.jmccpl.2024.100090
  12. J Biol Chem. 2024 Oct 04. pii: S0021-9258(24)02357-3. [Epub ahead of print] 107855
    Activity and phosphatidylcholine transfer protein interactions of skeletal muscle thioesterase Them2 enable hepatic steatosis and insulin resistance.
    Yang Xie, Xu Liu, Wenpeng Liu, Logan R Carr, Luke P Lee, Norihiro Imai, Eric A Ortlund, David E Cohen.
      Thioesterase superfamily member 2 (Them2), a long-chain fatty acyl-CoA thioesterase that is highly expressed in oxidative tissues, interacts with phosphatidylcholine transfer protein (PC-TP) to regulate hepatic lipid and glucose metabolism and to suppress insulin signaling. High-fat diet (HFD)-fed mice lacking Them2 globally or specifically in skeletal muscle, but not liver, exhibit reduced hepatic steatosis and insulin resistance. Here, we report that the capacity of Them2 in skeletal muscle to promote hepatic steatosis and insulin resistance depends on both its catalytic activity and interaction with PC-TP. Two residues of Them2 catalytic site were mutated (N50A/D65A) to produce the inactive enzyme while maintaining its homotetrameric structure and interaction with PC-TP. Restoration of skeletal muscle expression in Them2-/- mice using recombinant adeno-associated virus revealed that wild-type (WT), but not N50A/D65A Them2, promoted HFD-induced weight gain and hepatic steatosis. This was accompanied by greater impairment of insulin sensitivity in WT compared with N50A/D65A Them2. Pharmacological inhibition or genetic ablation of PC-TP attenuated these effects. In reductionist experiments, conditioned medium collected from WT primary cultured myotubes promoted excess lipid accumulation in oleic acid-treated primary cultured hepatocytes relative to Them2-/- myotubes, which was attributable to secreted extracellular vesicles (EV). Reconstitution of Them2 expression in Them2-/- myotubes affirmed the requirements for catalytic activity and PC-TP interactions for EV to promote lipid accumulation in hepatocytes. These studies provide valuable mechanistic insights whereby Them2 in skeletal muscle promotes hepatic steatosis and establish both Them2 and PC-TP as represent attractive targets for managing metabolic dysfunction-associated steatotic liver disease.
    Keywords:  fatty acid metabolism; glucose metabolism; hepatocyte; insulin resistance; lipid binding protein; skeletal muscle metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2024.107855
  13. EMBO J. 2024 Oct 08.
    DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.
    Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Kory R Johnson, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra.
      Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.
    Keywords:  Mitochondria Unfolded Protein Response (mt-UPR); Mitochondrial Disorders; Mitohormesis; Mitonuclear Communication; Mitophagy
    DOI:  https://doi.org/10.1038/s44318-024-00242-x
  14. JCI Insight. 2024 Oct 08. pii: e182599. [Epub ahead of print]
    Glucocorticoid chrono-pharmacology promotes glucose metabolism in heart through a cardiomyocyte-autonomous transactivation program.
    Hima Bindu Durumutla, Ashok Prabakaran, Fadoua El Abdellaoui Soussi, Olukunle Akinborewa, Hannah Latimer, Kevin McFarland, Kevin Piczer, Cole Werbrich, Mukesh K Jain, Saptarsi M Haldar, Mattia Quattrocelli.
      Circadian time-of-intake gates the cardioprotective effects of glucocorticoid administration in both healthy and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) and its co-factor, Krüppel-like factor (Klf15), play critical roles in maintaining normal heart function in the long-term and serve as pleiotropic regulators of cardiac metabolism. Despite this understanding, the cardiomyocyte-autonomous metabolic targets influenced by the concerted epigenetic action of GR-Klf15 axis remain undefined. Here, we demonstrate the critical roles of the cardiomyocyte-specific GR and Klf15 in orchestrating a circadian-dependent glucose oxidation program within the heart. Combining integrated transcriptomics and epigenomics with cardiomyocyte-specific inducible ablation of GR or Klf15, we identified their synergistic role in the activation of adiponectin receptor expression (Adipor1) and the mitochondrial pyruvate complex (Mpc1/2), thereby enhancing insulin-stimulated glucose uptake and pyruvate oxidation. Furthermore, in obese diabetic (db/db) mice exhibiting insulin resistance and impaired glucose oxidation, light-phase prednisone administration, as opposed to dark-phase prednisone dosing, effectively restored cardiomyocyte glucose oxidation and improved diastolic function towards control-like levels in a sex-independent manner. Collectively, our findings uncover novel cardiomyocyte-autonomous metabolic targets of the GR-Klf15 axis. This study highlights the circadian-dependent cardioprotective effects of glucocorticoids on cardiomyocyte glucose metabolism, providing critical insights into chrono-pharmacological strategies for glucocorticoid therapy in cardiovascular disease.
    Keywords:  Cardiology; Epigenetics; Glucose metabolism; Heart failure; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.182599
  15. Life Sci. 2024 Oct 05. pii: S0024-3205(24)00674-X. [Epub ahead of print]357 123084
    Inhibition of the FOXO1-ROCK1 axis mitigates cardiomyocyte injury under chronic hypoxia in Tetralogy of Fallot by maintaining mitochondrial quality control.
    Chunnian Ren, Linyun Xi, Hongbo Li, Zhengxia Pan, Yonggang Li, Gang Wang, Jiangtao Dai, Dawei He, Shulei Fan, Quan Wang.
       INTRODUCTION: Persistent chronic myocardial hypoxia causes disturbances in mitochondrial quality control (MQC), ultimately leading to increased cardiomyocyte injury in patients with Tetralogy of Fallot (TOF). The present study aimed to identify the key effector molecules of cardiomyocyte injury under chronic hypoxia in TOF.
    METHODS: Clinical data from TOF patients were collected and whole transcriptome sequencing was performed on myocardial samples. Chronic hypoxia models were established in cardiac-specific knockout mice and cardiomyocytes, and a series of molecular experiments were used to determine the specific mechanisms involved.
    RESULTS: Clinical cohort data and whole-transcriptome sequencing analysis of myocardial samples from TOF patients revealed that forkhead box O1 (FOXO1) plays an important role in chronic hypoxic cardiomyocyte injury. In a model of chronic hypoxia established in FOXO1 cardiac-specific knockout mice and FOXO1 gene-deficient cardiomyocytes, the AMPK signaling pathway regulates the expression of FOXO1, which in turn disrupts MQC by regulating the transcriptional activation of Rho-associated protein kinase 1 (ROCK1), and increasing the production of mitochondrial ROS, thereby exacerbating damage to cardiomyocytes. Excessive reactive oxygen species (ROS) production during MQC dysfunction further activates Cox7a2L to increase the assembly of the respiratory chain supercomplex. In addition, we found that miR-27b-3p partially binds to the 3' untranslated region of FOXO1 to exert a protective effect.
    CONCLUSIONS: Maintenance of MQC under chronic hypoxia is achieved through a series of injury-protection mechanisms, suggesting that FOXO1 inhibition may be crucial for future mitigation of chronic hypoxic cardiomyocyte injury in TOF.
    Keywords:  Chronic hypoxia; Cox7a2L; Forkhead box O1; Mitochondrial quality control; Tetralogy of Fallot
    DOI:  https://doi.org/10.1016/j.lfs.2024.123084
  16. J Dairy Sci. 2024 Oct 04. pii: S0022-0302(24)01188-3. [Epub ahead of print]
    Chromium and Palmitic Acid Supplementation Modulate Adipose Tissue Insulin Sensitivity in Postpartum Dairy Cows.
    Miguel Chirivi, Ursula Abou-Rjeileh, Jeff Gandy, Jair Parales-Giron, Vishal Panda, Leah Terrian, Sudin Bhattacharya, Adam L Lock, G Andres Contreras.
      Periparturient dairy cows exhibit intense lipolysis driven by reduced dry matter intake, enhanced energy needs, and the loss of adipose tissue (AT) insulin sensitivity. Extended periods of low insulin sensitivity and negative energy balance induce lipolysis dysregulation, leading to increased disease susceptibility and poor lactation performance. Chromium (Cr) supplementation improves systemic insulin sensitivity, while palmitic acid (PA) increases energy availability for milk production. However, the effect of supplementing Cr and PA alone or in combination on insulin sensitivity in AT is unknown. Thirty-two multiparous cows were used in a randomized complete block design experiment and randomly assigned to one of 4 diets fed from 1 to 24 DIM. Diets included: control, no supplementation (CON, n = 8); Cr (Cr-propionate at 0.45 ppm Cr/kg DM, n = 8); PA (1.5% DM, n = 8); or Cr+PA (n = 8). Plasma samples were collected at -13 ± 5.1 d prepartum (PreP), and 14.4 ± 1.9d (PP1) and 21 ± 1.9d (PP2) after calving for albumin, BHB, BUN, calcium, cholesterol, glucose, nonesterified fatty acids (NEFA), total protein, iron, transferrin, triglycerides, and oxylipids quantification. Subcutaneous AT (SCAT) explants were collected at PreP, PP1 and PP2 and incubated in the presence of the lipolytic agent isoproterenol (ISO = 1 µM, BASAL = 0 µM) for 3 h. The antilipolytic effect of insulin (1µL/L) on SCAT explants was evaluated during ISO stimulation (IN+ISO). Lipolysis was quantified by glycerol release in the media (nmol glycerol/mg AT). Macrophage infiltration and adipocyte size were measured using hematoxylin and eosin-stained AT sections and immunohistochemistry. Cr tended to reduce postpartum NEFA concentrations when compared with CON, PA, and Cr+PA. Likewise, Cr increased the percentage of large adipocytes (>9000 µm2) postpartum compared with other diets. In line with higher lipid content, Cr-fed cows had higher ex-vivo BASAL lipolysis at PP2 when compared with PA and Cr+PA. ISO induced higher lipolysis at PP1 and PP2 but it was not affected by Cr and PA. IN+ISO reduced lipolysis by 29.91 ± 11% in Cr compared with ISO. In contrast, IN+ISO did not affect ISO lipolysis in CON, PA, and Cr+PA. Plasma transferrin was reduced by Cr. At PP2, PA cows had 3.3-fold higher macrophage infiltration in SCAT when compared with CON and Cr. Plasma 9-HODE and 9-oxoODE were increased by Cr+PA. PA increased plasma 13-oxoODE and Cr increased the ratio of 13-HODE:13-oxoODE. PA increased 5-iso Prostaglandin F2α-VI. Our results demonstrate that supplementing Cr during the immediate postpartum enhances SCAT insulin sensitivity and lipid accumulation. Further studies should determine the effects and mechanisms of action of Cr and PA on AT lipogenesis, adipogenesis, and their impact on lactation performance.
    Keywords:  Adipose Tissue Inflammation; Chromium; Insulin Sensitivity; Palmitic acid
    DOI:  https://doi.org/10.3168/jds.2024-24972
  17. bioRxiv. 2024 Sep 25. pii: 2024.09.23.614489. [Epub ahead of print]
    An optimized pipeline for high-throughput bulk RNA-Seq deconvolution illustrates the impact of obesity and weight loss on cell composition of human adipose tissue.
    Cheehoon Ahn, Adeline Divoux, Mingqi Zhou, Marcus M Seldin, Lauren M Sparks, Katie L Whytock.
      Cellular heterogeneity of human adipose tissue, is linked to the pathophysiology of obesity and may impact the response to energy restriction and changes in fat mass. Here, we provide an optimized pipeline to estimate cellular composition in human abdominal subcutaneous adipose tissue (ASAT) from publicly available bulk RNA-Seq using signature profiles from our previously published full-length single nuclei (sn)RNA-Seq of the same depot. Individuals with obesity had greater proportions of macrophages and lower proportions of adipocyte sub-populations and vascular cells compared with lean individuals. Two months of diet-induced weight loss (DIWL) increased the estimated proportions of macrophages; however, two years of DIWL reduced the estimated proportions of macrophages, thereby suggesting a bi-phasic nature of cellular remodeling of ASAT during weight loss. Our optimized high-throughput pipeline facilitates the assessment of composition changes of highly characterized cell types in large numbers of ASAT samples using low-cost bulk RNA-Seq. Our data reveal novel changes in cellular heterogeneity and its association with cardiometabolic health in humans with obesity and following weight loss.
    Lead contact: Katie Whytock ( Katie.Whytock@adventhealth.com ).
    DOI:  https://doi.org/10.1101/2024.09.23.614489
  18. RNA Biol. 2024 Jan;21(1): 28-39
    Mitochondrial RNA maturation.
    Zofia M Chrzanowska-Lightowlers, Robert N Lightowlers.
      The vast majority of oxygen-utilizing eukaryotes need to express their own mitochondrial genome, mtDNA, to survive. In comparison to size of their nuclear genome, mtDNA is minimal, even in the most exceptional examples. Having evolved from bacteria in an endosymbiotic event, it might be expected that the process of mtDNA expression would be relatively simple. The aim of this short review is to illustrate just how wrong this assumption is. The production of functional mitochondrial RNA across species evolved in many directions. Organelles use a dizzying array of RNA processing, modifying, editing, splicing and maturation events that largely require the import of nuclear-encoded proteins from the cytosol. These processes are sometimes driven by the unusual behaviour of the mitochondrial genome from which the RNA is originally transcribed, but in many examples the complex processes that are essential for the production of functional RNA in the organelle, are fascinating and bewildering.
    Keywords:  Mitochondrial; maturation; messenger RNA; modifications; processing; translation
    DOI:  https://doi.org/10.1080/15476286.2024.2414157
  19. FASEB J. 2024 Oct 15. 38(19): e70071
    Overexpression of CPT1A disrupts the maintenance and regenerative function of muscle stem cells.
    Jiamin Qiu, Feng Yue, Kun Ho Kim, Xiyue Chen, Mennatallah A Khedr, Jingjuan Chen, Lijie Gu, Junxiao Ren, Christina R Ferreira, Jessica Ellis, Shihuan Kuang.
