bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–11–17
eighty-two papers selected by
Henver Brunetta, Karolinska Institutet
  1. The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.
  2. Deletion of MAPL ameliorates septic cardiomyopathy by mitigating mitochondrial dysfunction.
  3. ZIP7 contributes to the pathogenesis of diabetic cardiomyopathy by suppressing mitophagy in mouse hearts.
  4. Omentin increases glucose uptake, but not insulin sensitivity in human myotubes dependent on extracellular lactotransferrin.
  5. A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.
  6. eIF5A controls mitoprotein import by relieving ribosome stalling at TIM50 translocase mRNA.
  7. Klf9 is essential for cardiac mitochondrial homeostasis.
  8. Diet-induced impairment of skeletal muscle and adipose tissue metabolic homeostasis and its prevention by probiotic administration.
  9. Metabolomic characterization of unintentional weight loss among community-dwelling older Black and White men and women.
  10. Intermittent Fasting Improves Insulin Resistance by Modulating the Gut Microbiota and Bile Acid Metabolism in Diet-Induced Obesity.
  11. Increased exercise tolerance in humanized G6PD deficient mice.
  12. Weight loss and metabolic effects of an ALDH1A1-specific inhibitor, FSI-TN42, in a diet induced mouse model of obesity.
  13. Exercise training may reduce fragmented mitochondria in the ischemic-reperfused heart through DRP1.
  14. (Pro)renin receptor aggravates myocardial pyroptosis in diabetic cardiomyopathy through AMPK-NLRP3 pathway.
  15. Psmb8 inhibits mitochondrial fission and alleviates myocardial ischaemia/reperfusion injury by targeting Drp1 degradation.
  16. Metformin restores autophagic flux and mitochondrial function in late passage myoblast to impede age-related muscle loss.
  17. Expression profile of tsRNAs in white adipose tissue of vitamin D deficiency young male mice with or without obesity.
  18. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases.
  19. Apolipoprotein A-I priming via SR-BI and ABCA1 receptor binding upregulates mitochondrial metabolism to promote insulin secretion in INS-1E cells.
  20. NK2R control of energy expenditure and feeding to treat metabolic diseases.
  21. Estrogen Regulates Mitochondrial Activity Through Inducing Brain-Derived Neurotrophic Factor Expression in Skeletal Muscle.
  22. SIRT1 Ameliorates Lamin A/C Deficiency-Induced Cardiac Dysfunction by Promoting Mitochondrial Bioenergetics.
  23. Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
  24. Variable glucagon metabolic actions in diverse mouse models of obesity and type 2 diabetes.
  25. Attenuation of high-fat diet-induced weight gain by apolipoprotein A4.
  26. Mitochondrial Dysfunction and Metabolic Disturbances Induced by Viral Infections.
  27. Effects of breaking up prolonged sitting via exercise snacks intervention on the body composition and plasma metabolomics of sedentary obese adults: a randomized controlled trial.
  28. Tat-Beclin-1 Ameliorates Memory by Improving Neuronal Cytoarchitecture and Mitigating Mitochondrial Dysfunction in Scopolamine-Induced Amnesic Male Mice.
  29. Weight Loss Induces Changes in Vitamin D Status in Women with Obesity but not in Men: a Randomized Clinical Trial.
  30. Ischemic Rescue Potential of Conditioned Medium Derived from Skeletal Muscle Cells-Seeded Electrospun Fiber-Coated Human Amniotic Membrane Scaffolds.
  31. Differential Plin5 response to high-fat diet in cardiomyocytes isolated from young and aged mice.
  32. Euglena Attenuates High-Fat-Diet-Induced Obesity and Especially Glucose Intolerance.
  33. L-aspartate ameliorates diet-induced obesity by increasing adipocyte energy expenditure.
  34. Peroxisome proliferator‑activated receptor γ coactivator‑1α in heart disease (Review).
  35. IL1RAP Blockade With a Monoclonal Antibody Reduces Cardiac Inflammation and Preserves Heart Function in Viral and Autoimmune Myocarditis.
  36. Acute inflammation upregulates FAHFAs in adipose tissue and in co-cultured adipocytes.
  37. Dose-dependency of a combined EPA:DHA mixture on incorporation, washout, and protein synthesis in C2C12 myotubes.
  38. Methylation of the ESR1 promoters in visceral adipose tissue and its relationship with obesity.
  39. Contribution of glucose and glutamine to hypoxia-induced lipid synthesis decreases, while contribution of acetate increases, during 3T3-L1 differentiation.
  40. A qualitative study of the mental health outcomes in people being treated for obesity and type 2 diabetes with glucagon-like peptide-1 receptor agonists.
  41. Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA.
  42. FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice.
  43. Improved metabolic stability in iNOS knockout mice with Lactobacillus supplementation.
  44. Palmitoylcarnitine impairs immunity in decompensated cirrhosis.
  45. Mitochondrial Membrane Potential (ΔΨ) Fluctuations Associated with the Metabolic States of Mitochondria.
  46. High-fiber basil seed flour reduces insulin resistance and hepatic steatosis in high-fat diet mice.
  47. Oligonol®, an Oligomerized Polyphenol from Litchi chinensis, Enhances Branched-Chain Amino Acid Transportation and Catabolism to Alleviate Sarcopenia.
  48. Chest-CT-based radiomics feature of epicardial adipose tissue for screening coronary atherosclerosis.
  49. Proteomic and ubiquitinome analysis reveal that microgravity affects glucose metabolism of mouse hearts by remodeling non-degradative ubiquitination.
  50. Chicken GLUT4 function via enhancing mitochondrial oxidative phosphorylation and inhibiting ribosome pathway in skeletal muscle satellite cells.
  51. Engineered bacterial lipoate protein ligase A (lplA) restores lipoylation in cell models of lipoylation deficiency.
  52. Influence of hydrotherapy on change in weight: a narrative review.
  53. Fatty acid composition evaluation of abdominal adipose tissue using chemical shiftencoded MRI: Association with diabetes.
  54. TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis.
  55. Sevoflurane aggravates cognitive impairment in OSAS mice through tau phosphorylation and mitochondrial dysfunction.
  56. Daily GDF15 treatment has sex-specific effects on body weight and food intake and does not enhance the effects of voluntary physical activity in mice.
  57. CDKN1A as a target of senescence in heart failure: insights from a multiomics study.
  58. The impact of prolonged walking on fasting plasma glucose in type 2 diabetes: A randomised controlled crossover study.
  59. Opposing roles for AMPK in regulating distinct mitophagy pathways.
  60. Growth hormone attenuates obesity and reshapes gut microbiota in high-fat diet-fed mice.
  61. Structures of the multi-domain oxygen sensor DosP: remote control of a c-di-GMP phosphodiesterase by a regulatory PAS domain.
  62. TSPO Exacerbates Sepsis-Induced Cardiac Dysfunction by Inhibiting p62-Mediated Autophagic Flux via the ROS-RIP1/RIP3-Exosome Axis.
  63. Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis.
  64. Analyses of Off-Target Effects on Cardiac and Skeletal Muscles by Berberine, a Drug Used to Treat Cancers and Induce Weight Loss.
  65. ZLN005 Reduces Neuroinflammation and Improves Mitochondrial Function in Mice with Perioperative Neurocognitive Disorders.
  66. Prognostic utility of dynamic changes in epicardial adipose tissue in patients undergoing transcatheter aortic valve replacement.
  67. Dysglycemia and liver lipid content influence the link between insulin resistance and liver mitochondrial function in obesity - Author's reply.
  68. Expression of Concern: Punicalagin protects H9c2 cardiomyocytes from doxorubicin-induced toxicity through activation of Nrf2/HO-1 signaling.
  69. Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts.
  70. Protein Tyrosine Phosphatases in Metabolism: A New Frontier for Therapeutics.
  71. Effects of sodium-glucose cotransporter-2 inhibitor on atrial high-rate episodes in patients with cardiovascular implantable electronic device: a randomized controlled trial.
  72. The Relation Between Mitochondrial Membrane Potential and Reactive Oxygen Species Formation.
  73. Exercise Training in Patients With Hypertrophic Cardiomyopathy Without Left Ventricular Outflow Tract Obstruction: A Randomized Clinical Trial.
  74. Dopamine-D2-agonist targets mitochondrial dysfunction via diminishing Drp1 mediated fission and normalizing PGC1-α/SIRT3 pathways in a rodent model of Subarachnoid haemorrhage.
  75. [Activation of ALDH2 alleviates hypoxic pulmonary hypertension in mice by upregulating the SIRT1/PGC-1α signaling pathway].
  76. POLG p.A962T Mutation Leads to Neuronal Mitochondrial Dysfunction That is Restored After Mitochondrial Transplantation.
  77. Mitochondrial dynamics and energy metabolism interference therapy for promoting photothermal sensitization.
  78. Cardiac Resynchronization Therapy: New Perspectives.
  79. Dapagliflozin alleviates high-fat-induced obesity cardiomyopathy by inhibiting ferroptosis.
  80. Relating normal human cardiac development to the anatomical findings in the congenitally malformed heart.
  81. Mitigating environmental toxicity with hydrogen nanobubbles: A mitochondrial function-based approach to ecological restoration.
  82. Cap-independent translation directs stress-induced differentiation of the protozoan parasite Toxoplasma gondii.
  1. Nat Commun. 2024 Nov 13. 15(1): 9826
    The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.
    Tang Cam Phung Pham, Steffen Henning Raun, Essi Havula, Carlos Henriquez-Olguín, Diana Rubalcava-Gracia, Emma Frank, Andreas Mæchel Fritzen, Paulo R Jannig, Nicoline Resen Andersen, Rikke Kruse, Mona Sadek Ali, Andrea Irazoki, Jens Frey Halling, Stine Ringholm, Elise J Needham, Solvejg Hansen, Anders Krogh Lemminger, Peter Schjerling, Maria Houborg Petersen, Martin Eisemann de Almeida, Thomas Elbenhardt Jensen, Bente Kiens, Morten Hostrup, Steen Larsen, Niels Ørtenblad, Kurt Højlund, Michael Kjær, Jorge L Ruas, Aleksandra Trifunovic, Jørgen Frank Pind Wojtaszewski, Joachim Nielsen, Klaus Qvortrup, Henriette Pilegaard, Erik Arne Richter, Lykke Sylow.
      Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.
    DOI:  https://doi.org/10.1038/s41467-024-54183-4
  2. J Transl Med. 2024 Nov 11. 22(1): 1012
    Deletion of MAPL ameliorates septic cardiomyopathy by mitigating mitochondrial dysfunction.
    Yinghua Wang, Xiying Huang, Huanhuan Huo, Zhaohua Cai, Qingqi Ji, Yi Jiang, Fei Zhuang, Yi Li, Linghong Shen, Xia Wang, Ben He.
       AIM: Mitochondrial dysfunction is a critical factor in the pathogenesis of septic cardiomyopathy (SCM). Mitochondrial anchored protein ligase (MAPL), a small ubiquitin-like modifier (SUMO) E3 ligase, plays a significant role in mitochondrial function. However, the role of MAPL in SCM remains unclear.
    METHODS: To investigate the role of MAPL in SCM, cardiomyocyte-specific MAPL knockout mice were generated. A cecal ligation and puncture (CLP) procedure was employed to induce a sepsis-like condition.
    RESULTS: The expression of MAPL in heart tissues and H9C2 cardiomyocytes was elevated following CLP challenge or lipopolysaccharide (LPS) stimulation. MAPL deficiency ameliorated CLP-induced cardiac injury, dysfunction, and inflammation, and also improved the survival rate of mice following CLP operation. Additionally, MAPL deficiency or knockdown inhibited LPS-induced cardiomyocyte apoptosis, improved mitochondrial structural abnormalities, and increased ATP production. Furthermore, MAPL knockdown mitigated LPS-induced reductions in mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) production. Mechanistically, the expression of dynamin-related protein 1 (drp1) in the mitochondria of heart tissues or H9C2 cardiomyocytes was elevated under septic conditions. Accordingly, the SUMOylation of drp1 in heart tissues or H9C2 cardiomyocytes was increased under sepsis conditions, which was reduced by MAPL knockout or knockdown.
    CONCLUSION: Our results reveal that MAPL promotes cardiac injury/dysfunction and inflammation in SCM. Deficiency or knockdown of MAPL alleviates SCM by reducing drp1 SUMOylation as well as drp1-mediated mitochondrial dysfunction. These findings suggest that targeting MAPL may represent a therapeutic strategy for patients with SCM.
    Keywords:  MAPL; Mitochondria; SUMOylation; Septic cardiomyopathy
    DOI:  https://doi.org/10.1186/s12967-024-05836-x
  3. Cardiovasc Diabetol. 2024 Nov 07. 23(1): 399
    ZIP7 contributes to the pathogenesis of diabetic cardiomyopathy by suppressing mitophagy in mouse hearts.
    Ningzhi Yang, Rui Zhang, Hualu Zhang, Yonghao Yu, Zhelong Xu.
       BACKGROUND: Although the exact role of mitophagy in the pathogenesis of diabetic cardiomyopathy (DCM) caused by type 2 diabetes mellitus (T2DM) remains controversial, recent studies revealed inhibition of mitophagy exacerbates cardiac injury in DCM. The zinc transporter ZIP7 has been reported to be upregulated by high glucose in cardiomyocytes and ZIP7 upregulation leads to inhibition of mitophagy in mouse hearts in the setting of ischemia/reperfusion. Nevertheless, little is known about the role of ZIP7 and its relationship with mitophagy in DCM caused by T2DM.
    METHODS: T2DM was induced with high-fat diet (HFD) and streptozotocin. The cardiac-specific ZIP7 conditional knockout (ZIP7 cKO) mice were generated by adopting CRISPR/Cas9 system. Cardiac function was evaluated with echocardiography. Mitophagy was assessed by detecting mito-LC3II, mitoKeima, and mitoQC. Reactive oxygen species (ROS) were detected with DHE and mitoB.
    RESULTS: ZIP7 was upregulated by T2DM in mouse hearts and ZIP7 cKO reduced mitochondrial ROS generation in mouse hearts with T2DM. Mitophagy was suppressed by T2DM in mouse hearts, which was prevented by ZIP7 cKO. T2DM inhibited PINK1 and Parkin accumulation in cardiac mitochondria, an effect that was prevented by ZIP7 cKO, pointing to that ZIP7 upregulation mediates T2DM-induced suppression of mitophagy by inhibiting the PINK1/Parkin pathway. T2DM induced mitochondrial hyperpolarization and decrease of mitochondrial Zn2+ and this was blocked by ZIP7 cKO, indicating that upregulation of ZIP7 leads to mitochondrial hyperpolarization by reducing Zn2+ within mitochondria. Finally, ZIP7 cKO prevented cardiac dysfunction and fibrosis caused by T2DM.
    CONCLUSIONS: ZIP7 upregulation mediates the inhibition of mitophagy by T2DM in mouse hearts by suppressing the PINK1/Parkin pathway. Reduction of mitochondrial Zn2+ due to upregulation of ZIP7 accounts for the inhibition of the PINK1/Parkin pathway. Prevention of ZIP7 upregulation is essential for the treatment of T2DM-induced cardiomyopathy.
    Keywords:  Cardiomyopathy; Mitophagy; PINK1/Parkin pathway; T2DM; ZIP7
    DOI:  https://doi.org/10.1186/s12933-024-02499-2
  4. Obes Facts. 2024 Nov 11. 1-16
    Omentin increases glucose uptake, but not insulin sensitivity in human myotubes dependent on extracellular lactotransferrin.
    Jacqueline M Ratter-Rieck, Alexandra Zepina, Corinna Niersmann, Karin Röhrig, Fabien Riols, Mark Haid, Jutta Lintelmann, Stefanie M Hauck, Michael Roden, Cora Weigert, Christian Herder.
       INTRODUCTION: Omentin (intelectin-1) is an adipokine produced by the stromal vascular fraction of visceral adipose tissue and has been positively associated with insulin sensitivity. The underlying mechanism of action, however, is largely unknown. It has been described that omentin may increase insulin sensitivity and glucose uptake of adipocytes, but effects on other insulin-sensitive tissues such as skeletal muscle are unexplored. We therefore investigated effects of omentin on insulin sensitivity and metabolism of primary human myotubes.
    METHODS: Primary human myotubes were treated with 0.5 or 2 µg/mL omentin and subsequently protein detection, glucose uptake assay, lactate assay and lipidomics analysis were performed.
    RESULTS: Omentin did not affect skeletal muscle insulin signaling, as assessed by basal and insulin-stimulated phosphorylation of IRS1 and AKT. Omentin increased basal, but not insulin-stimulated glucose uptake. While increased glycolytic activity was confirmed by elevated lactate release after omentin treatment, effects on cellular lipid composition were limited to an increase in total triacylglycerol concentration. Increased glucose uptake by omentin was counteracted by addition of extracellular lactotransferrin, which can bind to omentin.