      The skeletal muscle satellite cells (SCs) mediate regeneration of myofibers upon injury. As they switch from maintenance (quiescence) to regeneration, their relative reliance on glucose and fatty acid metabolism alters. To explore the contribution of mitochondrial fatty acid oxidation (FAO) pathway to SCs and myogenesis, we examined the role of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO. CPT1A is highly expressed in quiescent SCs (QSCs) compared with activated and proliferating SCs, and its expression level decreases during myogenic differentiation. Myod1Cre-driven overexpression (OE) of Cpt1a in embryonic myoblasts (Cpt1aMTG) reduces muscle weight, grip strength, and contractile force without affecting treadmill endurance of adult mice. Adult Cpt1aMTG mice have reduced number of SC, impairing muscle regeneration and promoting lipid infiltration. Similarly, Pax7CreER-driven, tamoxifen-inducible Cpt1a-OE in QSCs of adult muscles (Cpt1aPTG) leads to depletion of SCs and compromises muscle regeneration. The reduced proliferation of Cpt1a-OE SCs is associated with elevated level of acyl-carnitine, and acyl-carnitine treatment impedes proliferation of wildtype SCs. These findings indicate that aberrant level of CPT1A elevates acyl-carnitine to impair the maintenance, proliferation and regenerative function of SCs.
    Keywords:  CPT1A; acyl‐carnitine; fatty acid oxidation; muscle regeneration; satellite cell
    DOI:  https://doi.org/10.1096/fj.202400947R
  20. bioRxiv. 2024 Sep 23. pii: 2024.09.23.614368. [Epub ahead of print]
    SGLT2 inhibitors protect against diabetic cardiomyopathy and atrial fibrillation through a CaMKII independent mechanism.
    Alex Severino, Oscar E Reyes-Gaido, Pauline Nguyen, Ahmed Elkarim, Elizabeth D Luczak, Olurotimi O Mesubi.
      Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) has been implicated as an important mediator of the increasingly evident cardioprotective benefits exerted by sodium- glucose transport protein 2 channel inhibitors (SGLT2i). However, the exact nature of the relationship between CaMKII and SGLT2i remains unclear. Here, we find that empagliflozin but not dapagliflozin attenuated susceptibility to atrial fibrillation (AF) in a type 2 diabetic (T2D) mouse model. However, both empagliflozin and dapagliflozin protected from diabetic cardiomyopathy in T2D mice. We then used real-time microscopy of neonatal rat ventricular cardiomyocytes (NRVMs) with the CaMKII biosensor - CaMKAR to demonstrate that direct inhibition of CaMKII is not essential for the effects of SGLT2i in these cells. Therefore, we conclude that the benefits of SGLT2i in heart disease likely occur through indirect modulation of CaMKII activity, or possibly through an alternative pathway altogether.
    DOI:  https://doi.org/10.1101/2024.09.23.614368
  21. J Adv Res. 2024 Oct 08. pii: S2090-1232(24)00437-5. [Epub ahead of print]
    Effect of mitochondrial translocator protein TSPO on LPS-induced cardiac dysfunction.
    Xingyue Li, Xiao Chen, Feng-Yuan Yang, Tingting Shu, Lintao Jiang, Bo He, Ming Tang, Xingbing Li, Dandong Fang, Pedro A Jose, Yu Han, Yongjian Yang, Chunyu Zeng.
       INTRODUCTION: Sepsis-induced cardiac dysfunction is one of the most serious complications of sepsis. The mitochondrial translocator protein (TSPO), a mitochondrial outer membrane protein, is widely used as a diagnostic marker of inflammation-related diseases and can also lead to the release of inflammatory components. However, whether TSPO has a therapeutic effect on sepsis-induced cardiac dysfunction is unclear.
    OBJECTIVES: The aim of this study is to investigate the involvement of TSPO in the pathogenesis of sepsis-induced cardiac dysfunction and elucidate its underlying mechanism, as well as develop therapeutic strategies targeting TSPO for the prevention and treatment of sepsis-induced cardiac dysfunction.
    METHODS: The sepsis-induced cardiac dysfunction model was established by intraperitoneal injection of lipopolysaccharide (LPS)in C57BL/6 mice (LPS-induced cardiac dysfunction, LICD). TSPO knockout mice were constructed,and the effects of TSPO was detected by survival rate, echocardiography, HE staining, mitochondrial electron microscopy, TUNEL staining. TSPO-binding proteins were identified by co-immunoprecipitation and mass spectrometry. The mechanisms underlying between TSPO and voltage-dependent anion channel (VDAC) was studied through western blot and immunofluorescence. Proteolysis-Targeting Chimeras (PROTAC) technology was used to construct TSPO-PROTAC molecules that can degrade TSPO.
    RESULTS: Our present study found that LPS increased cardiac TSPO expression. Knockout of TSPO in C57BL/6 mice with LICD attenuated the cardiac pathology, mitochondrial dysfunction, and apoptosis of cardiomyocytes and significantly improved cardiac function and survival rate. Co-immunoprecipitation and mass spectrometry identified VDAC as a TSPO binding protein.Down-regulation of TSPO reduced PKA-mediated VDAC phosphorylation and VDAC oligomerization, ameliorated mitochondrial function, and reduced cardiomyocyte apoptosis. The study has clinical translational potential, because administration of TSPO-PROTAC to degrade TSPO improved cardiac function in mice with LICD.
    CONCLUSION: This study elucidated the effect of TSPO in LICD, providing a new therapeutic strategy to down-regulate TSPO by administration of TSPO-PROTAC for the prevention and treatment of LICD.
    Keywords:  Mitochondrial function; PROTAC; Sepsis-induced cardiac dysfunction; TSPO; VDAC oligomerization
    DOI:  https://doi.org/10.1016/j.jare.2024.10.004
  22. Genetics. 2024 Oct 08. pii: iyae154. [Epub ahead of print]
    Evidence for a hydrogen sulfide-sensing E3 ligase in yeast.
    Zane Johnson, Yun Wang, Benjamin M Sutter, Benjamin P Tu.
      In yeast, control of sulfur amino acid metabolism relies upon Met4, a transcription factor that activates the expression of a network of enzymes responsible for the biosynthesis of cysteine and methionine. In times of sulfur abundance, the activity of Met4 is repressed via ubiquitination by the SCFMet30 E3 ubiquitin ligase, but the mechanism by which the F-box protein Met30 senses sulfur status to tune its E3 ligase activity remains unresolved. Herein, we show that Met30 responds to flux through the trans-sulfuration pathway to regulate the MET gene transcriptional program. In particular, Met30 is responsive to the biological gas hydrogen sulfide, which is sufficient to induce ubiquitination of Met4 in vivo. Additionally, we identify important cysteine residues in Met30's WD-40 repeat region that sense the availability of sulfur in the cell. Our findings reveal how SCFMet30 dynamically senses the flow of sulfur metabolites through the trans-sulfuration pathway to regulate the synthesis of these special amino acids.
    Keywords:  E3 ubiquitin ligase; amino acid; metabolism; nutrients; sensor; sulfur; yeast
    DOI:  https://doi.org/10.1093/genetics/iyae154
  23. J Cardiovasc Transl Res. 2024 Oct 10.
    Drp1 Promotes Macrophage M1 Polarization and Inflammatory Response in Autoimmune Myocarditis by Driving Mitochondrial Fission.
    Lin Lin, Jin Wei, Jiahong Xue, Gang Fan, Wenjing Zhu, Yanhe Zhu, Ruiyun Wu.
      Autoimmune myocarditis (AM) is characterized by an intricate inflammatory response within the myocardium. Dynamin-related protein 1 (Drp1), a pivotal modulator of mitochondrial fission, plays a role in the pathogenesis of various diseases. A myosin-induced experimental autoimmune myocarditis (EAM) mouse model was successfully established. Flow cytometry was employed to detect M1/M2-like macrophages. Mitochondrial fragmentation was assessed using Mito-Tracker Red CMXRos. Drp1 was upregulated and activated in EAM mice. Depletion of Drp1 was observed to mitigate inflammation, macrophage infiltration and M1 polarization within the cardiac tissue of EAM mice. In M1-like macrophages derived from the hearts of EAM mice, Drp1 was found to promote mitochondrial fission and diminish mitochondrial fusion. Furthermore, the depletion of Drp1 reduced the NF-κB-related pro-inflammatory response in EAM-associated M1-like macrophages. Drp1 drives mitochondrial fission in macrophages, driving their M1 polarization and the subsequent inflammatory response. Drp1 may represent an effective target for the prevention and treatment of AM.
    Keywords:  Autoimmune myocardioptis; Drp1; EAM mouse model; M1 polarization; Mitochondrial fission
    DOI:  https://doi.org/10.1007/s12265-024-10570-2
  24. J Agric Food Chem. 2024 Oct 09.
    Rab8a Is a Key Target That Melatonin Prevents Lipid Disorder from Atrazine.
    Tian-Ning Yang, Yu-Xiang Wang, Ping-An Jian, Xiang-Yu Ma, Yi-Fei Ren, Ning-Ning Huang, Xue-Nan Li, Jin-Long Li.
      Atrazine (ATZ), a widely used herbicide, disrupts mitochondrial function and lipid metabolism in the liver. Melatonin (MLT), a naturally synthesized hormone, combats mitochondrial dysfunction and alleviates lipid toxicity. However, the mechanisms behind ATZ-induced lipid metabolism toxicity and the protective effects of MLT remain unexplored. Mice were randomly assigned to four groups: control (Con), 5 mg/kg MLT, 170 mg/kg ATZ, and a cotreatment group receiving 170 mg/kg ATZ with 5 mg/kg MLT (ATZ+MLT). Additionally, we analyzed the effects of MLT and Rab8a on mRNA and proteins related to mitochondrial function and lipid metabolism disrupted by ATZ in AML12 cells. In conclusion, ATZ induced mitochondrial stress and disrupted fatty acid metabolism in mouse hepatocytes and AML12 cells. Exogenous MLT restores Rab8a levels, regulating fatty acid utilization in mitochondria and mitochondrial function. Notably, targeting Rab8a does not significantly affect mitochondrial function but prevents ATZ-induced lipid metabolism disorders in hepatocytes.
    Keywords:  Rab8a; atrazine; fatty acid; hepatocytes; melatonin
    DOI:  https://doi.org/10.1021/acs.jafc.4c07006
  25. Eur J Cell Biol. 2024 Oct 01. pii: S0171-9335(24)00077-3. [Epub ahead of print]103(4): 151460
    Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy.
    Hsiang-Ling Huang, Andrejus Suchenko, Giovanna Grandinetti, Mohan K Balasubramanian, Krishna Chinthalapudi, Sarah M Heissler.
      Cardiac muscle α-actin is a key protein of the thin filament in the muscle sarcomere that, together with myosin thick filaments, produce force and contraction important for normal heart function. Missense mutations in cardiac muscle α-actin can cause hypertrophic cardiomyopathy, a complex disorder of the heart characterized by hypercontractility at the molecular scale that leads to diverse clinical phenotypes. While the clinical aspects of hypertrophic cardiomyopathy have been extensively studied, the molecular mechanisms of missense mutations in cardiac muscle α-actin that cause the disease remain largely elusive. Here we used cryo-electron microscopy to reveal the structures of hypertrophic cardiomyopathy-associated actin mutations M305L and A331P in the filamentous state. We show that the mutations have subtle impacts on the overall architecture of the actin filament with mutation-specific changes in the nucleotide binding cleft active site, interprotomer interfaces, and local changes around the mutation site. This suggests that structural changes induced by M305L and A331P have implications for the positioning of the thin filament protein tropomyosin and the interaction with myosin motors. Overall, this study supports a structural model whereby altered interactions between thick and thin filament proteins contribute to disease mechanisms in hypertrophic cardiomyopathy.
    Keywords:  Actin; Cytoskeleton; Hypertrophic cardiomyopathy; Mutation; Myosin
    DOI:  https://doi.org/10.1016/j.ejcb.2024.151460
  26. Nutr Res. 2024 Sep 14. pii: S0271-5317(24)00122-2. [Epub ahead of print]131 135-146
    The high-fat diet and low-dose streptozotocin type-2 diabetes model induces hyperinsulinemia and insulin resistance in male but not female C57BL/6J mice.
    Kathryn C Racine, Lisard Iglesias-Carres, Jacob A Herring, Kristopher L Wieland, Peter N Ellsworth, Jeffery S Tessem, Mario G Ferruzzi, Colin D Kay, Andrew P Neilson.
      Translation of preclinical findings on the efficacy of dietary interventions for metabolic disease to human clinical studies is challenging due to the predominant use of male rodents in animal research. Our objective was to evaluate a combined high-fat (HF) diet and low-dose streptozotocin (STZ) model for induction of type-2 diabetes (T2D) in male and female C57BL/6J mice. We hypothesized that T2D biomarkers would differ significantly between sexes. Mice were administered either a low-fat (LF) diet (10% kcal from fat), or HF diet (60% kcal from fat) + STZ injections (30 mg/kg/d for 3 days). Both sexes gained weight and developed impaired postprandial oral glucose tolerance on the HF+STZ treatment compared to LF. Only male mice on HF + STZ developed fasting hyperglycemia, fasting hyperinsulinemia and insulin resistance, suggesting that the underlying causes of postprandial hyperglycemia differed between sexes. Principal component analysis of measures such as body weights, glucose and insulin concentrations indicated metabolic derangement for males only on HF+STZ treatment, while LF group males and both groups of females significantly overlapped. Based on our data, we accept our hypothesis that the combined high-fat diet and low-dose STZ model for T2D phenotypes differs significantly in its effect on mice based on sex. The HF diet + low-dose STZ model is not useful for studying insulin resistance in females. Other models are needed to model T2D, and study the effects of dietary interventions in this disease, in females. Sexual dimorphism remains a significant challenge for both preclinical and clinical research.
    Keywords:  Beta cells; Diabetes; High-fat diet; Insulin; Sexual dimorphism
    DOI:  https://doi.org/10.1016/j.nutres.2024.09.008
  27. Life Sci Alliance. 2024 Dec;pii: e202403038. [Epub ahead of print]7(12):
    Mitochondrial apolipoprotein MIC26 is a metabolic rheostat regulating central cellular fuel pathways.
    Melissa Damiecki, Ritam Naha, Yulia Schaumkessel, Philipp Westhoff, Nika Atanelov, Anja Stefanski, Patrick Petzsch, Kai Stühler, Karl Köhrer, Andreas Pm Weber, Ruchika Anand, Andreas S Reichert, Arun Kumar Kondadi.
      Mitochondria play central roles in metabolism and metabolic disorders such as type 2 diabetes. MIC26, a mitochondrial contact site and cristae organising system complex subunit, was linked to diabetes and modulation of lipid metabolism. Yet, the functional role of MIC26 in regulating metabolism under hyperglycemia is not understood. We used a multi-omics approach combined with functional assays using WT and MIC26 KO cells cultured in normoglycemia or hyperglycemia, mimicking altered nutrient availability. We show that MIC26 has an inhibitory role in glycolysis and cholesterol/lipid metabolism under normoglycemic conditions. Under hyperglycemia, this inhibitory role is reversed demonstrating that MIC26 is critical for metabolic adaptations. This is partially mediated by alterations of mitochondrial metabolite transporters. Furthermore, MIC26 deletion led to a major metabolic rewiring of glutamine use and oxidative phosphorylation. We propose that MIC26 acts as a metabolic "rheostat," that modulates mitochondrial metabolite exchange via regulating mitochondrial cristae, allowing cells to cope with nutrient overload.
    DOI:  https://doi.org/10.26508/lsa.202403038
  28. Heart Fail Rev. 2024 Oct 08.
    Pericardiotomy as a novel treatment for heart failure with preserved ejection fraction.
    Shunichi Doi, Barry A Borlaug.
      The pericardium plays an important role in modulating cardiac performance and hemodynamics in patients with heart failure with preserved ejection fraction (HFpEF). Pericardial constraint increases filling pressures in patients with HFpEF, particularly those with the obesity phenotype, atrial myopathy, right ventricular dysfunction, and tricuspid regurgitation. Preclinical and early stage clinical studies indicate that pericardiotomy may become a novel treatment for HFpEF. This review summarizes and discusses the pathophysiology of pericardial restraint and the possibility of pericardiotomy in HFpEF.
    Keywords:  Catheter intervention; Heart failure with preserved ejection fraction; Pericardiotomy; Pericardium
    DOI:  https://doi.org/10.1007/s10741-024-10451-5
  29. BMC Genomics. 2024 Oct 07. 25(1): 938
    Characteristics of gene expression in epicardial adipose tissue and subcutaneous adipose tissue in patients at risk for heart failure undergoing coronary artery bypass grafting.
    Christoffer Frisk, Mattias Ekström, Maria J Eriksson, Matthias Corbascio, Camilla Hage, Hans Persson, Cecilia Linde, Bengt Persson.
       BACKGROUND: Epicardial adipose tissue (EAT) surrounds the heart and is hypothesised to play a role in the development of heart failure (HF). In this study, we first investigated the differences in gene expression between epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) in patients undergoing elective coronary artery bypass graft (CABG) surgery (n = 21; 95% male). Secondly, we examined the association between EAT and SAT in patients at risk for HF stage A (n = 12) and in pre-HF patients, who show signs but not symptoms of HF, stage B (n = 9).
    RESULTS: The study confirmed a distinct separation between EAT and SAT. In EAT 17 clusters of genes were present, of which several novel gene modules are associated with characteristics of HF. Notably, seven gene modules showed significant correlation to measures of HF, such as end diastolic left ventricular posterior wall thickness, e'mean, deceleration time and BMI. One module was particularly distinct in EAT when compared to SAT, featuring key genes such as FLT4, SEMA3A, and PTX3, which are implicated in angiogenesis, inflammation regulation, and tissue repair, suggesting a unique role in EAT linked to left ventricular dysfunction. Genetic expression was compared in EAT across all pre-HF and normal phenotypes, revealing small genetic changes in the form of 18 differentially expressed genes in ACC/AHA Stage A vs. Stage B.
    CONCLUSIONS: The roles of subcutaneous and epicardial fat are clearly different. We highlight the gene expression difference in search of potential modifiers of HF progress. The true implications of our findings should be corroborated in other studies since HF ACC/AHA stage B patients are common and carry a considerable risk for progression to symptomatic HF.
    Keywords:  Bioinformatics; Epicardial adipose tissue; Gene expression; Heart failure; Weighted gene cluster
    DOI:  https://doi.org/10.1186/s12864-024-10851-9
  30. Commun Biol. 2024 Oct 05. 7(1): 1267
    Metabolic regulation of mitochondrial morphologies in pancreatic beta cells: coupling of bioenergetics and mitochondrial dynamics.
    Wen-Wei Tseng, Ching-Hsiang Chu, Yi-Ju Lee, Shirui Zhao, Chen Chang, Yi-Ping Ho, An-Chi Wei.
      Cellular bioenergetics and mitochondrial dynamics are crucial for the secretion of insulin by pancreatic beta cells in response to elevated levels of blood glucose. To elucidate the interactions between energy production and mitochondrial fission/fusion dynamics, we combine live-cell mitochondria imaging with biophysical-based modeling and graph-based network analysis. The aim is to determine the mechanism that regulates mitochondrial morphology and balances metabolic demands in pancreatic beta cells. A minimalistic differential equation-based model for beta cells is constructed that includes glycolysis, oxidative phosphorylation, calcium dynamics, and fission/fusion dynamics, with ATP synthase flux and proton leak flux as main regulators of mitochondrial dynamics. The model shows that mitochondrial fission occurs in response to hyperglycemia, starvation, ATP synthase inhibition, uncoupling, and diabetic conditions, in which the rate of proton leakage exceeds the rate of mitochondrial ATP synthesis. Under these metabolic challenges, the propensities of tip-to-tip fusion events simulated from the microscopy images of the mitochondrial networks are lower than those in the control group and prevent the formation of mitochondrial networks. The study provides a quantitative framework that couples bioenergetic regulation with mitochondrial dynamics, offering insights into how mitochondria adapt to metabolic challenges.
    DOI:  https://doi.org/10.1038/s42003-024-06955-3
  31. ESC Heart Fail. 2024 Oct 07.
    Commonalities of platelet dysfunction in heart failure with preserved ejection fraction and underlying comorbidities.
    Giorgia D'Italia, Blanche Schroen, Judith M E M Cosemans.
      Heart failure with preserved ejection fraction (HFpEF) is characterized by a lack of a specific targeted treatment and a complex, partially unexplored pathophysiology. Common comorbidities associated with HFpEF are hypertension, atrial fibrillation, obesity and diabetes. These comorbidities, combined with advanced age, play a crucial role in the initiation and development of the disease through the promotion of systemic inflammation and consequent changes in cardiac phenotype. In this context, we suggest platelets as important players due to their emerging role in vascular inflammation. This review provides an overview of the role of platelets in HFpEF and its associated comorbidities, including hypertension, atrial fibrillation, obesity and diabetes mellitus, as well as the impact of age and sex on platelet function. These major HFpEF-associated comorbidities present alterations in platelet behaviour and in features linked to platelet size, content and reactivity. The resulting dysfunctional platelets can contribute to further increase inflammation, oxidative stress and endothelial dysfunction, suggesting an active role of these cells in the initiation and progression of HFpEF. Recent evidence shows that reduced platelet count and elevated mean platelet volume are associated with worsening heart failure in HFpEF patients. However, the specific mechanisms by which platelets contribute to HFpEF development and progression are still largely unexplored, with only a few studies investigating platelet function in HFpEF. We discuss the limited yet significant body of research investigating platelet function in HFpEF, emphasizing the need for more comprehensive studies. Additionally, we explore the potential mechanisms through which platelets may influence HFpEF, such as their interactions with the vascular endothelium and the secretion of bioactive molecules like cytokines, chemokines and RNA molecules. These interactions and secretions may play a role in modulating vascular inflammation and contributing to the pathophysiological landscape of HFpEF. The review underscores the necessity for future research to elucidate the precise contributions of platelets to HFpEF, aiming to potentially identify novel therapeutic targets and improve patient outcomes. The evidence presented herein supports the hypothesis that platelets are not merely passive bystanders but active participants in the pathophysiology of HFpEF and its comorbidities.
    Keywords:  ageing; atrial fibrillation; diabetes mellitus; heart failure with preserved ejection fraction; hypertension; obesity; platelets; sex
    DOI:  https://doi.org/10.1002/ehf2.15090
  32. PLoS One. 2024 ;19(10): e0308908
    Mild burn amplifies the locomotive depression in demyelinated mice without muscle pathophysiological changes.
    Juquan Song, Amina Ei Ayadi, Victoria G Rontoyanni, Steven E Wolf.
       INTRODUCTION: Patients with mild burns take most accounts, however, the impact of mild burns is less known. Nerve destruction leads to muscle atrophy. We posit that even mild burn injury could worsen demyelinated nerves related to muscle pathophysiological impairment.
    METHODS: Young adult C57BL/6 (male, n = 60) mice were randomly fed with either a 0.2% cuprizone diet or a regular rodent diet for 4 weeks. At week 5, all mice were then grouped into mild scald burn with 10% TBSA and sham injury groups. Mice received animal behavior tests and in situ muscle isometric force measurement before euthanasia for tissue collection.
    RESULTS: Total horizontal ambulation and vertical activity were significantly reduced in mice with mild burn injury (p<0.05). Mice with the cuprizone diet had significantly less time to fall than those with the regular diet on day 7 after burn (p<0.05). No significant difference was found in gastrocnemius tissue weight among the groups, nor muscle isometric tensions (all p>0.05). The cuprizone diet increased the maximal phosphorylating respiration in mice muscle mitochondria (p<0.05). The muscle protein expressions of caspase 3, Fbx-32, and Murf1 significantly increased in mice with the cuprizone diet 3 days after burn (p<0.05). The signal expression of S100B significantly increased in mice with the cuprizone diet, and its expression was even greater on day 7 after burn injury. (p<0.05).
    CONCLUSION: The cuprizone diet-induced locomotion and cognitive disorders were amplified by the mild burn injury in mice, which is associated with muscle intracellular signal alterations. However, mild burn injury does not cause mouse muscle weight loss and function impairment. The potential risk of pre-existed neural impairment could be aware when patients encounter even small or mild burns.
    DOI:  https://doi.org/10.1371/journal.pone.0308908
  33. Cell Signal. 2024 Oct 08. pii: S0898-6568(24)00424-8. [Epub ahead of print] 111451
    Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation.
    Qingmiao Lu, Xiao Hu, Qing Hou, Long Yu, Kai Cao, Dafa Ding, Yibing Lu, Chunsun Dai.
      Podocyte senescence can cause persistent podocyte injury and albuminuria in diabetic kidney disease (DKD), but the mechanism remains obscure. In this study, podocyte senescence was confirmed by immunohistochemical staining in podocytes from patients and mice with DKD. Rheb1 knockout in podocytes aggravated podocyte senescence and injury in diabetic mice, but mitigated podocyte injury in mice with podocyte-specific mTORC1 activation induced by Tsc1 deletion. In cultured podocytes, Rheb1 knockdown remarkably accelerated podocyte senescence, independent of mTORC1. Mechanistically, PDH phosphorylation in podocyte was correlated with podocyte senescence in DKD patients. Rheb1 deficiency decreased ATP, mitochondrial membrane potential and partial components of respiratory chain complex, and enhanced ROS production and PDH phosphorylation, which indicates mitochondrial dysfunction, both in vitro and in vivo. Furthermore, Rheb1 interacted with Atp5f1c, and regulated its acetylation under a high-glucose condition. Together, Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation, in an mTORC1-independent manner, which provides experimental basis for the treatment of DKD.
    Keywords:  Diabetic kidney disease; Mitochondria; Podocyte senescence; Rheb1
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111451
  34. Nat Commun. 2024 Oct 09. 15(1): 8749
    Author Correction: Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice.
    Sara Ranjbarvaziri, Aliya Zeng, Iris Wu, Amara Greer-Short, Farshad Farshidfar, Ana Budan, Emma Xu, Reva Shenwai, Matthew Kozubov, Cindy Li, Melissa Van Pell, Francis Grafton, Charles E MacKay, Xiaomei Song, James R Priest, Gretchen Argast, Mohammad A Mandegar, Timothy Hoey, Jin Yang.
      
    DOI:  https://doi.org/10.1038/s41467-024-52831-3
  35. bioRxiv. 2024 Sep 26. pii: 2024.09.24.612951. [Epub ahead of print]
    SNRK regulates TGFβ levels in atria to control cardiac fibrosis.
    Karthikeyan Thirugnanam, Farhan Rizvi, Arshad Jahangir, Peter Homar, Fathima Shabnam, Sean P Palecek, Suresh N Kumar, Amy Pan, Xiaowen Bai, Hidekazu Sekine, Ramani Ramchandran.
      Atrial fibrosis is central to the pathology of heart failure (HF) and atrial fibrillation (AF). Identifying precise mechanisms underlying atrial fibrosis will provide effective strategies for clinical intervention. This study investigates a metabolic serine threonine kinase gene, sucrose non-fermenting related kinase (SNRK), that we previously reported to control cardiac metabolism and function. Conditional knockout of Snrk in mouse cardiomyocytes ( Snrk cmcKO) leads to atrial fibrosis and subsequently HF. The precise mechanism underlying cardiomyocyte SNRK-driven repression of fibrosis is not known. Here, using mouse, rat, and human tissues, we demonstrate that SNRK expression is high in atria, especially in atrial cardiomyocytes. SNRK expression correlates with lower levels of pro-fibrotic protein transforming growth factor-beta 1 (TGFβ1) in the atrial cardiomyocytes. In HL-1 adult immortalized mouse atrial cells, using siRNA approaches, we show that Snrk knockdown cells show more TGFβ1 secretion, which was also observed in heart lysates from Snrk cardiac-specific knockout mice in vivo. These effects were exacerbated upon infusion of Angiotensin II. Results from Snrk knockdown cardiomyocytes co-cultured with cardiac fibroblasts suggest that SNRK represses TGFβ1 signaling (Smad 2/3) in atrial CMs and prevents paracrine cardiac fibroblast activation (α-SMA marker). In conclusion, high SNRK expression in atria regulates cardiac homeostasis, by preventing the release of TGFβ1 secretion to block cardiac fibrosis. These studies will assist in developing heart chamber-specific fibrosis therapy for non-ischemic HF and AF.