    CONCLUSIONS: Overall, increased basal glucose uptake in skeletal muscle cells suggests differential effects of omentin on insulin-sensitive tissues. Moreover, an involvement of lactotransferrin in omentin's mechanism of action may partially explain contradictory results of epidemiological studies on the role of omentin in different diseases.
    DOI:  https://doi.org/10.1159/000541915
  5. Autophagy. 2024 Nov 09.
    A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.
    Wenjuan Wang, Jinbao Liu, Jie Li, Huabo Su.
      PRKN-dependent mitophagy plays a crucial role in maintaining mitochondrial health. Yet, PRKN-deficient mice do not exhibit mitochondrial and cardiac phenotypes at baseline, suggesting the existence of other mitochondrial ubiquitin (Ub) ligases. Here, we discuss our recent work identifying RNF7/RBX2 as a novel mitochondrial Ub ligase. Upon mitochondrial depolarization, RNF7 proteins are recruited to the mitochondria, where they directly ubiquitinate mitochondrial proteins and stabilize PINK1 expression, thereby promoting the clearance of damaged mitochondria and regulating mitochondrial turnover in the heart. The actions of RNF7 in mitochondria do not require PRKN. Ablation of Rnf7 in mouse hearts results in severe mitochondrial dysfunction and heart failure. Our findings demonstrate that RNF7 is indispensable for mitochondrial turnover and cardiac homeostasis. These results open new avenues for exploring new PRKN-independent pathways that regulate mitophagy, which could have significant implications for developing therapeutic interventions for cardiac diseases.
    Keywords:  Heart failure; RBX2/SAG; mitophagy; parkin; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2024.2423329
  6. J Cell Biol. 2024 Dec 02. pii: e202404094. [Epub ahead of print]223(12):
    eIF5A controls mitoprotein import by relieving ribosome stalling at TIM50 translocase mRNA.
    Marina Barba-Aliaga, Vanessa Bernal, Cynthia Rong, Madeleine E Volfbeyn, Keguang Zhang, Brian M Zid, Paula Alepuz.
      Efficient import of nuclear-encoded proteins into mitochondria is crucial for proper mitochondrial function. The conserved translation factor eIF5A binds ribosomes, alleviating stalling at polyproline-encoding sequences. eIF5A impacts mitochondrial function across species, though the precise molecular mechanism is unclear. We found that eIF5A depletion in yeast reduces the translation and levels of the TCA cycle and oxidative phosphorylation proteins. Loss of eIF5A causes mitoprotein precursors to accumulate in the cytosol and triggers a mitochondrial import stress response. We identify an essential polyproline protein as a direct target of eIF5A: the mitochondrial inner membrane protein and translocase component Tim50. Thus, eIF5A controls mitochondrial protein import by alleviating ribosome stalling along Tim50 mRNA at the mitochondrial surface. Removal of polyprolines from Tim50 partially rescues the mitochondrial import stress response and translation of oxidative phosphorylation genes. Overall, our findings elucidate how eIF5A impacts the mitochondrial function by promoting efficient translation and reducing ribosome stalling of co-translationally imported proteins, thereby positively impacting the mitochondrial import process.
    DOI:  https://doi.org/10.1083/jcb.202404094
  7. Nat Cardiovasc Res. 2024 Nov;3(11): 1318-1336
    Klf9 is essential for cardiac mitochondrial homeostasis.
    Lei Zhang, Menglin Zhang, Jinlong Huang, Jincan Huang, Yujie Zhang, Yinliang Zhang, Houzao Chen, Cuizhe Wang, Xiangwen Xi, Heng Fan, Jikui Wang, Dingsheng Jiang, Jinwei Tian, Jun Zhang, Yongsheng Chang.
      Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Krüppel-like factor 9 (Klf9) is dysregulated in human and rodent cardiomyopathy. Both global and cardiac-specific Klf9-deficient mice displayed hypertrophic cardiomyopathy. Klf9 knockout led to mitochondrial disarray and fragmentation, impairing mitochondrial respiratory function in cardiomyocytes. Furthermore, cardiac Klf9 deficiency inhibited mitophagy, thereby causing accumulation of dysfunctional mitochondria and acceleration of heart failure in response to angiotensin II treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function. Mechanistically, Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2, thereby regulating mitochondrial dynamics and mitophagy. Finally, adeno-associated virus-mediated Mfn2 rescue in Klf9-CKO hearts improved cardiac mitochondrial and systolic function. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure.
    DOI:  https://doi.org/10.1038/s44161-024-00561-6
  8. Pflugers Arch. 2024 Nov 14.
    Diet-induced impairment of skeletal muscle and adipose tissue metabolic homeostasis and its prevention by probiotic administration.
    Angela Di Porzio, Valentina Barrella, Luisa Cigliano, Gianluigi Mauriello, Antonio Dario Troise, Andrea Scaloni, Susanna Iossa, Arianna Mazzoli.
      Western dietary pattern is one of the main contributors to the increased risk of obesity and chronic diseases, through oxidative stress and inflammation, that are the two key mechanisms targeting metabolic organs, such as skeletal muscle and adipose tissue. The chronic exposure to high levels of dietary fatty acids can increase the amount of intramyocellular lipids in skeletal muscle, altering glucose homeostasis and contributing to a reduction in mitochondrial oxidative capacity. Probiotic administration is a promising approach as preventive strategy to attenuate metabolic damage induced by Western diet. Here, we investigated the beneficial effect of Limosillactobacillus reuteri DSM 17938 on the inflammatory state and oxidative balance in the skeletal muscle and adipose tissue of adult rats fed a western diet for 8 weeks, focusing on the role of skeletal muscle mitochondria. Limosillactobacillus reuteri DSM 17938 administration protected the skeletal muscle from mitochondrial dysfunction and oxidative stress, preventing the establishment of inflammation and insulin resistance. Interestingly, a further beneficial effect of the probiotic was exerted on body composition, favoring the deposition of protein mass and preventing adipose tissue hypertrophy and inflammation. These results open the possibility for the use of this probiotic in therapeutic approaches for nutrition-related diseases.
    Keywords:  Adipose tissue; Inflammation; Mitochondria; Probiotics; Skeletal muscle; Western diet
    DOI:  https://doi.org/10.1007/s00424-024-03041-9
  9. Aging Cell. 2024 Nov 15. e14410
    Metabolomic characterization of unintentional weight loss among community-dwelling older Black and White men and women.
    Shanshan Yao, Megan M Marron, Samaneh Farsijani, Iva Miljkovic, George C Tseng, Ravi V Shah, Venkatesh L Murthy, Anne B Newman.
      This study aims to understand the metabolic mechanisms of unintentional weight loss in older adults. We investigated plasma metabolite associations of subsequent weight change over 2 years in 1536 previously weight stable participants (mean age 74.6 years, 50% women, 35% Black) from the Health, Aging and Body Composition (Health ABC) Study. Multinomial logistic regressions were used to examine associations of the 442 metabolites with weight loss with/without an intention and weight gain >3% annually relative to weight stability. The metabolite associations of unintentional weight loss differed from those of intentional weight loss and weight gain. Lower levels of aromatic amino acids, phospholipids, long-chain poly-unsaturated triglycerides, and higher levels of amino acid derivatives, poly-unsaturated fatty acids, and carbohydrates were associated with higher odds of unintentional weight loss after adjusting for age, sex, race, and BMI categories. Prevalent diseases attenuated four and lower mid-thigh muscle mass and poorer appetite each attenuated 2 of 77 identified metabolite associations by >20%, respectively. Other factors (e.g., energy expenditure, diet, and medication) attenuated all associations by <20%. While 16 metabolite associations were attenuated by 20%-48% when adjusting for all these risk factors, 47 metabolite associations remained significant. Altered amino acid metabolism, impaired mitochondrial fatty acid oxidation, and inflammaging implicated by identified metabolites appear to precede unintentional weight loss in Health ABC older adults. Furthermore, these pathways seem to be associated with prevalent diseases especially diabetes, lower muscle mass, and poorer appetite.
    Keywords:  appetite; metabolism; metabolomics; sarcopenia; weight loss
    DOI:  https://doi.org/10.1111/acel.14410
  10. Mol Nutr Food Res. 2024 Nov 09. e2400451
    Intermittent Fasting Improves Insulin Resistance by Modulating the Gut Microbiota and Bile Acid Metabolism in Diet-Induced Obesity.