    DOI:  https://doi.org/10.1101/2024.09.24.612951
  36. Cell Rep. 2024 Oct 10. pii: S2211-1247(24)01190-2. [Epub ahead of print]43(10): 114839
    Mitochondrial MOF regulates energy metabolism in heart failure via ATP5B hyperacetylation.
    Yuehuai Hu, Yongjia Zheng, Cui Liu, Yuyu You, Ying Wu, Panxia Wang, Yiyang Wu, Hongjun Ba, Jing Lu, Yanqiu Yuan, Peiqing Liu, Yang Mao.
      Lysine acetylation is a conserved post-translational modification involved in energy metabolism in mitochondria and heart function. This study investigates the role of mitochondria-localized lysine acetyltransferase MOF (males absent on the first) in heart failure (HF). We find that MOF is upregulated in mitochondria during HF, and overexpression of mitochondria-targeted MOF (mtMOF) in mouse models results in mitochondria dysfunction, cardiac remodeling, and HF. Furthermore, sirtuin 3 (SIRT3) knockout aggravates mtMOF-induced damages, underscoring the role of MOF-catalyzed hyperacetylation in HF. Quantitative lysine acetylome analysis identifies ATP5B as a substrate of MOF. We demonstrate that the acetylation of ATP5B at K201, co-regulated by MOF and SIRT3, impairs mitochondrial respiration and energy metabolism both in vitro and in vivo. These findings suggest that the role of MOF in HF could be attributed to its regulation of ATP5B acetylation. Overall, our results highlight the disruptive impact of mitochondrial MOF on cardiac function and emphasize the significance of enzyme-catalyzed acetylation in mitochondria.
    Keywords:  ATP5B; CP: Metabolism; CP: Molecular biology; KAT8; MOF; SIRT3; acetylation; heart failure; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2024.114839
  37. Apoptosis. 2024 Oct 11.
    Sirtuin 7 ameliorates cuproptosis, myocardial remodeling and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling.
    Yu-Fei Chen, Rui-Qiang Qi, Jia-Wei Song, Si-Yuan Wang, Zhao-Jie Dong, Yi-Hang Chen, Ying Liu, Xin-Yu Zhou, Jing Li, Xiao-Yan Liu, Jiu-Chang Zhong.
      Myocardial fibrosis is a typical pathological manifestation of hypertension. However, the exact role of sirtuin 7 (SIRT7) in myocardial remodeling remains largely unclear. Here, spontaneously hypertensive rats (SHRs) and angiotensin (Ang) II-induced hypertensive mice were pretreated with recombinant adeno-associated virus (rAAV)-SIRT7, copper chelator tetrathiomolybdate (TTM) or copper ionophore elesclomol, respectively. Compared with normotensive controls, reduced SIRT7 expression and augmented cuproptosis were observed in hearts of hypertensive rats and mice with decreased FDX1 levels and increased HSP70 levels. Notably, intervention with rAAV-SIRT7 and TTM strikingly prevented DLAT oligomers aggregation, and elevated ATP7A and TOM20 expressions, contributing to the alleviation of cuproptosis, mitochondrial injury, myocardial remodeling and heart dysfunction in spontaneously hypertensive rats and Ang II-induced hypertensive mice. In cultured rat primary cardiac fibroblasts (CFs), rhSIRT7 alleviated CuCl2, Ang II or elesclomol-induced cuproptosis and fibroblast activation by blunting DLAT oligomers accumulation and downregulating α-SMA expression. Additionally, conditioned medium from rhSIRT7-pretreated CFs remarkably mitigated cellular hypertrophy and mitochondrial impairments of neonatal rat cardiomyocytes, as well as cell migration and polarization of RAW 264.7 macrophages. Importantly, verteporfin reduced CuCl2-induced cuproptosis, mitochondrial injury and fibrotic activation in CFs. Knockdown of ATP7A with si-ATP7A blocked cellular protective effects of rhSIRT7 and verteporfin in CFs. In conclusion, SIRT7 attenuates cuproptosis, myocardial fibrosis and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling. Targeting SIRT7 is of vital importance for developing therapeutic strategies in hypertension and hypertensive heart disorders.
    Keywords:  Cardiac remodeling; Cuproptosis; Hypertension; Mitochondrial impairment; Sirtuin 7
    DOI:  https://doi.org/10.1007/s10495-024-02021-9
  38. bioRxiv. 2024 Sep 24. pii: 2024.09.24.614765. [Epub ahead of print]
    Adipocyte metabolic state regulates glial phagocytic function.
    Mroj Alassaf, Akhila Rajan.
      Obesity and type 2 diabetes are well-established risk factors for neurodegenerative disorders 1-4 , yet the underlying mechanisms remain poorly understood. The adipocyte-brain axis is crucial for brain function, as adipocytes secrete signaling molecules, including lipids and adipokines, that impinge on neural circuits to regulate feeding and energy expenditure 5 . Disruptions in the adipocyte-brain axis are associated with neurodegenerative conditions 6 , but the causal links are not fully understood. Neural debris accumulates with age and injury, and glial phagocytic function is crucial for clearing this debris and maintaining a healthy brain microenvironment 7-9 . Using adult Drosophila, we investigate how adipocyte metabolism influences glial phagocytic activity in the brain. We demonstrate that a prolonged obesogenic diet increases adipocyte fatty acid oxidation and ketogenesis. Genetic manipulations that mimic obesogenic diet-induced changes in adipocyte lipid and mitochondrial metabolism unexpectedly reduce the expression of the phagocytic receptor Draper in Drosophila microglia-like cells in the brain. We identify Apolpp -the Drosophila equivalent of human apolipoprotein B (ApoB)-as a critical adipocyte-derived signal that regulates glial phagocytosis. Additionally, we show that Lipoprotein Receptor 1 (LpR1), the LDL receptor on phagocytic glia, is required for glial capacity to clear injury-induced neuronal debris. Our findings establish that adipocyte-brain lipoprotein signaling regulates glial phagocytic function, revealing a novel pathway that links adipocyte metabolic disorders with neurodegeneration.
    Highlights: Prolonged exposure to an obesogenic diet result in a starvation-like metabolic response in adipose tissue.Obesogenic diet-induced mitochondrial lipid catabolism in adipose tissue impacts glial phagocytic function.Adipocyte ApoB is a novel regulator of glial phagocytic function.LpR1, on ensheathing glia, is required for glial response to axonal injury.
    Graphical abstract:
    DOI:  https://doi.org/10.1101/2024.09.24.614765
  39. iScience. 2024 Oct 18. 27(10): 110913
    Sorafenib induces cachexia by impeding transcriptional signaling of the SET1/MLL complex on muscle-specific genes.
    Bushra Khan, Chiara Lanzuolo, Valentina Rosti, Philina Santarelli, Andreas Pich, Theresia Kraft, Mamta Amrute-Nayak, Arnab Nayak.
      Chemotherapeutics used in cancer therapy are often linked to muscle wasting or cachexia. Insights into the molecular basis of chemotherapy-induced cachexia is essential to improve treatment strategies. Here, we demonstrated that Sorafenib-tyrosine kinase inhibitor (TKI) class of chemotherapeutic agents-induced cachexia. System-wide analyses revealed that Sorafenib alters the global transcriptional program and proteostasis in muscle cells. Mechanistically, Sorafenib treatment reduced active epigenetic mark H3K4 methylation on distinct muscle-specific genes by impeding chromatin association of SET1A-catalytic component of the SET1/MLL histone methyltransferase complex. This mechanism favored transcriptional disorientation that led to disrupted sarcomere assembly, calcium homeostasis and mitochondrial respiration. Consequently, the contractile ability of muscle cells was severely compromised. Interestingly, the other prominent TKIs Nilotinib and Imatinib did not exert similar effects on muscle cell physiology. Collectively, we identified an unanticipated transcriptional mechanism underlying Sorafenib-induced cachexia. Our findings hold the potential to strategize therapy regimens to minimize chemotherapy-induced cachexia.
    Keywords:  Health sciences; Internal medicine; Medical specialty; Medicine; Oncology
    DOI:  https://doi.org/10.1016/j.isci.2024.110913
  40. Int J Cardiol. 2024 Oct 09. pii: S0167-5273(24)01253-1. [Epub ahead of print] 132631
    Drug-induced increase in dispersion of ventricular repolarization in patients with heart failure with preserved ejection fraction.
    Fatimah Alhurayri, Heather A Jaynes, Brian R Overholser, Kevin M Sowinski, Richard J Kovacs, James E Tisdale.
       BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with enhanced response to drug-induced QT interval lengthening. We determined the influence of HFpEF on drug-induced lengthening of dispersion of repolarization, a measure of proarrhythmic risk.
    METHODS: We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched controls without HF. 12‑lead electrocardiograms were obtained prior to, during, and serially for 8 h post-ibutilide. Tpeak-Tend, a measure of dispersion of ventricular repolarization, and heart rate-corrected J-Tpeak, representing early repolarization, were measured by an investigator blinded to study groups.
    RESULTS: Baseline (pre-ibutilide) Tpeak-Tend and J-Tpeakc were not significantly different in the HFpEF and control groups. Maximum Tpeak-Tend was longer in the HFpEF group than in the control group (85 ± 10 vs 73 ± 8 ms, p = 0.01). Additionally, % change from baseline in Tpeak-Tend was longer in the HFpEF group [median (IQR) 17 (11) vs 8 (3)%, p = 0.03]. The area under the effect curve (AUEC) for Tpeak-Tend was also larger in the HFpEF group (600 ± 42 vs. 543 ± 49 ms•hr, p = 0.03). Maximum J-Tpeakc, % change from baseline in J-Tpeakc and AUEC for J-Tpeakc in the two groups were not significantly different.
    CONCLUSION: HFpEF is associated with enhanced response to drug-induced increases in dispersion of repolarization.
    Keywords:  Dispersion of repolarization; Heart failure with preserved ejection fraction; J-Tpeakc; Tpeak-tend
    DOI:  https://doi.org/10.1016/j.ijcard.2024.132631
  41. J Pharm Technol. 2024 Oct;40(5): 223-229
    Utilization of Glucagon-Like Peptide-1 Receptor Agonist and Dipeptidyl Peptidase-4 Inhibitors at the Veterans Health Administration.
    Aditya Krishnan, Sowmya K Suryanarayanan, Ishak A Mansi.
      Background: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) are incretin-based therapies commonly used in the management of type 2 diabetes. Public interest in GLP-1RA soared after discovering their ability to lower body weight in patients without diabetes. Objective: To examine recent trends in usage of GLP-1RA and DPP-4i in the Veterans Health Administration (VHA). Methods: We extracted GLP-1RA and DPP-4i use from the national VHA Corporate Data Workhouse (CDW) between fiscal years (FYs) 2011 to 2021, which encompass medication class, name, dosage, date of filled prescription, and patients' characteristics. Results: A total of 3 037 006 prescriptions for DPP-4i and 2 183 294 prescriptions for GLP-1RA were filled during FY 2011 to 2021. More patients were prescribed DPP-4i (273 002 subjects) compared with GLP-1RA (157 209 subjects) from FY 2011 to 2021. Overall, 10.7% used DPP-4i for 90 days or less in comparison to 9.1% in GLP-1RA (P < 0.001). The proportion of patients prescribed DPP-4i who were 75 years of age or older was relatively stable over the years 2011 to 2021 (mean proportion = 19%). However, the proportion of patients who were 75 years of age or older prescribed GLP-1RA increased from 4.2% in 2011 to 16.9% in 2021. Conclusions: Incretin-based therapies have become a well-established class of drugs within the VHA. Even though DPP-4i usage in older adults has remained stable over the past 10 years, prescriptions for GLP-1RA in older adults have increased multifold over the last few years, which might be attributed to recent trial evidence showing benefit in cardiovascular outcomes and weight reduction.
    Keywords:  Veterans Health Administration; dipeptidyl peptidase-4 inhibitors; glucagon-like peptide-1 receptor agonist; type 2 diabetes
    DOI:  https://doi.org/10.1177/87551225241266773
  42. Front Endocrinol (Lausanne). 2024 ;15 1390778
    Adipose tissue insulin resistance in young Japanese women is associated with metabolic abnormalities and dehydroepiandrosterone-sulfate.
    Motonori Sato, Yoshifumi Tamura, Hideyoshi Kaga, Nozomu Yamasaki, Satoshi Kadowaki, Daisuke Sugimoto, Takashi Nakagata, Yuki Someya, Yuya Nishida, Ryuzo Kawamori, Hirotaka Watada.
       Objective: The proportion of young Japanese women who are underweight is exceptionally high. We previously showed that the prevalence of impaired glucose tolerance (IGT) was high in underweight young Japanese women, and that IGT was characterized by high free fatty acid levels and adipose tissue insulin resistance (ATIR). As the next step, this study aimed to explore factors associated with elevated ATIR in this population.
    Participants: Ninety-eight young, healthy, underweight women participated in this study.
    Design: To investigate the relationship between ATIR and metabolic parameters, participants were divided into three groups (Low, Medium, and High) according to ATIR level. Body composition examination, oral glucose tolerance testing, and blood biochemical analysis were performed; Adipo-IR and the Matsuda index were used as indices of ATIR and systemic insulin sensitivity, respectively.
    Results: Participants in the High ATIR group had the highest prevalence of IGT (25%), and significantly higher body fat percentage, whole-body insulin resistance, and levels of insulin-like growth factor-1 and dehydroepiandrosterone sulfate (DHEA-S) than the other two groups. They were also significantly younger and had higher systolic blood pressure than the Low ATIR group. Multiple regression analysis showed that DHEA-S, which is known to enhance lipolysis in adipose tissue, was an independent correlate of ATIR.
    Conclusions: Underweight Japanese women with high ATIR had impaired metabolism, a higher prevalence of IGT, higher systemic insulin resistance, and higher systolic blood pressure. DHEA-S was a determinant of high ATIR levels.
    Keywords:  adipose tissue insulin resistance; dehydroepiandrosterone-sulfate; impaired glucose tolerance; metabolic abnormality; underweight young women
    DOI:  https://doi.org/10.3389/fendo.2024.1390778
  43. Sports Med. 2024 Oct 10.
    Effects of Exercise Training on Mitochondrial and Capillary Growth in Human Skeletal Muscle: A Systematic Review and Meta-Regression.
    Knut Sindre Mølmen, Nicki Winfield Almquist, Øyvind Skattebo.
       BACKGROUND: Skeletal muscle mitochondria and capillaries are crucial for aerobic fitness, and suppressed levels are associated with chronic and age-related diseases. Currently, evidence-based exercise training recommendations to enhance these characteristics are limited. It is essential to explore how factors, such as fitness level, age, sex, and disease affect mitochondrial and capillary adaptations to different exercise stimuli.
    OBJECTIVES: The main aim of this study was to compare the effects of low- or moderate intensity continuous endurance training (ET), high-intensity interval or continuous training (HIT), and sprint interval training (SIT) on changes in skeletal muscle mitochondrial content and capillarization. Secondarily, the effects on maximal oxygen consumption (VO2max), muscle fiber cross-sectional area, and fiber type proportion were investigated.
    METHODS: A systematic literature search was conducted in PubMed, Web of Science, and SPORTDiscus databases, with no data restrictions, up to 2 February 2022. Exercise training intervention studies of ET, HIT, and SIT were included if they had baseline and follow-up measures of at least one marker of mitochondrial content or capillarization. In total, data from 5973 participants in 353 and 131 research articles were included for the mitochondrial and capillary quantitative synthesis of this review, respectively. Additionally, measures of VO2max, muscle fiber cross-sectional area, and fiber type proportion were extracted from these studies.
    RESULTS: After adjusting for relevant covariates, such as training frequency, number of intervention weeks, and initial fitness level, percentage increases in mitochondrial content in response to exercise training increased to a similar extent with ET (23 ± 5%), HIT (27 ± 5%), and SIT (27 ± 7%) (P > 0.138), and were not influenced by age, sex, menopause, disease, or the amount of muscle mass engaged. Higher training frequencies (6 > 4 > 2 sessions/week) were associated with larger increases in mitochondrial content. Per total hour of exercise, SIT was ~ 2.3 times more efficient in increasing mitochondrial content than HIT and ~ 3.9 times more efficient than ET, while HIT was ~ 1.7 times more efficient than ET. Capillaries per fiber increased similarly with ET (15 ± 3%), HIT (13 ± 4%) and SIT (10 ± 11%) (P = 0.556) after adjustments for number of intervention weeks and initial fitness level. Capillaries per mm2 only increased after ET (13 ± 3%) and HIT (7 ± 4%), with increases being larger after ET compared with HIT and SIT (P < 0.05). This difference coincided with increases in fiber cross-sectional area after ET (6.5 ± 3.5%), HIT (8.9 ± 4.9%), and SIT (11.9 ± 15.1%). Gains in capillarization occurred primarily in the early stages of training (< 4 weeks) and were only observed in untrained to moderately trained participants. The proportion of type I muscle fibers remained unaltered by exercise training (P > 0.116), but ET and SIT exhibited opposing effects (P = 0.041). VO2max increased similarly with ET, HIT, and SIT, although HIT showed a tendency for greater improvement compared with both ET and SIT (P = 0.082), while SIT displayed the largest increase per hour of exercise. Higher training frequencies (6 > 4 > 2 sessions/week) were associated with larger increases in VO2max. Women displayed greater percentage gains in VO2max compared with men (P = 0.008). Generally, lower initial fitness levels were associated with greater percentage improvements in mitochondrial content, capillarization, and VO2max. SIT was particularly effective in improving mitochondrial content and VO2max in the early stages of training, while ET and HIT showed slower but steady improvements over a greater number of training weeks.
    CONCLUSIONS: The magnitude of change in mitochondrial content, capillarization, and VO2max to exercise training is largely determined by the initial fitness level, with greater changes observed in individuals with lower initial fitness. The ability to adapt to exercise training is maintained throughout life, irrespective of sex and presence of disease. While training load (volume × intensity) is a suitable predictor of changes in mitochondrial content and VO2max, this relationship is less clear for capillary adaptations.
    DOI:  https://doi.org/10.1007/s40279-024-02120-2
  44. J Card Fail. 2024 Oct 03. pii: S1071-9164(24)00420-2. [Epub ahead of print]
    FINEARTS Restoration: Revisiting the Role of Steroidal Mineralocorticoid Receptor Antagonists in Heart Failure with Mildly-Reduced or Preserved Ejection Fraction Following FINEARTS-HF.
    Ricky D Turgeon, Craig J Beavers.
      
    DOI:  https://doi.org/10.1016/j.cardfail.2024.09.011
  45. Heliyon. 2024 Sep 30. 10(18): e38018
    Crosstalk between macrophages and immunometabolism and their potential roles in tissue repair and regeneration.
    Hongbo Ma, Limei Gao, Rong Chang, Lihong Zhai, Yanli Zhao.
      Immune metabolism is a result of many specific metabolic reactions, such as glycolysis, the tricarboxylic acid (TCA) pathway, the pentose phosphate pathway (PPP), mitochondrial oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), fatty acid biosynthesis (FAs) and amino acid pathways, which promote cell proliferation and maintenance with structural and pathological energy to regulate cellular signaling. The metabolism of macrophages produces many metabolic intermediates that play important regulatory roles in tissue repair and regeneration. The metabolic activity of proinflammatory macrophages (M1) mainly depends on glycolysis and the TCA cycle system, but anti-inflammatory macrophages (M2) have intact functions of the TCA cycle, which enhances FAO and is dependent on OXPHOS. However, the metabolic mechanisms of macrophages in tissue repair and regeneration have not been well investigated. Thus, we review how three main metabolic mechanisms of macrophages, glucose metabolism, lipid metabolism, and amino acid metabolism, regulate tissue repair and regeneration.
    Keywords:  Amino acid metabolism; Glucose metabolism; Lipid metabolism; Macrophages; Tissue repair and regeneration
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e38018
  46. Cell Struct Funct. 2024 Oct 10.
    The expression of the formin Fhod3 in mouse tongue striated muscle.
    Hikaru Nakagawa, Yohko Kage, Ayako Miura, Hikmawan Wahyu Sulistomo, Sho Matsuyama, Yoshihiro Yamashita, Ryu Takeya.
      The sarcomere is the contractile unit of striated muscle and is composed of actin and myosin filaments. There is increasing evidence to support that actin assembly mediated by Fhod3, a member of the formin family of proteins, is critical for sarcomere formation and maintenance in cardiac muscle. Fhod3, which is abundantly expressed in the heart, localizes to the center of sarcomeres and contributes to the regulation of the cardiac function, as evidenced by the fact that mutations in Fhod3 cause cardiomyopathy. However, the role of Fhod3 in skeletal muscle, another type of striated muscle, is unclear. We herein show that Fhod3 is expressed in the tongue at both mRNA and protein levels, although in smaller amounts than in the heart. To determine the physiological role of Fhod3 expressed in the tongue, we generated embryos lacking Fhod3 in the tongue. The tongue tissue of the Fhod3-depleted embryos did not show any significant structural defects, suggesting that Fhod3 is dispensable for normal development of the mouse tongue. Unexpectedly, the immunostaining analysis revealed the absence of specific sarcomeric signals for Fhod3 in the wild-type tongue when compared to the Fhod3-depleted tongue as a negative control, despite the use of antibodies that had previously been validated by immunostaining of heart tissues. Taken together, although Fhod3 protein is expressed at a significant level in the tongue, Fhod3 in the tongue does not appear to exhibit the same sarcomeric pattern as observed in the heart, suggesting a different role for Fhod3 in the tongue muscles.Key words: actin, formin, sarcomere, striated muscle.
    Keywords:  actin; formin; sarcomere; striated muscle
    DOI:  https://doi.org/10.1247/csf.24044
  47. Int J Nanomedicine. 2024 ;19 10077-10095
    Cold Exposure Alleviates T2DM Through Plasma-Derived Extracellular Vesicles.
    Fu-Xing-Zi Li, Feng Xu, Chang-Chun Li, Li-Min Lei, Su-Kang Shan, Ming-Hui Zheng, Xiao Lin, Bei Guo, Ke-Xin Tang, Jia-Yue Duan, Yun-Yun Wu, Ye-Chi Cao, Jun-Jie Liu, Ling-Qing Yuan.
       Purpose: Anecdotal reports have praised the benefits of cold exposure, exemplified by activities like winter swimming and cold water immersion. Cold exposure has garnered acclaim for its potential to confer benefits and potentially alleviate diabetes. We posited that systemic cold temperature (CT, 4-8°C) likely influences the organism's blood components through ambient temperature, prompting our investigation into the effects of chronic cold exposure on type 2 diabetic (T2DM) mice and our initial exploration of how cold exposure mitigates the incidence of T2DM.
    Methods: The effects of CT (4-8°C) or room temperature (RT, 22-25°C) on T2DM mice were investigated. Mice blood and organ specimens were collected for fully automated biochemical testing, ELISA, HE staining, immunohistochemistry, and immunofluorescence. Glucose uptake was assessed using flow cytometry with 2-NBDG. Changes in potential signaling pathways such as protein kinase B (AKT), phosphorylated AKT (p-AKT), insulin receptor substrates 1 (IRS1), and phosphorylated IRS1 (p-IRS1) were evaluated by Western blot.
    Results: CT or CT mice plasma-derived extracellular vesicles (CT-EVs) remarkably reduced blood glucose levels and improved insulin sensitivity in T2DM mice. This treatment enhanced glucose metabolism, systemic insulin sensitivity, and insulin secretion function while promoting glycogen accumulation in the liver and muscle. Additionally, CT-EVs treatment protected against the streptozocin (STZ)-induced destruction of islets in T2DM mice by inhibiting β-cell apoptosis. CT-EVs also shielded islets from destruction and increased the expression of p-IRS1 and p-AKT in adipocytes and hepatocytes. In vitro experiments further confirmed its pro-insulin sensitivity effect.
    Conclusion: Our data indicate that cold exposure may have a potentially beneficial effect on the development of T2DM, mainly through the anti-diabetic effect of plasma-derived EVs released during cold stimulation. This phenomenon could significantly contribute to understanding the lower prevalence of diabetes in colder regions.
    Keywords:  cold exposure; insulin sensitivity; plasma-derived extracellular vesicles; type 2 diabetes; β‑cell destruction
    DOI:  https://doi.org/10.2147/IJN.S441847
  48. Neurobiol Sleep Circadian Rhythms. 2024 Nov;17 100106
    Synergy between time-restricted feeding and time-restricted running is necessary to shift the muscle clock in male wistar rats.
    Ayano Shiba, Paul de Goede, Roberta Tandari, Ewout Foppen, Nikita L Korpel, Tom V Coopmans, Tom P Hellings, Merel W Jansen, Annelou Ruitenberg, Wayne I G R Ritsema, Chun-Xia Yi, Joram D Mul, Dirk Jan Stenvers, Andries Kalsbeek.
      Circadian disruption is an important factor driving the current-day high prevalence of obesity and type-2 diabetes. While the impact of incorrect timing of caloric intake on circadian disruption is widely acknowlegded, the contribution of incorrect timing of physical activity remains relatively understudied. Here, we modeled the incorrect timing of physical activity in nightshift workers in male Wistar rats, by restricting running wheel access to the innate inactive (light) phase (LR). Controls included no wheel access (NR); access only during the innate active (dark) period (DR); or unrestricted (ad libitum) access (ALR). LR did not shift the phase of the muscle or liver clock, but dampened the muscle clock amplitude. As our previous study demonstrated that light-phase restricted feeding did shift the liver clock, but made the muscle clock arrhythmic, we next combined the time restriction of wheel and food access to either the light phase (LRLF) or dark phase (DRDF). LRLF produced a ∼12 h shift in the majority of clock gene rhythms in both skeletal muscle and liver. On the other hand, DRDF was most effective in reducing body weight and the accumulation of fat mass. Therefore, in order to shift the muscle clock in male Wistar rats, synergy between the timing of feeding and physical activity is necessary. These findings may contribute to further improve the design of lifestyle strategies that try to limit metabolic misalignment caused by circadian disruption.
    Keywords:  Circadian misalignment; Energy metabolism; Liver; Muscle; Time restriction; Wheel running
    DOI:  https://doi.org/10.1016/j.nbscr.2024.100106
  49. Lancet Diabetes Endocrinol. 2024 Oct 03. pii: S2213-8587(24)00221-3. [Epub ahead of print]
    Association of BMI, lipid-lowering medication, and age with prevalence of type 2 diabetes in adults with heterozygous familial hypercholesterolaemia: a worldwide cross-sectional study.
    European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (EAS FHSC)
       BACKGROUND: Statins are the cornerstone treatment for patients with heterozygous familial hypercholesterolaemia but research suggests it could increase the risk of type 2 diabetes in the general population. A low prevalence of type 2 diabetes was reported in some familial hypercholesterolaemia cohorts, raising the question of whether these patients are protected against type 2 diabetes. Obesity is a well known risk factor for the development of type 2 diabetes. We aimed to investigate the associations of known key determinants of type 2 diabetes with its prevalence in people with heterozygous familial hypercholesterolaemia.