    Sha Lei, Guanghui Liu, Shouli Wang, Guannan Zong, Xiaoya Zhang, Lingling Pan, Junfeng Han.
       SCOPE: Adipose tissue macrophages (ATMs) are crucial in the pathogenesis of insulin resistance (IR). Intermittent fasting (IF) is an effective intervention for obesity. However, the underlying mechanism by which IF improves IR remains unclear.
    METHODS AND RESULTS: Male C57BL/6J mice are fed chow-diet and high-fat diet (HFD) for 12 weeks, then is randomized into ad libitum feeding or every other day fasting for 8 weeks. Markers of ATMs and expression of uncoupling protein 1 (UCP-1) are determined. Gut microbiota and bile acids (BAs) are profiled using 16S rRNA sequencing and targeted metabolomics analysis. Results indicate that IF improves IR in HFD-induced obesity. IF decreases ATM infiltration, pro-inflammatory M1 gene expression, and promotes white adipose tissue (WAT) browning by elevating UCP-1 expression. IF restructures microbiota composition, significantly expanding the abundance of Verrucomicrobia particularly Akkermansia muciniphila, with the decrease of that of Firmicutes. IF increases the level of total BAs and alters the composition of BAs with higher proportion of 12α-hydroxylated (12α-OH) BAs. The changes in these BAs are correlated with differential bacteria.
    CONCLUSION: The findings indicate that IF improves IR partially mediated by the interplay between restructured gut microbiota and BAs metabolism, which has implications for the dietary management in obesity.
    Keywords:  bile acid; gut microbiota; insulin resistance; intermittent fasting; obesity
    DOI:  https://doi.org/10.1002/mnfr.202400451
  11. Blood Adv. 2024 Nov 08. pii: bloodadvances.2024013968. [Epub ahead of print]
    Increased exercise tolerance in humanized G6PD deficient mice.
    Francesca I Cendali, Christina Lisk, Monika Dzieciatkowska, Ian S LaCroix, Julie A Reisz, Julie Harral, Daniel Stephenson, Ariel M Hay, Eric Wartchow, Anza Darehshouri, Karolina Dziewulska, Paul W Buehler, Philip J Norris, Xutao Deng, Michael P Busch, Eric J Earley, Grier P Page, Kirk C Hansen, James C Zimring, David Irwin, Travis Nemkov, Angelo D'Alessandro.
      Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects 500 million people globally, impacting red blood cell (RBC) antioxidant pathways and increasing susceptibility to hemolysis under oxidative stress. Despite the systemic generation of reactive oxygen species during exercise, the effects of exercise on individuals with G6PD deficiency remain poorly understood This study utilized humanized mouse models expressing the G6PD Mediterranean variant (S188F, with 10% enzymatic activity) to investigate exercise performance and molecular outcomes. Surprisingly, despite decreased enzyme activity, G6PD-deficient mice have faster critical speed (CS) compared to mice expressing human canonical G6PD. Post-exercise, deficient mice did not exhibit differences in RBC morphology or hemolysis, but had improved cardiac function, including cardiac output, stroke volume, sarcomere length and mitochondrial content. Proteomics analyses of cardiac and skeletal muscles (gastrocnemius, soleus) from G6PD deficient compared to sufficient mice revealed improvements in mitochondrial function and increased protein turnover via ubiquitination, especially for mitochondrial and structural myofibrillar proteins. Mass spectrometry-based metabolomics revealed alterations in energy metabolism and fatty acid oxidation. These findings challenge the traditional assumptions regarding hemolytic risk during exercise in G6PD deficiency, suggesting a potential metabolic advantage in exercise performance for individuals carrying non-canonical G6PD variants.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013968
  12. Int J Obes (Lond). 2024 Nov 11.
    Weight loss and metabolic effects of an ALDH1A1-specific inhibitor, FSI-TN42, in a diet induced mouse model of obesity.
    Jisun Paik, Andy Kim, Kevin Fogassy, Jessica M Snyder, Thea Brabb, Kimberly A Dill-McFarland, Qianchuan He, John K Amory.
       BACKGROUND: Retinoic acid (RA) participates in weight regulation and energy metabolism. Mice lacking ALDH1A1, one of the major enzymes responsible for RA biosynthesis, are resistant to diet-induced obesity. Previously, we identified FSI-TN42 (N42) as an ALDH1A1-specific inhibitor and reported its pharmacokinetics and pharmacodynamics as well as its efficacy in weight suppression.
    METHODS: In the first study, C57BL/6 J male mice were fed a high fat diet for 8 weeks to induce obesity. Mice were then divided into three groups and fed (1) moderate fat diet (MFD), (2) MFD + WIN 18,446 (1 g/kg diet), or (3) MFD + N42 (1 g/kg diet) for 8 weeks. A control group of mice were fed a low-fat diet for the entire period. Mice were weighed weekly and fasting glucose was determined every 4 weeks. Tissues were examined for potential toxicity using histopathology and complete blood counts. In the second study, we examined influences of N42 on energy balance and/or appetite by determining food intake, activity and energy expenditure in mice with obesity treated with MFD or MFD + N42. Lastly, we tested fertility with a mating study.
    RESULTS: N42 significantly accelerated weight loss compared to MFD alone in mice with obesity by reducing fat mass without decreasing lean mass. N42 did not alter food intake or activity levels. While mice treated with N42 lost significantly more weight, they maintained a similar level of energy expenditure compared to mice fed MFD only. Mice fed N42 preferentially used fat postprandially, especially under thermoneutral or mild cold challenge. N42 did not affect male fertility.
    CONCLUSIONS: N42 promotes weight loss when used with MFD in mice with diet-induced obesity without causing significant organ toxicity or male infertility. Future studies will determine if N42 can be used to promote further weight loss if combined with current weight loss drugs.
    DOI:  https://doi.org/10.1038/s41366-024-01676-3
  13. J Gen Physiol. 2024 Dec 02. pii: e202313485. [Epub ahead of print]156(12):
    Exercise training may reduce fragmented mitochondria in the ischemic-reperfused heart through DRP1.
    Mathilde Dubois, Florian Pallot, Maxime Gouin-Gravezat, Doria Boulghobra, Florence Coste, Guillaume Walther, Gregory Meyer, Isabelle Bornard, Cyril Reboul.
      Mitochondrial fission is a key trigger of cardiac ischemia-reperfusion injuries (IR). Exercise training is an efficient cardioprotective strategy, but its impact on mitochondrial fragmentation during IR remains unknown. Using isolated rat hearts, we found that exercise training limited the activation of dynamin-like protein 1 and limited mitochondrial fragmentation during IR. These results support the hypothesis that exercise training contributes to cardioprotection through its capacity to modulate the mitochondrial fragmentation during IR.
    DOI:  https://doi.org/10.1085/jgp.202313485
  14. Front Pharmacol. 2024 ;15 1453647
    (Pro)renin receptor aggravates myocardial pyroptosis in diabetic cardiomyopathy through AMPK-NLRP3 pathway.
    Shengnan Li, Jingjing Zhang, Yuewen Zhao, Li Kang, Haipeng Jie, Bo Dong.
       Introduction: As one of the most common complications of diabetes, diabetic cardiomyopathy (DCM) is the main cause of heart failure in patients with diabetes. However, the lack of effective treatments for DCM remains a clinical challenge. (Pro) renin receptor (PRR) is a member of renin angiotensin aldosterone system (RAAS). Here, we aim to determine whether PRR is involved in myocardial pyroptosis in diabetic cardiomyopathy.
    Methods: We established diabetic rats model by intraperitoneal injection of streptozotocin (STZ). PRR overexpression adenovirus or PRR knockdown adenovirus was injected into the tail vein. Western blot, histopathology and immunohistochemistry staining, ELISA and Echocardiography were used to detect cardiac function changes and myocardial injury levels of DCM rats. Primary cardiomyocytes were stimulated with high glucose and PRR overexpression or PRR knockdown was achieved by adenovirus transfection, we also used the inhibitor of AMPK to decrease the activity of AMPK. Western blot, Real-time PCR, Immunofluorescence and ELISA were used to detect the level of PRR and pyroptosis in cardiomyocyte.
    Results: We found that high glucose increased the expression of PRR in heart. After overexpression of PRR, the expression of the pyroptosis related proteins such as Caspase-1, IL-1β, IL-18, and NLRP3 was significantly increased, the phosphorylation level of AMPK was significantly decreased, and the fibrosis level was significantly increased, thus aggravating the cardiac function injury of DCM. On the contrary, PRR knockdown can alleviate the level of myocardial pyroptosis in DCM and improve cardiac function. The related mechanism was that PRR could inhibit AMPK phosphorylation and promote the activation of NLRP3 inflammasome.