    METHODS: This worldwide cross-sectional study used individual-level data from the EAS FHSC registry and included adults older than 18 years with a clinical or genetic diagnosis of heterozygous familial hypercholesterolaemia who had data available on age, BMI, and diabetes status. Those with known or suspected homozygous familial hypercholesterolaemia and type 1 diabetes were excluded. The main outcome was prevalence of type 2 diabetes overall and by WHO region, and in relation to obesity (BMI ≥30·0 kg/m2) and lipid-lowering medication as predictors. The study population was divided into 12 risk categories based on age (tertiles), obesity, and receiving statins, and the risk of type 2 diabetes was investigated using logistic regression.
    FINDINGS: Among 46 683 adults with individual-level data in the FHSC registry, 24 784 with heterozygous familial hypercholesterolaemia were included in the analysis from 44 countries. 19 818 (80%) had a genetically confirmed diagnosis of heterozygous familial hypercholesterolaemia. Type 2 diabetes prevalence in the total population was 5·7% (1415 of 24 784), with 4·1% (817 of 19 818) in the genetically diagnosed cohort. Higher prevalence of type 2 diabetes was observed in the Eastern Mediterranean (58 [29·9%] of 194), South-East Asia and Western Pacific (214 [12·0%] of 1785), and the Americas (166 [8·5%] of 1955) than in Europe (excluding the Netherlands; 527 [8·0%] of 6579). Advancing age, a higher BMI category (obesity and overweight), and use of lipid-lowering medication were associated with a higher risk of type 2 diabetes, independent of sex and LDL cholesterol. Among the 12 risk categories, the probability of developing type 2 diabetes was higher in people in the highest risk category (aged 55-98 years, with obesity, and receiving statins; OR 74·42 [95% CI 47·04-117·73]) than in those in the lowest risk category (aged 18-38 years, without obesity, and not receiving statins). Those who did not have obesity, even if they were in the upper age tertile and receiving statins, had lower risk of type 2 diabetes (OR 24·42 [15·57-38·31]). The corresponding results in the genetically diagnosed cohort were OR 65·04 (40·67-104·02) for those with obesity in the highest risk category and OR 20·07 (12·73-31·65) for those without obesity.
    INTERPRETATION: Adults with heterozygous familial hypercholesterolaemia in most WHO regions have a higher type 2 diabetes prevalence than in Europe. Obesity markedly increases the risk of diabetes associated with age and use of statins in these patients. Our results suggest that heterozygous familial hypercholesterolaemia does not protect against type 2 diabetes, hence managing obesity is essential to reduce type 2 diabetes in this patient population.
    FUNDING: Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi-Sankyo, and Regeneron.
    DOI:  https://doi.org/10.1016/S2213-8587(24)00221-3
  50. Life Sci. 2024 Oct 05. pii: S0024-3205(24)00686-6. [Epub ahead of print]357 123096
    Hypoxanthine ameliorates diet-induced insulin resistance by improving hepatic lipid metabolism and gluconeogenesis via AMPK/mTOR/PPARα pathway.
    Sizhe Huang, Hengmiao Liang, Yuting Chen, Ce Liu, Piao Luo, Huijun Wang, Qingfeng Du.
       AIM: Insulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism.
    METHODS: We utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism.
    KEY FINDINGS: Hx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway.
    SIGNIFICANCE: This study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications.
    Keywords:  AMP-activated protein kinase; Gluconeogenesis; Hypoxanthine; Insulin resistance; Lipid metabolism
    DOI:  https://doi.org/10.1016/j.lfs.2024.123096
  51. Redox Biol. 2024 Oct 04. pii: S2213-2317(24)00357-4. [Epub ahead of print]77 103379
    Regulation of cardiovascular diseases by histone deacetylases and NADPH oxidases.
    Hui Yan, Yidan Yin, Yichen Zhou, Zhanghang Li, Yuxing Li, Lingxuan Ren, Jiazheng Wen, Weirong Wang.
      Histone deacetylases (HDACs) play critical roles in cardiovascular diseases (CVDs). In addition, reactive oxygen species (ROS) produced by NADPH oxidases (NOXs) exert damaging effects due to oxidative stress on heart and blood vessels. Although NOX-dependent ROS production is implicated in pathogenesis, the relationship between HDACs and NOXs in CVDs remains to be elucidated. Here, we present an overview of the regulatory effects and interconnected signaling pathways of HDACs and NOXs in CVDs. Improved insights into these relationships will facilitate the discovery of novel therapeutic agents that target HDACs, oxidase stress pathways, and the interactions between these systems which may be highly effective in the prevention and treatment of cardiovascular disorders.
    Keywords:  Cardiovascular diseases; Histone deacetylases; NADPH oxidases; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.redox.2024.103379
  52. Cardiovasc Res. 2024 Oct 07. pii: cvae210. [Epub ahead of print]
    Fibroblast-specific TGF-β signaling mediates cardiac dysfunction, fibrosis, and hypertrophy in obese diabetic mice.
    Izabela Tuleta, Anis Hanna, Claudio Humeres, Jennifer T Aguilan, Simone Sidoli, Fenglan Zhu, Nikolaos G Frangogiannis.
       AIMS: Transforming growth factor (TGF)-β is up-regulated in the diabetic myocardium and may mediate fibroblast activation. We aimed at examining the role of TGF-β-induced fibroblast activation in the pathogenesis of diabetic cardiomyopathy.
    METHODS AND RESULTS: We generated lean and obese db/db mice with fibroblast-specific loss of TbR2, the Type 2 receptor-mediating signaling through all three TGF-β isoforms, and mice with fibroblast-specific Smad3 disruption. Systolic and diastolic function, myocardial fibrosis, and hypertrophy were assessed. Transcriptomic studies and in vitro experiments were used to dissect mechanisms of fibroblast activation. Fibroblast-specific TbR2 loss attenuated systolic and diastolic dysfunction in db/db mice. The protective effects of fibroblast TbR2 loss in db/db mice were associated with attenuated fibrosis and reduced cardiomyocyte hypertrophy, suggesting that in addition to their role in fibrous tissue deposition, TGF-β-stimulated fibroblasts may also exert paracrine actions on cardiomyocytes. Fibroblast-specific Smad3 loss phenocopied the protective effects of fibroblast TbR2 loss in db/db mice. Db/db fibroblasts had increased expression of genes associated with oxidative response (such as Fmo2, encoding flavin-containing monooxygenase 2), matricellular genes (such as Thbs4 and Fbln2), and Lox (encoding lysyl oxidase). Ingenuity pathway analysis (IPA) predicted that neurohumoral mediators, cytokines, and growth factors (such as AGT, TGFB1, and TNF) may serve as important upstream regulators of the transcriptomic profile of diabetic mouse fibroblasts. IPA of scRNA-seq data identified TGFB1, p53, MYC, PDGF-BB, EGFR, and WNT3A/CTNNB1 as important upstream regulators underlying fibroblast activation in db/db hearts. Comparison of the transcriptome of fibroblasts from db/db mice with fibroblast-specific Smad3 loss and db/db Smad3 fl/fl controls identified Thbs4 [encoding thrombospondin-4 (TSP-4), a marker of activated fibroblasts] as a candidate diabetes-induced fibrogenic mediator. However, in vitro experiments showed no significant activating effects of matricellular or intracellular TSP-4 on cardiac fibroblasts.
    CONCLUSION: Fibroblast-specific TGF-β/Smad3 signaling mediates ventricular fibrosis, hypertrophy, and dysfunction in Type 2 diabetes.
    Keywords:  Diabetic cardiomyopathy; Fibrosis; Heart failure; Hypertrophy; TGF-β
    DOI:  https://doi.org/10.1093/cvr/cvae210
  53. Cardiovasc Res. 2024 Oct 09. pii: cvae224. [Epub ahead of print]
    Interleukin 11 therapy causes acute left ventricular dysfunction.
    Mark Sweeney, Katie O'Fee, Chelsie Villanueva-Hayes, Ekhlas Rahman, Michael Lee, Chung Nga Tam, Eneko Pascual-Navarro, Henrike Maatz, Eric L Lindberg, Konstantinos Vanezis, Chrishan J Ramachandra, Ivan Andrew, Emma R Jennings, Wei-Wen Lim, Anissa A Widjaja, David Carling, Derek J Hausenloy, Norbert Hubner, Paul J R Barton, Stuart A Cook.
       AIMS: Interleukin 11 (IL11) was initially thought important for platelet production, which led to recombinant IL11 being developed as a drug to treat thrombocytopenia. IL11 was later found to be redundant for haematopoiesis and its use in patients is associated with unexplained and severe cardiac side effects. Here we aim to identify, for the first time, direct cardiomyocyte toxicities associated with IL11, which was previously believed cardioprotective.
    METHODS AND RESULTS: We injected recombinant mouse lL11 (rmIL11) into mice and studied its molecular effects in the heart using immunoblotting, qRT-PCR, bulk RNA-seq, single nuclei RNA-seq (snRNA-seq) and ATAC-seq. The physiological impact of IL11 was assessed by echocardiography in vivo and using cardiomyocyte contractility assays in vitro. To determine the activity of IL11 specifically in cardiomyocytes we made two cardiomyocyte-specific Il11ra1 knockout (CMKO) mouse models using either AAV9-mediated and Tnnt2-restricted (vCMKO) or Myh6 (m6CMKO) Cre expression and an Il11ra1 floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition on rmIL11-induced cardiac toxicities. Injection of rmIL11 caused acute and dose-dependent impairment of left ventricular ejection fraction (saline: 62.4% ± 1.9; rmIL11: 32.6% ± 2.9, p<0.001, n=5). Following rmIL11 injection, myocardial STAT3 and JNK phosphorylation were increased and bulk RNA-seq revealed upregulation of pro-inflammatory pathways (TNFα, NFκB and JAK/STAT) and perturbed calcium handling. snRNA-seq showed rmIL11-induced expression of stress factors (Ankrd1, Ankrd23, Xirp2), activator protein-1 (AP-1) transcription factor genes and Nppb in the cardiomyocyte compartment. Following rmIL11 injection, ATAC-seq identified the Ankrd1 and Nppb genes and loci enriched for stress-responsive, AP-1 transcription factor binding sites. Cardiomyocyte-specific effects were examined in vCMKO and m6CMKO mice, which were both protected from rmIL11-induced left ventricular impairment and molecular pathobiologies. In mechanistic studies, inhibition of JAK/STAT signalling with either ruxolitinib or tofacitinib prevented rmIL11-induced cardiac dysfunction.
    CONCLUSIONS: Injection of IL11 directly activates IL11RA/JAK/STAT3 in cardiomyocytes to cause acute heart failure. Our data overturn the earlier assumption that IL11 is cardioprotective and explain the serious cardiac side effects associated with IL11 therapy.
    DOI:  https://doi.org/10.1093/cvr/cvae224
  54. bioRxiv. 2024 Sep 28. pii: 2024.09.27.615276. [Epub ahead of print]
    Selection promotes age-dependent degeneration of the mitochondrial genome.
    Ekaterina Korotkevich, Daniel N Conrad, Zev J Gartner, Patrick H O'Farrell.
      Somatic mutations in mitochondrial genomes (mtDNA) accumulate exponentially during aging. Using single cell sequencing, we characterize the spectrum of age-accumulated mtDNA mutations in mouse and human liver and identify directional forces that accelerate the accumulation of mutations beyond the rate predicted by a neutral model. "Driver" mutations that give genomes a replicative advantage rose to high cellular abundance and carried along "passenger" mutations, some of which are deleterious. In addition, alleles that alter mtDNA-encoded proteins selectively increased in abundance overtime, strongly supporting the idea of a "destructive" selection that favors genomes lacking function. Overall, this combination of selective forces acting in hepatocytes promotes somatic accumulation of mutations in coding regions of mtDNA that are otherwise conserved in evolution. We propose that these selective processes could contribute to the population prevalence of mtDNA mutations, accelerate the course of heteroplasmic mitochondrial diseases and promote age-associated erosion of the mitochondrial genome.
    DOI:  https://doi.org/10.1101/2024.09.27.615276
  55. Cell Death Dis. 2024 Oct 10. 15(10): 736
    BCKDH kinase promotes hepatic gluconeogenesis independent of BCKDHA.
    Feiye Zhou, Chunxiang Sheng, Xiaoqin Ma, Tianjiao Li, Xing Ming, Shushu Wang, Jialin Tan, Yulin Yang, Haipeng Sun, Jieli Lu, Jianmin Liu, Ruyuan Deng, Xiao Wang, Libin Zhou.
      Elevated circulating branched-chain amino acids (BCAAs) are tightly linked to an increased risk in the development of type 2 diabetes mellitus. The rate limiting enzyme of BCAA catabolism branched-chain α-ketoacid dehydrogenase (BCKDH) is phosphorylated at E1α subunit (BCKDHA) by its kinase (BCKDK) and inactivated. Here, the liver-specific BCKDK or BCKDHA knockout mice displayed normal glucose tolerance and insulin sensitivity. However, knockout of BCKDK in the liver inhibited hepatic glucose production as well as the expression of key gluconeogenic enzymes. No abnormal gluconeogenesis was found in mice lacking hepatic BCKDHA. Consistent with the vivo results, BT2-mediated inhibition or genetic knockdown of BCKDK decreased hepatic glucose production and gluconeogenic gene expressions in primary mouse hepatocytes while BCKDK overexpression exhibited an opposite effect. Whereas, gluconeogenic gene expressions were not altered in BCKDHA-silenced hepatocytes. Mechanistically, BT2 treatment attenuated the interaction of cAMP response element binding protein (CREB) with CREB-binding protein and promoted FOXO1 protein degradation by increasing its ubiquitination. Our findings suggest that BCKDK regulates hepatic gluconeogenesis through CREB and FOXO1 signalings, independent of BCKDHA-mediated BCAA catabolism.
    DOI:  https://doi.org/10.1038/s41419-024-07071-0
  56. iScience. 2024 Oct 18. 27(10): 110888
    Aged gut microbiota promotes arrhythmia susceptibility via oxidative stress.
    Zhi-Ping Fu, Yi-Ge Ying, Rui-Yao Wang, Yu-Qing Wang.
      Arrhythmias and sudden cardiac death (SCD) impose a significant burden. Their prevalence rises with age and is linked to gut dysbiosis. Our study aimed to determine whether aged gut microbiota affects arrhythmogenesis. Here, we demonstrated that arrhythmia susceptibility in aged mice could be transmitted to young mice using fecal microbiota transplantation (FMT). Mechanistically, increased intestinal reactive oxygen species (ROS) in aged mice reduced ion channel protein expression and promoted arrhythmias. Gut microbiota depletion by an antibiotic cocktail reduced ROS and arrhythmia in aged mice. Interestingly, oxidative stress in heart induced by hydrogen peroxide (H2O2) increased arrhythmia. Moreover, aged gut microbiota could induce oxidative stress in young mice colon by gut microbiota metabolites transplantation. Vitexin could reduce aging and arrhythmia through OLA1-Nrf2 signaling pathway. Overall, our study demonstrated that the gut microbiota of aged mice reduced cardiac ion channel protein expression through systemic oxidative stress, thereby increased the risk of arrhythmias.
    Keywords:  Cardiovascular medicine; Microbiome
    DOI:  https://doi.org/10.1016/j.isci.2024.110888
  57. Eur J Pharmacol. 2024 Oct 04. pii: S0014-2999(24)00725-8. [Epub ahead of print] 177035
    Glibenclamide reverses cardiac damage and NLRP3 inflammasome activation associated with a high refined sugar diet.
    Renata Gomes Miranda E Castor, Alexandre Santos Bruno, Camila André Pereira, Fernanda Luiza Menezes Bello, Yuri Blanc Rodrigues, Mychel Gonçalves Silva, Sara Santos Bernardes, Marina Gomes Miranda E Castor, Anderson Jose Ferreira, Rita de Cassia Tostes, Stefany Bruno de Assis Cau.
      Increased energy intake from carbohydrates has been associated with major cardiovascular outcomes. Mice fed a highly-refined carbohydrate (HC) diet develop cardiac hypertrophy and inflammation. During cardiac injury, NLRP3 inflammasome is activated which results in a local inflammatory response. In this study, we hypothesized that a nom-hypoglycemic dose of glibenclamide may reverses sugar diet-induced cardiac damage by NRLP3 inflammasome inhibition. Mice were fed the HC diet for eight weeks and divided into a group treated with glibenclamide (20 mg/kg, gavage) and another with vehicle for four weeks. Afterward, hearts were excised for morphometric analysis and ex vivo function determination. NLRP3 inflammasome activation was investigated by western blotting and in situ fluorescent detection of reactive oxygen species (ROS) and active caspase-1. The HC diet promotes heart hypertrophy and collagen deposition, which were reverted by glibenclamide without ameliorating HC diet-induced insulin resistance. Changes in cardiac performance were observed in vivo by invasive catheterization and in Langendorff-perfused hearts due to the HC diet, which were prevented by glibenclamide. Hearts from HC diet mice had increased levels of NLRP3 and cleaved IL-1β. Glibenclamide reversed ROS production and caspase-1 activity induced by HC diet. These findings suggest glibenclamide's cardioprotective effects on heart damage caused by the HC diet are related to its inhibitory action on the NLRP3 inflammasome.
    Keywords:  NLRP3 inflammasome; cardiac damage; glibenclamide; high carbohydrate diet
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177035
  58. Iran J Basic Med Sci. 2024 ;27(11): 1440-1446
    Antiarrhythmic potentials of irisin in ischemia/reperfusion injury of diabetic rats through modulating mitochondria-endoplasmic reticulum interaction and inhibiting pyroptosis.
    Xiaona Zhang Zhang, Kai Jing, Wei Ma, Jin Wang.
       Objectives: Myocardial arrhythmia is a major complication of ischemia-reperfusion (I/R) injury in patients with diabetes. Irisin has significant cardioprotective effects, while its role in the pathophysiology of I/R injury-induced myocardial arrhythmia in the presence of diabetes is not well identified. Here, we aimed to investigate the potential antiarrhythmic impacts and mechanisms (mitochondrial biogenesis, endoplasmic reticulum (ER) stress, and pyroptosis) by which irisin reduces I/R injury-induced myocardial arrhythmia in diabetic rats.
    Materials and Methods: Thirty high-fat diet-induced diabetic rats were subjected to I/R injury and myocardial arrhythmia. Irisin (0.5 μg/kg/day) was injected intraperitoneally before induction of I/R injury. Electrocardiography was used to measure the incidence and severity of ventricular arrhythmias. ELISA and western blotting analyses were employed to quantify the expression of mitochondrial biogenesis, ER stress, and pyroptosis-related proteins in ischemic myocardium.
    Results: Irisin treatment in diabetic rats significantly decreased the lactate dehydrogenase level and the number and severity of arrhythmia induced by I/R injury. Irisin up-regulated the expression of mitochondrial biogenesis-related proteins while down-regulating the expression of ER stress and pyroptosis-related proteins. Furthermore, the inhibition of mitochondrial quality control by mdivi-1 significantly abolished the cardioprotective effect of irisin.
    Conclusion: Our findings suggest that irisin reduced myocardial arrhythmia induced by I/R injury in diabetic rats by modulating the interaction of mitochondrial biogenesis and ER stress proteins and inhibiting the pyroptosis pathway. These findings provide a promising strategy for managing myocardial arrhythmia in diabetic patients, but supplementary studies are needed to confirm the clinical efficacy of irisin in these patients.
    Keywords:  Arrhythmia Cardioprotection; Diabetes; Inflammation; Pyroptosis; Reperfusion
    DOI:  https://doi.org/10.22038/ijbms.2024.78069.16878
  59. JACC Adv. 2024 Sep;3(9): 101188
    Artificial Intelligence Prediction of Cardiovascular Events Using Opportunistic Epicardial Adipose Tissue Assessments From Computed Tomography Calcium Score.
    Tao Hu, Joshua Freeze, Prerna Singh, Justin Kim, Yingnan Song, Hao Wu, Juhwan Lee, Sadeer Al-Kindi, Sanjay Rajagopalan, David L Wilson, Ammar Hoori.
       Background: Recent studies have used basic epicardial adipose tissue (EAT) assessments (eg, volume and mean Hounsfield unit [HU]) to predict risk of atherosclerosis-related, major adverse cardiovascular events (MACEs).
    Objectives: The purpose of this study was to create novel, hand-crafted EAT features, "fat-omics," to capture the pathophysiology of EAT and improve MACE prediction.
    Methods: We studied a cohort of 400 patients with low-dose cardiac computed tomography calcium score examinations. We purposefully used a MACE-enriched cohort (56% event rate) for feature engineering purposes. We divided the cohort into training/testing sets (80%/20%). We segmented EAT using a previously validated, deep-learning method with optional manual correction. We extracted 148 initial EAT features (eg, morphologic, spatial, and HU), dubbed fat-omics, and used Cox elastic-net for feature reduction and prediction of MACE. Bootstrap validation gave CIs.
    Results: Traditional EAT features gave marginal prediction (EAT-volume/EAT-mean-HU/BMI gave C-indices 0.53/0.55/0.57, respectively). Significant improvement was obtained with the 15-feature fat-omics model (C-index = 0.69, test set). High-risk features included the volume-of-voxels-having-elevated-HU-[-50,-30-HU] and HU-negative-skewness, both of which assess high HU values in EAT, a property implicated in fat inflammation. Other high-risk features include kurtosis-of-EAT-thickness, reflecting the heterogeneity of thicknesses, and EAT-volume-in-the-top-25%-of-the-heart, emphasizing adipose near the proximal coronary arteries. Kaplan-Meyer plots of Cox-identified, high- and low-risk patients were well separated with the median of the fat-omics risk, with the high-risk group having an HR 2.4 times that of the low-risk group (P < 0.001).
    Conclusions: Preliminary findings indicate an opportunity to use finely tuned, explainable assessments on EAT for improved cardiovascular risk prediction.
    Keywords:  CT calcium score; Cox; epicardial adipose tissue; machine learning; major adverse cardiovascular event; radiomics; risk prediction
    DOI:  https://doi.org/10.1016/j.jacadv.2024.101188
  60. Histol Histopathol. 2024 Sep 13. 18814
    Melatonin protects against sarcopenia in middle-aged mice.
    Fei Fang, Ping Yu, Xiaoying Sun, Zhixing Shen, Fan Zhang, Jianwei Sun.
       BACKGROUND: Sarcopenia is a common age-related disease. Melatonin (MEL) is an age-related endocrine hormone, which displays a crucial role in resisting oxidative stress during aging. Importantly, the antioxidant properties of MEL can be mediated by mitochondria.
    OBJECTIVE: Therefore, we wondered whether MEL could mitigate oxidative stress caused by mitochondria in sarcopenia.
    METHODS: The middle-aged mice were administered 5 mg/kg/d and 10 mg/kg/d of MEL for 2 months. Young mice were used as the control group.
    RESULTS: After treatment with MEL, the grip strength of the fore/hind limbs, running time, and distance were elevated, and the weights of the gastrocnemius (GA), tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) were enhanced in middle-aged mice. Additionally, MEL was observed to alleviate histological damage and increase the cross-sectional area of muscle fibers in GA tissues of middle-aged mice. Furthermore, following MEL treatment, there was an increase in the percentage and size of normal mitochondria as well as mtDNA copy number but a reduction in the levels of malondialdehyde (MDA), protein carbonyl, and reactive oxygen species (ROS) in the GA tissues of middle-aged mice. At the molecular level, MEL repressed the levels of ATROGIN-1, muscle RING-finger protein-1 (MURF-1), and the ratio of p-P38/P38, but elevated the expression of cytochrome c oxidase subunit 4 (COX4), cystatin C (CYTC), nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in the GA tissues of middle-aged mice. Importantly, 10 mg/kg MEL was more efficacious in the treatment of sarcopenia than 5 mg/kg MEL.
    CONCLUSION: MEL attenuates sarcopenia in middle-aged mice, and the mechanism may relate to mitochondria-induced oxidative stress and the PGC-1α/TFAM pathway.
    DOI:  https://doi.org/10.14670/HH-18-814
  61. Clin Nucl Med. 2024 Oct 10.
    FDG Uptake in Brown Adipose Tissue Activated by a Long-Acting β2-Adrenergic Receptor Agonist Inhaler Prescribed for Bronchial Asthma.
    Akira Nitta, Tomoya Kotani, Chio Okuyama.
       ABSTRACT: We herein report a case of an elderly woman in whom brown adipose tissue (BAT) was visible on 18 F-FDG PET imaging performed in the summer. In this patient, none of the well-known factors that induce BAT activation in adults, including cold exposure, catecholamine-producing tumors, or β3-adrenergic receptor agonists administration, were present. Daily inhalation of a long-acting β2-adrenergic agonist for treatment of her bronchial asthma was considered the cause of her BAT visualization. This case suggests the need to consider β2-adrenergic receptor agonists as a cause of BAT visualization.
    DOI:  https://doi.org/10.1097/RLU.0000000000005529
  62. Virulence. 2024 Dec;15(1): 2412750
    Histone-like transcription factor Hfl1p in Candida albicans harmonizes nuclear and mitochondrial genomic network in regulation of energy metabolism and filamentation development.
    Xiaodong She, Xiaowei Zhou, Meng Zhou, Lulu Zhang, Richard Calderone, Joseph A Bellanti, Weida Liu, Dongmei Li.
      Candida albicans is an opportunistic fungal pathogen known for surviving in various nutrient-limited conditions within the host and causing infections. Our prior research revealed that Hfl1p, an archaeal histone-like or Hap5-like protein, is linked to mitochondrial ATP generation and yeast-hyphae morphogenesis. However, the specific roles of Hfl1p in these virulence behaviours, through its function in the CBF/NF-Y complex or as a DNA polymerase II subunit, remain unclear. This study explores Hfl1p's diverse functions in energy metabolism and morphogenesis. By combining proteomic analysis and phenotypic evaluations of the hfl1Δ/hfl1Δ mutant with ChIP data, we found that Hfl1p significantly impacts mitochondrial DNA-encoded CI subunits, the tricarboxylic acid (TCA) cycle, and morphogenetic pathways. This influence occurs either independently or alongside other transcription factors recognizing a conserved DNA motif (TAXXTAATTA). These findings emphasize Hfl1p's critical role in linking carbon metabolism and mitochondrial respiration to the yeast-to-filamentous form transition, enhancing our understanding of C. albicans' metabolic adaptability during morphological transition, an important pathogenic trait of this fungus. This could help identify therapeutic targets by disrupting the relationship between energy metabolism and cell morphology in C. albicans.
    Keywords:  Candida albicans; ChIP-seq analysis; filamentation repressor; glycolysis; mitochondrial function; mitochondrial transcriptional factor
    DOI:  https://doi.org/10.1080/21505594.2024.2412750
  63. bioRxiv. 2024 Sep 24. pii: 2024.09.20.614121. [Epub ahead of print]
    Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.
    Hyejin Hwang, Brandon J Berry, Claudette St Croix, Andrew P Wojtovich, Sruti P Shiva, Arjumand Ghazi.
      Reproductive status influences metabolism and health across lifespan in diverse ways and mitochondrial function playing a critical role in mediating this relationship. Using the Caenorhabditis elegans germline ablation model, we investigated the impact of germline stem cell (GSC) loss on mitochondrial dynamics and respiratory function. Our results show that GSC loss reduces mitochondrial volume and respiratory function in young adulthood but preserves mitochondrial activity during aging and upon exposure to hypothermic stress, correlating with enhanced survival. We found that the transcription factor NHR-49/PPARα, but not DAF-16/FOXO3A, was essential for preserving mitochondrial function and hypothermia resistance in these long-lived mutants. Together, these findings reveal the impact of germline signals on somatic mitochondrial health and underscore the intricate relationship between reproductive fitness and organismal health.