    Discussion: PRR aggravated pyroptosis of cardiomyocyte, increased the dysfunction of cardiomyocyte, and may be related to the decrease of AMPK phosphorylation and the overactivation of NLRP3. This may provide new ideas and targets for the treatment of DCM.
    Keywords:  (pro)renin receptor; AMPK (AMP-activated protein kinase); NLRP3; diabetic cardiomyopathy; pyroptosis
    DOI:  https://doi.org/10.3389/fphar.2024.1453647
  15. Cell Death Dis. 2024 Nov 08. 15(11): 803
    Psmb8 inhibits mitochondrial fission and alleviates myocardial ischaemia/reperfusion injury by targeting Drp1 degradation.
    Hui-Xiang Su, Luo-Luo Xu, Pang-Bo Li, Hai-Lian Bi, Wen-Xi Jiang, Hui-Hua Li.
      The mitochondrial dynamic imbalance is an important cause of myocardial ischaemia/reperfusion (I/R) injury and dysfunction. Psmb8, as one of the immunoproteasome catalytic subunits, is a key regulator of protein homoeostasis, inflammation and some cardiac diseases. Here, we found that the expression level and activity of Psmb8 were significantly reduced in the heart of I/R mice and in subjects with myocardial infarction (MI). Cardiomyocyte-specific Psmb8 overexpression in mice markedly ameliorated I/R-mediated cardiac injury and dysfunction, which was accompanied by reduced mitochondrial division via the downregulation of dynamin-related protein-1 (Drp1). However, Psmb8 knockout (KO) mice exhibited the opposite changes. The effects of Psmb8 on mitochondrial fission and apoptosis was confirmed in primary cardiomyocytes with overexpression or knockdown of Psmb8 in vitro. Mechanistically, Psmb8 was directly associated with Drp1 and enhanced its degradation, which subsequently suppressed I/R-mediated mitochondrial fission and cardiac injury. Conversely, knockdown of Drp1 in Psmb8-KO mice restored I/R-induced cardiac dysfunction and mitochondrial dynamic imbalance. Our study identified a new cardioprotective role of Psmb8 in cardiac I/R damage through targeting Drp1, and highlight that increasing Psmb8 activity may constitute a promising therapy for ischaemic heart disease.
    DOI:  https://doi.org/10.1038/s41419-024-07189-1
  16. Biomed Pharmacother. 2024 Nov;pii: S0753-3322(24)00865-5. [Epub ahead of print]180 116981
    Metformin restores autophagic flux and mitochondrial function in late passage myoblast to impede age-related muscle loss.
    Sooyoon Bang, Dong-Eun Kim, Hee-Taik Kang, Jong Hun Lee.
      Sarcopenia, which refers to age-related muscle loss, presents a significant challenge for the aging population. Age-related changes that contribute to sarcopenia include cellular senescence, decreased muscle stem cell number and regenerative capacity, impaired autophagy, and mitochondrial dysfunction. Metformin, an anti-diabetic agent, activates AMP-activated protein kinase (AMPK) and affects various cellular processes in addition to reducing hepatic gluconeogenesis, lowering blood glucose levels, and improving insulin resistance. However, its effect on skeletal muscle cells remains unclear. This study aimed to investigate the effects of metformin on age-related muscle loss using a late passage C2C12 cell model. The results demonstrated that metformin alleviated hallmarks of cellular senescence, including SA-β-gal activity and p21 overexpression. Moreover, treatment with pharmacological concentrations of metformin restored the reduced differentiation capacity in late passage cells, evident through increased myotube formation ability and enhanced expression of myogenic differentiation markers such as MyoD, MyoG, and MHC. These effects of metformin were attributed to enhanced autophagic activity, normalization of mitochondrial membrane potential, and improved mitochondrial respiratory capacity. These results suggest that pharmacological concentrations of metformin alleviate the hallmarks of cellular senescence, restore differentiation capacity, and improve autophagic flux and mitochondrial function. These findings support the potential use of metformin for the treatment of sarcopenia.
    Keywords:  Autophagy; Cellular senescence; Metformin; Mitochondrial dysfunction; Myogenic differentiation; Sarcopenia
    DOI:  https://doi.org/10.1016/j.biopha.2024.116981
  17. Sci Rep. 2024 11 11. 14(1): 27486
    Expression profile of tsRNAs in white adipose tissue of vitamin D deficiency young male mice with or without obesity.
    Qiaowei Jia, Yan Zhao.
      The expression of tsRNA in white adipose tissue (WAT) of VD deficiency male mice with obesity has not been reported. The healthy male C57BL/6J mice aged 4-6 weeks were divided into 4 groups according to the VD3 and fat energy supplement in daily diets. The qPCR verification further demonstrated that tRF5-20-HisGTG-3 were significantly up-regulated and mt-tRF3a-ProTGG was significantly down-regulated not only in HFVDD vs HFVDS, but aslo in HFVDD vs ConVDS. tRF5-22-CysGCA-27 were significantly up-regulated and mt-5'tiRNA-32-SerTGA, mt-5'tiRNA-33-SerTGA and mt-5'tiRNA-33-AlaTGC was significantly down-regulated only in HFVDD vs ConVDS. Enrichment analysis of the qPCR verified DE tsRNAs showed that the 3 up-regulated tsRNAs seemed to be associated with FoxO signaling pathway, GnRH secretion, 2-Oxocarboxylic acid metabolism, Autophagy-animal, Glucagon and insulin signaling pathway, while 4 down-regulated tsRNA seemed to be associated with cell communication, primary metabolic process, metabolic process, response to stimulus, multicellular organismal process, cellular metabolic process, cellular process and biological regulation. The tsRNAs were differentially expressed in VD deficiency with obesity, especially tRF5-20-HisGTG-3, tRF5-22-CysGCA-27, tRF3a-GlyGCC-1, mt-5'tiRNA-33-AlaTGC, mt-5'tiRNA-33-SerTGA, mt-5'tiRNA-32-SerTGA and mt-tRF3a-ProTGG. These tsRNAs seemed to be associated with FoxO signaling pathway, GnRH secretion, 2-oxocarboxylic acid metabolism, autophagy, glucagon and insulin signaling pathway, metabolic process and biological regulation.
    Keywords:  Adipose tissue; Obesity; TRFs; TiRNAs; TsRNA expression profile; Vitamin D
    DOI:  https://doi.org/10.1038/s41598-024-77910-9
  18. ACS Pharmacol Transl Sci. 2024 Nov 08. 7(11): 3279-3298
    Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases.
    Linh Thi Truc Pham, Supachoke Mangmool, Warisara Parichatikanond.
      Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.
    DOI:  https://doi.org/10.1021/acsptsci.4c00240
  19. PLoS One. 2024 ;19(11): e0311039
    Apolipoprotein A-I priming via SR-BI and ABCA1 receptor binding upregulates mitochondrial metabolism to promote insulin secretion in INS-1E cells.
    Claire L Lyons, Elaine Cowan, Oktawia Nilsson, Manca Mohar, Pablo Peña-Martínez, Lena Eliasson, Jens O Lagerstedt.
      Apolipoprotein A-I (ApoA-I), the primary component of high-density lipoprotein (HDL) cholesterol primes β-cells to increase insulin secretion, however, the mechanisms involved are not fully defined. Here, we aimed to confirm ApoA-I receptors in β-cells and delineate ApoA-I-receptor pathways in β-cell insulin output. An LRC-TriCEPS experiment was performed using the INS-1E rat β-cell model and ApoA-I for unbiased identification of ApoA-I receptors. Identified targets, alongside ATP binding cassette transporter A1 (ABCA1) (included control) were silenced in the same cells, and insulin secretion (ELISA) and mitochondrial metabolism (seahorse) were assessed with/without ApoA-I priming. Human β-cell expression data was used to investigate ApoA-I receptor pathways in type 2 diabetes (T2D). Scavenger receptor B1 (SR-BI) and regulator of microtubule dynamics 1 were identified as ApoA-I targets. SR-BI or ABCA1 silencing abolished ApoA-I induced increases in insulin secretion. ApoA-I priming increased mitochondrial OXPHOS, however this was greatly attenuated with SR-BI or ABCA1 silencing. Supporting this, human β-cell expression data investigations found SR-BI and ABCA1 to be correlated with genes associated with mitochondrial pathways. In all, SR-BI and ABCA1 correlated with 73 and 3 genes differentially expressed in T2D, respectively. We confirm that SR-BI and ABCA1 are the primary β-cell ApoA-I receptors and demonstrate that ApoA-I priming enhances β-cell insulin secretion via the upregulation of mitochondrial metabolism through ApoA-I-SR-BI and ApoA-I-ABCA1 pathways. We propose that SR-BI relies on mitochondrial and exocytotic pathways, while ABCA1 depends solely on mitochondrial pathways. Our findings uncover new targets in ApoA-I β-cell mechanism for T2D therapies.
    DOI:  https://doi.org/10.1371/journal.pone.0311039
  20. Nature. 2024 Nov 13.
    NK2R control of energy expenditure and feeding to treat metabolic diseases.
    Frederike Sass, Tao Ma, Jeppe H Ekberg, Melissa Kirigiti, Mario G Ureña, Lucile Dollet, Jenny M Brown, Astrid L Basse, Warren T Yacawych, Hayley B Burm, Mette K Andersen, Thomas S Nielsen, Abigail J Tomlinson, Oksana Dmytiyeva, Dan P Christensen, Lindsay Bader, Camilla T Vo, Yaxu Wang, Dylan M Rausch, Cecilie K Kristensen, María Gestal-Mato, Wietse In Het Panhuis, Kim A Sjøberg, Stace Kernodle, Jacob E Petersen, Artem Pavlovskyi, Manbir Sandhu, Ida Moltke, Marit E Jørgensen, Anders Albrechtsen, Niels Grarup, M Madan Babu, Patrick C N Rensen, Sander Kooijman, Randy J Seeley, Anna Worthmann, Joerg Heeren, Tune H Pers, Torben Hansen, Magnus B F Gustafsson, Mads Tang-Christensen, Tuomas O Kilpeläinen, Martin G Myers, Paul Kievit, Thue W Schwartz, Jakob B Hansen, Zachary Gerhart-Hines.
      The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity and type 2 diabetes1. Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects2-4, and so far, no safe energy-expending option has reached the clinic. Here we show that activation of neurokinin 2 receptor (NK2R) is sufficient to suppress appetite centrally and increase energy expenditure peripherally. We focused on NK2R after revealing its genetic links to obesity and glucose control. However, therapeutically exploiting NK2R signalling has previously been unattainable because its endogenous ligand, neurokinin A, is short-lived and lacks receptor specificity5,6. Therefore, we developed selective, long-acting NK2R agonists with potential for once-weekly administration in humans. In mice, these agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signalling. Additionally, a hyperinsulinaemic-euglycaemic clamp reveals that NK2R agonism acutely enhances insulin sensitization. In diabetic, obese macaques, NK2R activation significantly decreases body weight, blood glucose, triglycerides and cholesterol, and ameliorates insulin resistance. These findings identify a single receptor target that leverages both energy-expending and appetite-suppressing programmes to improve energy homeostasis and reverse cardiometabolic dysfunction across species.
    DOI:  https://doi.org/10.1038/s41586-024-08207-0
  21. J Cell Physiol. 2024 Nov 12.
    Estrogen Regulates Mitochondrial Activity Through Inducing Brain-Derived Neurotrophic Factor Expression in Skeletal Muscle.
    Margaret Chui Ling Tse, Brian Pak Shing Pang, Xinyi Bi, Teresa Xinci Ooi, Wing Suen Chan, Jiangwen Zhang, Chi Bun Chan.
      Estrogen is an essential hormone for the development and functional activities of reproductive organs. Recent studies showed that estrogen signaling is also an important regulator of lipid and glucose metabolism in a number of tissues, but the molecular mechanism is not fully understood. We report here that estrogen is a stimulator of brain-derived neurotrophic factor (BDNF) synthesis in the skeletal muscle. Estradiol (E2), but not testosterone, induces a dose- and time-dependent BDNF production in cultured myotubes. Estrogen depletion in ovariectomized mice significantly reduced Bdnf expression in the glycolytic myofibers, which could be rescued after E2 administration. Mechanistically, E2 stimulation triggered the tethering of estrogen receptor (ER) α, but not ERβ, to the estrogen-responsive element on promoter VI of the Bdnf gene in skeletal muscle. When Bdnf production was inhibited by shRNA in C2C12 myotubes, E2-induced mitochondria activation and pyruvate dehydrogenase kinase 4 expressions were jeopardized. Collectively, our results demonstrate that BDNF is an underrecognized effector of estrogen in regulating mitochondrial activity and fuel metabolism in the skeletal muscle.
    Keywords:  brain‐derived neurotrophic factor; estrogen; mitochondrial activity; skeletal muscle
    DOI:  https://doi.org/10.1002/jcp.31483
  22. JACC Basic Transl Sci. 2024 Oct;9(10): 1211-1230
    SIRT1 Ameliorates Lamin A/C Deficiency-Induced Cardiac Dysfunction by Promoting Mitochondrial Bioenergetics.
    Zunhui Du, Yanting Zhou, Qiheng Li, Yuan Xie, Tingfang Zhu, Jing Qiao, Ruihong Zhang, Yangyang Bao, Lingjie Wang, Yinyin Xie, Jinwei Quan, Menglu Lin, Ning Zhang, Qi Jin, Wenbin Liang, Liqun Wu, Tong Yin, Yucai Xie.
      Dilated cardiomyopathy (DCM) is associated with high mortality despite advanced therapies. The LMNA gene encodes lamin A/C and is the second most frequently mutated gene associated with DCM, for which therapeutic options are limited. Here we generated Lmna -/- mice and found they exhibited cardiac dysfunction at the age of 1 month but not at 2 weeks. Proteomics showed down-regulation of mitochondrial function-related pathways in Lmna -/- hearts. Moreover, early injured mitochondria with decreased cristae density and sirtuin 1 (SIRT1) down-regulation were observed in 2-week-old Lmna -/- hearts. Adenoviral overexpression of SIRT1 in lamin A/C knockdown neonatal rat ventricular myocytes improved mitochondrial oxidative respiration capacity. Adeno-associated virus-mediated SIRT1 overexpression alleviated mitochondrial injury, cardiac systolic dysfunction, ventricular dilation, and fibrosis, and prolonged lifespan in Lmna -/- mice. Mechanistically, LMNA maintains mitochondrial bioenergetics through the SIRT1-PARKIN axis. Our results suggest that targeting the SIRT1 signaling pathway is expected to be a novel therapeutic strategy for LMNA mutation-associated DCM.
    Keywords:  LMNA; SIRT1; dilated cardiomyopathy; mitochondrial bioenergetics; proteomics
    DOI:  https://doi.org/10.1016/j.jacbts.2024.05.011
  23. JCI Insight. 2024 Nov 08. pii: e187849. [Epub ahead of print]9(21):
    Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
    Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Luis Cedeño-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.
      
    DOI:  https://doi.org/10.1172/jci.insight.187849
  24. Mol Metab. 2024 Nov 11. pii: S2212-8778(24)00195-9. [Epub ahead of print] 102064
    Variable glucagon metabolic actions in diverse mouse models of obesity and type 2 diabetes.
    Yuqin Wu, Andrea Y Chan, Jana Hauke, Okka Htin Aung, Ashish Foollee, Maria Almira S Cleofe, Helen Stölting, Mei-Ling Han, Katherine J Jeppe, Christopher K Barlow, Jürgen G Okun, Patricia M Rusu, Adam J Rose.
       OBJECTIVE: The study aimed to investigate the effects of glucagon on metabolic pathways in mouse models of obesity, fatty liver disease, and type 2 diabetes (T2D) to determine the extent and variability of hepatic glucagon resistance in these conditions.
    METHODS: We investigated glucagon's effects in mouse models of fatty liver disease, obesity, and type 2 diabetes (T2D), including male BKS-db/db, high-fat diet-fed, and western diet-fed C57Bl/6 mice. Glucagon tolerance tests were performed using the selective glucagon receptor agonist acyl-glucagon (IUB288). Blood glucose, serum and liver metabolites include lipids and amino acids were measured. Additionally, liver protein expression related to glucagon signalling and a comprehensive liver metabolomics were performed.