    DOI:  https://doi.org/10.1101/2024.09.20.614121
  64. J Basic Clin Physiol Pharmacol. 2024 Oct 10.
    Bimagrumab: an investigational human monoclonal antibody against activin type II receptors for treating obesity.
    Manmeet Kaur, Saurav Misra.
      Bimagrumab is a human monoclonal antibody that prevents activin type II receptors (ActRII) from functioning. This antibody has a higher affinity for muscle activin-2 receptors than natural ligands such as activin and myostatin, which act as negative muscle growth regulators. Blocking the activin receptor with bimagrumab could be a new pharmaceutical approach for managing patients with obesity and type 2 diabetes mellitus (T2DM). Bimagrumab has anabolic effects on skeletal muscle mass by preventing myostatin binding and other negative muscle growth regulators. Preclinical animal models have also shown that ActRII blockade promotes actions beyond skeletal muscle, including effects on brown adipose tissue (BAT) differentiation and activity. In a phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of total body fat mass (FM), lean mass (LM) gain, and metabolic improvements over 48 weeks in overweight or obese patients with type 2 diabetes. The trial involved [number of participants], and the results showed [specific findings]. Currently, Bimagrumab is being evaluated for its potential to treat muscle wasting, functional loss in hip fractures and sarcopenia, as well as obesity. However, it is essential to note that Bimagrumab also blocks the effects of other ActRII ligands, which play a role in the neurohormonal axes, pituitary, gonads, and adrenal glands. These observations suggest that bimagrumab might represent a new approach for treating patients with obesity and related metabolic disturbances.
    Keywords:  activin type II receptors (ActRII); bimagrumab; myostatin; obesity
    DOI:  https://doi.org/10.1515/jbcpp-2024-0065
  65. Biomed Rep. 2024 Dec;21(6): 180
    Salidroside rescues hypoxic cardiomyocytes by regulating the EGLN1/HIF‑1α pathway.
    Wenmao Zhang, Ziling Liao, Chengfeng Xu, Xinping Lin.
      Myocardial infarction is characterized by oxygen deficiency caused by arterial flow restriction. Salidroside (SAL) protects against myocardial damage via antioxidant production and inhibition of apoptosis. The present study aimed to investigate potential rescue mechanism of SAL on hypoxic cardiomyocytes. H9C2 cardiomyocytes were divided into normoxia, hypoxia and hypoxia + SAL groups. The inhibitory rate of hypoxia and the optimal concentration and rescue effect of SAL were determined using Cell Counting Kit-8 assay and flow cytometry. Ca2+ concentration following hypoxia treatment and SAL intervention were detected by Fluo-4/acetoxymethyl. Tandem mass tag (TMT) proteomics was used to analyze the differential expression of hypoxia-associated proteins among the three groups. SAL exerted a protective effect on hypoxia-injured cardiomyocytes by enhancing aerobic metabolism during hypoxia and rescuing cardiomyocytes from hypoxic damage. SAL promoted cell proliferation, decreased apoptosis and increased Ca2+ levels in cell membranes of hypoxic cardiomyocytes. TMT proteomics results showed that the expression levels of intracellular hypoxia inducible factor-1 (HIF)-1α and Egl-9 family HIF 1 (EGLN1) in H9C2 cells were elevated under hypoxic conditions. However, SAL significantly decreased expression levels of HIF-1α and EGLN1. SAL inhibited mitochondrial calcium overload in hypoxic cardiomyocytes and attenuated expression of hypoxia-associated factors. SAL exerted its rescue effect on hypoxic cardiomyocytes through the EGLN1/HIF-1α pathway, thereby suppressing cardiomyocyte apoptosis, improving mitochondrial energy metabolism efficiency and rescuing cardiomyocytes from hypoxic injury.
    Keywords:  Egl-9 family hypoxia inducible factor 1; hypoxia inducible factor-1α; myocardial hypoxia; proteomics; salidroside
    DOI:  https://doi.org/10.3892/br.2024.1868
  66. PLoS One. 2024 ;19(10): e0311761
    CRISPR/Cas9 gene editing in induced pluripotent stem cells to investigate the feline hypertrophic cardiomyopathy causing MYBPC3/R820W mutation.
    Luke C Dutton, Jayesh Dudhia, Deborah J Guest, David J Connolly.
      Hypertrophic cardiomyopathy (HCM) is the most common heart disease in domestic cats, often leading to congestive heart failure and death, with current treatment strategies unable to reverse or prevent progression of the disease. The underlying pathological processes driving HCM remain unclear, which hinders novel drug discovery. The aim of this study was to generate a cellular model of the feline HCM-causing MYBPC3 mutation R820W. Using CRISPR/Cas9 gene editing we introduced the R820W mutation into a human induced pluripotent stem cell (iPSC) line. We differentiated both homozygous mutant clones and isogenic control clones to cardiomyocytes (iPSC-CMs). Protein quantification indicated that haploinsufficiency is not the disease mechanism of the mutation. Homozygous mutant iPSC-CMs had a larger cell area than isogenic controls, with the sarcomere structure and incorporation of cMyBP-C appearing similar between mutant and control iPSC-CMs. Contraction kinetic analysis indicated that homozygous iPSC-CMs have impaired relaxation and are hypocontractile compared to isogenic control iPSC-CMs. In summary, we demonstrate successful generation of an iPSC model of a feline MYBPC3 mutation, with the cellular model recapitulating aspects of HCM including cellular hypertrophy and impaired relaxation kinetics. We anticipate that further study of this model will lead to improved understanding of the disease-causing molecular mechanism, ultimately leading to novel drug discovery.
    DOI:  https://doi.org/10.1371/journal.pone.0311761
  67. Cell Commun Signal. 2024 Oct 10. 22(1): 485
    Loss of mitochondrial Ca2+ response and CaMKII/ERK activation by LRRK2R1441G mutation correlate with impaired depolarization-induced mitophagy.
    Eunice Eun-Seo Chang, Huifang Liu, Zoe Yuen-Kiu Choi, Yasine Malki, Steffi Xi-Yue Zhang, Shirley Yin-Yu Pang, Michelle Hiu-Wai Kung, David B Ramsden, Shu-Leong Ho, Philip Wing-Lok Ho.
       BACKGROUND: Stress-induced activation of ERK/Drp1 serves as a checkpoint in the segregation of damaged mitochondria for autophagic clearance (mitophagy). Elevated cytosolic calcium (Ca2+) activates ERK, which is pivotal to mitophagy initiation. This process is altered in Parkinson's disease (PD) with mutations in leucine-rich repeat kinase 2 (LRRK2), potentially contributing to mitochondrial dysfunction. Pathogenic LRRK2 mutation is linked to dysregulated cellular Ca2+ signaling but the mechanism involved remains unclear.
    METHODS: Mitochondrial damages lead to membrane depolarization. To investigate how LRRK2 mutation impairs cellular response to mitochondrial damages, mitochondrial depolarization was induced by artificial uncoupler (FCCP) in wild-type (WT) and LRRK2R1441G mutant knockin (KI) mouse embryonic fibroblasts (MEFs). The resultant cytosolic Ca2+ flux was assessed using live-cell Ca2+ imaging. The role of mitochondria in FCCP-induced cytosolic Ca2+ surge was confirmed by co-treatment with the mitochondrial sodium-calcium exchanger (NCLX) inhibitor. Cellular mitochondrial quality and function were evaluated by Seahorse™ real-time cell metabolic analysis, flow cytometry, and confocal imaging. Mitochondrial morphology was visualized using transmission electron microscopy (TEM). Activation (phosphorylation) of stress response pathways were assessed by immunoblotting.
    RESULTS: Acute mitochondrial depolarization induced by FCCP resulted in an immediate cytosolic Ca2+ surge in WT MEFs, mediated predominantly via mitochondrial NCLX. However, such cytosolic Ca2+ response was abolished in LRRK2 KI MEFs. This loss of response in KI was associated with impaired activation of Ca2+/calmodulin-dependent kinase II (CaMKII) and MEK, the two upstream kinases of ERK. Treatment of LRRK2 inhibitor did not rescue this phenotype indicating that it was not caused by mutant LRRK2 kinase hyperactivity. KI MEFs exhibited swollen mitochondria with distorted cristae, depolarized mitochondrial membrane potential, and reduced mitochondrial Ca2+ store and mitochondrial calcium uniporter (MCU) expression. These mutant cells also exhibited lower cellular ATP: ADP ratio albeit higher basal respiration than WT, indicating compensation for mitochondrial dysfunction. These defects may hinder cellular stress response and signals to Drp1-mediated mitophagy, as evident by impaired mitochondrial clearance in the mutant.
    CONCLUSIONS: Pathogenic LRRK2R1441G mutation abolished mitochondrial depolarization-induced Ca2+ response and impaired the basal mitochondrial clearance. Inherent defects from LRRK2 mutation have weakened the cellular ability to scavenge damaged mitochondria, which may further aggravate mitochondrial dysfunction and neurodegeneration in PD.
    Keywords:  Calcium-dependent pathways; Cellular stress response; LRRK2 mutation; Mitochondrial dysfunction; Mitophagy; NCLX; Parkinson disease
    DOI:  https://doi.org/10.1186/s12964-024-01844-y
  68. J Am Heart Assoc. 2024 Oct 11. e036626
    Cardiomyocyte Reduction of Hybrid/Complex N-Glycosylation in the Adult Causes Heart Failure With Reduced Ejection Fraction in the Absence of Cellular Remodeling.
    Anthony M Young, John A Miller, Andrew R Ednie, Eric S Bennett.
       BACKGROUND: Heart failure (HF) presents a massive burden to health care with a complex pathophysiology that results in HF with reduced left ventricle ejection fraction (EF) or HF with preserved EF. It has been shown that relatively modest changes in protein glycosylation, an essential posttranslational modification, are associated with clinical presentations of HF. We and others previously showed that such aberrant protein glycosylation in animal models can lead to HF.
    METHODS AND RESULTS: We develop and characterize a novel, tamoxifen-inducible, cardiomyocyte Mgat1 knockout mouse strain, achieved through deletion of Mgat1, alpha-1,3-mannosyl-glycoproten 2-beta-N-acetlyglucosaminyltransferase, which encodes N-acetylglucosaminyltransferase I. We investigate the role of hybrid/complex N-glycosylation in adult HFrEF pathogenesis at the ion channel, cardiomyocyte, tissue, and gross cardiac level. The data demonstrate successful reduction of N-acetylglucosaminyltransferase I activity and confirm that hybrid/complex N-glycans modulate gating of cardiomyocyte voltage-gated calcium channels. A longitudinal study shows that the tamoxifen-inducible, cardiomyocyte Mgat1 knockout mice present with significantly reduced systolic function by 28 days post induction that progresses into HFrEF by 8 weeks post induction, without significant ventricular dilation or hypertrophy. Further, there was minimal, if any, physiologic or pathophysiologic cardiomyocyte electromechanical remodeling or fibrosis observed before (10-21 days post induction) or after (90-130 days post induction) HFrEF development.
    CONCLUSIONS: The tamoxifen-inducible, cardiomyocyte Mgat1 knockout mouse strain created and characterized here provides a model to describe novel mechanisms and causes responsible for HFrEF onset in the adult, likely occurring primarily through tissue-level reductions in electromechanical activity in the absence of (or at least before) cardiomyocyte remodeling and fibrosis.
    Keywords:  EC coupling; N‐glycosylation; echocardiography; heart failure; voltage‐gated ion channels
    DOI:  https://doi.org/10.1161/JAHA.124.036626
  69. Brain Nerve. 2024 Oct;76(10): 1127-1135
    [Taurine for Mitochondrial Diseases].
    Yoshihide Sunada.
      Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is characterized by a mitochondrial DNA mutation that leads to defective taurine modification of the leucine tRNA anticodon, with consequent impaired translation of the UUG codon. This defect reduces synthesis of respiratory chain complexes, which causes energy failure. Taurine supplementation improved mitochondrial function in MELAS model cells. A physician-initiated clinical trial reported that high-dose taurine supplementation therapy suppressed stroke-like episodes and improved taurine modification rates in leukocytes.
    DOI:  https://doi.org/10.11477/mf.1416202748
  70. J Exp Bot. 2024 Oct 08. pii: erae420. [Epub ahead of print]
    Genomic and biochemical analysis of lipid biosynthesis in Cyanophora paradoxa: Limited role of chloroplast in fatty acid synthesis.
    Naoki Sato, Eri Ikemura, Mana Uemura, Koichiro Awai.
      Archaeplastida, a group of photosynthetic organisms with primary plastids, consists of green algae (plus plants), red algae, and glaucophytes. In contrast to green and red algae, information on lipids and lipid biosynthesis still needs to be included in the glaucophytes. The chloroplast is the site of photosynthesis and fatty acid synthesis in all photosynthetic organisms known to date. However, the genomic data of the glaucophyte Cyanophora paradoxa suggested the lack of acetyl CoA carboxylase and most components of fatty acid synthase in the chloroplast. Instead, multifunctional fatty acid synthase and acetyl CoA carboxylase are likely to reside in the cytosol. To examine this hypothesis, we measured fatty acid synthesis in isolated chloroplasts and whole cells using stable isotope labeling. The chloroplasts had very low activity of fatty acid synthesis, if any. Most processes of fatty acid synthesis, including elongation and desaturation, must be performed within the cytosol, and the fatty acids imported into the chloroplasts are assembled into the chloroplast lipids by the enzymes common to other algae and plants. Cyanophora paradoxa is a rare organism in which fatty acid synthesis and photosynthesis are not tightly linked. This could question the common origin of these two biosynthetic processes in Archaeplastida.
    Keywords:   Cyanophora paradoxa ; acetyl CoA carboxylase; carbon isotope assimilation; chloroplast; comparative genomics; fatty acid synthesis
    DOI:  https://doi.org/10.1093/jxb/erae420
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