    RESULTS: Western diet-fed mice displayed impaired glucagon response, with reduced blood glucose and PKA activation. In contrast, high-fat diet-fed and db/db mice maintained normal glucagon sensitivity, showing significant elevations in blood glucose and phospho-PKA motif protein expression. Acyl-glucagon treatment also lowered liver alanine and histidine levels in high-fat diet-fed mice, but not in western diet-fed mice. Additionally, some amino acids, such as methionine, were increased by acyl-glucagon only in chow diet control mice. Despite normal glucagon sensitivity in PKA signalling, db/db mice had a distinct metabolomic response, with acyl-glucagon significantly altering 90 metabolites in db/+ mice but only 42 in db/db mice, and classic glucagon-regulated metabolites, such as cyclic adenosine monophosphate (cAMP), being less responsive in db/db mice.
    CONCLUSIONS: The study reveals that hepatic glucagon resistance in obesity and T2D is complex and not uniform across metabolic pathways, underscoring the complexity of glucagon action in these conditions.
    Keywords:  Acylcarnitine; Amino acids; Diabetes; Glucagon; Obesity
    DOI:  https://doi.org/10.1016/j.molmet.2024.102064
  25. Obesity (Silver Spring). 2024 Nov 14.
    Attenuation of high-fat diet-induced weight gain by apolipoprotein A4.
    Hsuan-Chih N Kuo, Zachary LaRussa, Flora Mengyang Xu, Leslie A Consitt, Min Liu, W Sean Davidson, Vishwajeet Puri, Karen T Coschigano, Haifei Shi, Chunmin C Lo.
       OBJECTIVE: Apolipoprotein A4 (APOA4) is synthesized by the small intestine in response to dietary lipids. Chronic exposure to a high-fat diet (HFD) desensitizes lipid-induced APOA4 production and attenuates brown adipose tissue (BAT) thermogenesis. We hypothesized that exogenous APOA4 could increase BAT thermogenesis and energy expenditure in HFD-fed mice, resulting in decreased obesity and improved glucose tolerance.
    METHODS: BAT and inguinal white adipose tissue (IWAT) thermogenesis, body composition, energy intake and expenditure, and locomotor activity were measured using an infrared camera, immunoblots, quantitative magnetic resonance imaging, and a comprehensive lab animal monitoring system. An intraperitoneal glucose tolerance test and hepatic lipid accumulation and steatosis were assayed.
    RESULTS: Mice receiving continuous infusion of APOA4 for the last 4 weeks of 10 weeks of HFD feeding gained no additional body weight and had reduced fat mass but enhanced BAT and IWAT thermogenesis and energy expenditure, despite unaltered food intake and locomotor activity. Additionally, APOA4 infusion elevated fatty acid β oxidation; decreased lipogenesis, lipid accumulation, and steatosis in liver; and improved glucose tolerance.
    CONCLUSIONS: Maintenance of plasma APOA4 via exogenous APOA4 protein parallels elevation of BAT and IWAT thermogenesis, hepatic fatty acid β oxidation, and overall energy expenditure, with subsequent prevention of additional weight gain in HFD-fed obese mice.
    DOI:  https://doi.org/10.1002/oby.24155
  26. Cells. 2024 Oct 29. pii: 1789. [Epub ahead of print]13(21):
    Mitochondrial Dysfunction and Metabolic Disturbances Induced by Viral Infections.
    Sandra E Pérez, Monika Gooz, Eduardo N Maldonado.
      Viruses are intracellular parasites that utilize organelles, signaling pathways, and the bioenergetics machinery of the cell to replicate the genome and synthesize proteins to build up new viral particles. Mitochondria are key to supporting the virus life cycle by sustaining energy production, metabolism, and synthesis of macromolecules. Mitochondria also contribute to the antiviral innate immune response. Here, we describe the different mechanisms involved in virus-mitochondria interactions. We analyze the effects of viral infections on the metabolism of glucose in the Warburg phenotype, glutamine, and fatty acids. We also describe how viruses directly regulate mitochondrial function through modulation of the activity of the electron transport chain, the generation of reactive oxygen species, the balance between fission and fusion, and the regulation of voltage-dependent anion channels. In addition, we discuss the evasion strategies used to avoid mitochondrial-associated mechanisms that inhibit viral replication. Overall, this review aims to provide a comprehensive view of how viruses modulate mitochondrial function to maintain their replicative capabilities.
    Keywords:  VDACs; Warburg; electron transport chain; fatty acids; glucose; glutamine; innate immunity; metabolic reprogramming; mitochondria; reactive oxygen species; virus
    DOI:  https://doi.org/10.3390/cells13211789
  27. Endocr J. 2024 Nov 14.
    Effects of breaking up prolonged sitting via exercise snacks intervention on the body composition and plasma metabolomics of sedentary obese adults: a randomized controlled trial.
    Jianming Zhou, Xiaoning Gao, Dandan Zhang, Chuanwu Jiang, Wenbing Yu.
      Obesity resulting from long-term sedentary a significant threat to human health. This study explores the effects of exercise snack intervention on body composition and plasma metabolomics in sedentary obese adults. Participants in the snack group were subjected to 4 days of sprint exercises by stair-climbing per week for 12 weeks. Systemic and regional fat mass, epicardial adipose tissue (EAT), abdominal visceral (AVFA) and subcutaneous (ASFA) fat area and plasma metabolomics data were measured before and after intervention. A higher improvement of EAT, AVFA and ASFA in the snack group compared to that in the control group, with a significant interaction effect (p < 0.05). The key differential metabolites between the two groups include isoleucine, glycine and serine. The proposed exercise snack effectively reduced the amount of AVFA and EAT. The change in body composition may be associated with the altered pathways of isoleucine, glycine, and serine metabolism.
    Keywords:  Exercise snacks; Obese adults; Plasma metabolomics
    DOI:  https://doi.org/10.1507/endocrj.EJ24-0377
  28. ACS Pharmacol Transl Sci. 2024 Nov 08. 7(11): 3462-3475
    Tat-Beclin-1 Ameliorates Memory by Improving Neuronal Cytoarchitecture and Mitigating Mitochondrial Dysfunction in Scopolamine-Induced Amnesic Male Mice.
    Ela Mishra, Mahendra Kumar Thakur.
      Mitophagy, the targeted breakdown of damaged mitochondria, plays a vital role in maintaining cellular homeostasis. As impairment of mitophagy leads to neurodegeneration and memory decline, the current study explores the therapeutic potential of an autophagy inducer Tat-Beclin-1 during scopolamine-induced amnesia. Tat-Beclin-1 improved contextual and recognition memory and also mitochondrial ultrastructure by restoring mitochondrial length and area and reducing the number of fragmented mitochondria. Tat-Beclin-1 upregulated the expression of genes associated with mitophagy (PTEN-induced kinase 1, Parkin, Lamp2, and LC3), mitochondrial fusion (Mfn1, Mfn2, and optic atrophy1), and fission (dynamin-related protein 1 and Fis1) in amnesic mice. Subsequently, these results were supported by a decreased level of p-Drp1 (S616) and Drp 1 ratios and an increased level of Mfn2, LC3BI, and BII in Tat-Beclin-1-treated mice. Moreover, Tat-Beclin-1 maintained mitochondrial membrane potential and complex I/V activity in amnesic mice. Tat-Beclin-1 enhanced myelination and diminished the activity of acetylcholinesterase and caspase-3 activity. Sholl analysis revealed augmented dendritic branching and length, elevated dendritic spine density, and upregulated the expression of synaptophysin and PSD95 proteins, indicating neuronal plasticity enhancement by Tat-Beclin-1. Thus, these findings provide valuable insights into the therapeutic potential of Tat-Beclin-1, addressing mitochondrial dysfunction to mitigate cognitive impairment associated with amnesic conditions.
    DOI:  https://doi.org/10.1021/acsptsci.4c00283
  29. J Clin Endocrinol Metab. 2024 Nov 12. pii: dgae775. [Epub ahead of print]
    Weight Loss Induces Changes in Vitamin D Status in Women with Obesity but not in Men: a Randomized Clinical Trial.
    Rune Holt, Joachim Holt, Mads Joon Jorsal, Rasmus M Sandsdal, Simon B K Jensen, Sarah Byberg, Christian Rimer Juhl, Julie Rehné Lundgren, Charlotte Janus, Bente Merete Stallknecht, Jens Juul Holst, Anders Juul, Sten Madsbad, Martin Blomberg Jensen, Signe Sørensen Torekov.
       CONTEXT: Obesity is associated with low vitamin D and recent studies have suggested a difference in vitamin D metabolism between females and males.
    OBJECTIVE: The aim of this study was to investigate the effects of weight loss on vitamin D status in individuals with obesity, and secondarily, whether vitamin D metabolism differs between women and men.
    METHODS: Secondary analysis from a randomized placebo-controlled trial, designed to investigate the efficacy of 52 weeks of treatment with either liraglutide, exercise or combined, compared with placebo on weight loss maintenance after an 8-week low-calorie diet-induced weight loss in 195 individuals with obesity (BMI 32-43 kg/m2).
    RESULTS: The low-calorie diet-induced weight loss resulted in an increase in serum 25(OH)D in both women and men (12 nmol/L (95%CI 9-15) and 13 nmol/L (95%CI 8-17); p < 0.001 for both). Women who experienced a further weight loss during the 52 weeks of intervention had an increase in serum 25(OH)D compared with women regaining weight (14 nmol/L (95%CI 6-22); p = 0.001). Interestingly, women experiencing further weight loss at week 52 had a lower serum 25(OH)D at baseline compared with women regaining weight (54 nmol/L (SD 19) vs. 70 nmol/L (SD 25); p < 0.001).
    CONCLUSION: Weight loss induced by a low-calorie diet resulted in an increase in serum 25(OH)D in both women and men. Only in women, further weight loss had an additional beneficial impact on vitamin D. Additionally, initial low serum 25(OH)D was associated with successful weight loss maintenance in women, but not men.
    Keywords:  Glucagon-like peptide-1 (GLP-1) receptor agonist; Obesity; Sex differences; Vitamin D; Weight loss
    DOI:  https://doi.org/10.1210/clinem/dgae775
  30. Int J Mol Sci. 2024 Oct 30. pii: 11697. [Epub ahead of print]25(21):
    Ischemic Rescue Potential of Conditioned Medium Derived from Skeletal Muscle Cells-Seeded Electrospun Fiber-Coated Human Amniotic Membrane Scaffolds.
    Hanis Nazihah Hasmad, Abid Nordin, Shiplu Roy Chowdhury, Nadiah Sulaiman, Yogeswaran Lokanathan.
      Revascularization procedures such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are crucial to restore blood flow to the heart and are used in the treatment of myocardial infarction (MI). However, these techniques are known to cause myocardial reperfusion injury in the ischemic heart. The present study aims to mimic ischemia-reperfusion injury in vitro on primary human cardiomyocytes (HCMs) and use the established injury model to study the rescue mechanism of skeletal muscle cell (SkM)-seeded electrospun fiber-coated human amniotic membrane scaffold (EF-HAM) on injured cardiomyocytes through paracrine secretion. An in vitro ischemia-reperfusion injury model was established by exposing the HCM to 5 h of hypoxia, followed by a 6 h reoxygenation period. Six different conditioned media (CM) including three derived from SkM-seeded EF-HAMs were introduced to the injured cells to investigate the cardioprotective effect of the CM. Cell survival analysis, caspase-3 and XIAP expression profiling, mitochondrial membrane potential analysis, and measurement of reactive oxygen species (ROS) were conducted to evaluate the outcomes of the study. The results revealed a significant increase in the viability of HCM exposed to H/R injury by 77.2% (p < 0.01), 111.8% (p < 0.001), 68.7% (p < 0.05), and 69.5% (p < 0.05) when supplemented with HAM CM, EF-HAM 3 min CM, EF-HAM 5 min CM, and EF-HAM 7 min CM, respectively. Furthermore, CM derived from SkM-seeded EF-HAM scaffolds positively impacted hypoxia-/reoxygenation-induced changes in caspase-3 expression, mitochondrial membrane potential, and reactive oxygen species generation, but not in XIAP expression. These findings suggest that EF-HAM composite scaffolds can exert antiapoptotic and cardioregenerative effects on primary human cardiomyocytes through the paracrine mechanism.
    Keywords:  amnion; electrospun fiber; ischemia; paracrine signaling; skeletal muscle cells
    DOI:  https://doi.org/10.3390/ijms252111697
  31. Mech Ageing Dev. 2024 Nov 06. pii: S0047-6374(24)00104-0. [Epub ahead of print]222 112004
    Differential Plin5 response to high-fat diet in cardiomyocytes isolated from young and aged mice.
    Patricia Baumgarten, Tobias Jung, Christiane Ott, Tilman Grune.
      This study investigates the differences in the heart response to an 8-week high-fat diet between young and aged mice. Isolated cardiomyocytes reveal a significant lower level in the lipid droplet-associated protein Plin5 in aged mice. High-fat diet, however, leads to an induction of Plin5 in aged mice and a low-response of lipid metabolism, whereas in cardiomyocytes from young animals the Plin5 level was largely unaffected by high-fat diet whereas several lipid metabolizing enzymes were induced. Therefore, the high-fat diet induced lipid droplet accumulation is more pronounced in cardiomyocytes isolated from aged animals.
    Keywords:  Aging; Heart; High-fat diet; Plin5
    DOI:  https://doi.org/10.1016/j.mad.2024.112004
  32. Nutrients. 2024 Nov 04. pii: 3780. [Epub ahead of print]16(21):
    Euglena Attenuates High-Fat-Diet-Induced Obesity and Especially Glucose Intolerance.
    Tengteng Ji, Bing Fang, Yutong Jin, Chenyan Zheng, Xinlei Yuan, Jianguo Dong, Le Cheng, Fang Wu.
      Background: Obesity, a global disease, can lead to different chronic diseases and a series of social health problems. Lifestyle changes, especially dietary changes, are the most effective way to treat obesity. Euglena, a novel food, has attracted much attention. Previous studies have shown that Euglena is an important modulator of the host immune response. In this study, the effects of Euglena as a nutritional intervention in high-fat-diet-induced obese C57BL/6J mice were investigated regarding adipose tissue accumulation and lipid and glucose metabolism by gavage at the dose of 100 mg/kg bodyweight for 9 weeks. This study is one of the few to investigate, in detail, the preventive effects of dietary Euglena on obesity. Methods: Five-week-old male C57BL/6J mice were fed with a high-fat diet (HFD) to induce obesity. An obesity model was created by feeding the high-fat diet for a period of 10 weeks. Obese mice were randomized into 2 groups with the same mean body weight, and no significant differences were observed between the groups: (1) the mice in the HEG group were maintained on a high-fat diet and daily gavaged with Euglena (100 mg/kg body weight) dissolved in saline (n = 7); and (2) the mice in the HFD group were maintained on a high-fat diet and daily gavaged with saline with the same volume (n = 7). The experiment finished after a nine-week period. Results: The results showed that Euglena could reduce the accumulation of white body fat, including subcutaneous fat and visceral fat, and mainly targeted subcutaneous fat. Euglena also reduced adipocyte particle size expansion, promoted lipolysis in adipose (adipose triglyceride lipase and hormone-sensitive triglyceride lipase) and liver tissue (reduced non-esterified fatty acid content), and improved obesity-induced ectopic fat deposition and glucose tolerance. Conclusions: Our findings suggest that Euglena, as a nutritional intervention in HFDs, efficiently reduces body weight and white adipose tissue deposition. The mechanism of Euglena is mainly though enhancing lipolysis. It is worth noting that Euglena β-glucan recovers the hyperglycemia and accumulation of ectopic fat within the liver induced by HFD. Our study is one of the few studies to report in detail the preventive effects of dietary Euglena on obesity in vivo. This study revealed that Euglena also has an important ameliorative effect on obesity and metabolic disorders, which laid a theoretical foundation for its future application in functional foods.
    Keywords:  Euglena; anti-obesity; fat deposition; weight loss
    DOI:  https://doi.org/10.3390/nu16213780
  33. Diabetes Obes Metab. 2024 Nov 11.
    L-aspartate ameliorates diet-induced obesity by increasing adipocyte energy expenditure.
    Shi-Yao Guo, Yu-Tao Hu, Yong Rao, Zhi Jiang, Chan Li, Yu-Wei Lin, Shu-Min Xu, Dan-Dan Zhao, Li-Yuan Wei, Shi-Liang Huang, Qing-Jiang Li, Jia-Heng Tan, Shuo-Bin Chen, Zhi-Shu Huang.
       AIMS: Obesity always leads to profound perturbation of metabolome. Metabolome studies enrich the knowledge on associations between endogenous metabolites and obesity, potentially providing innovative strategies for the development of novel anti-obesity pharmacotherapy. This study aims to identify an endogenous metabolite that regulates energy expenditure and to explore its application for obesity treatment.
    MATERIALS AND METHODS: C57BL/6 mice were fed with a high-fat and high-cholesterol (HFC) diet, comprising 60% fat and 1.2% cholesterol, for 12 weeks to induce obesity. Significant metabolites were identified in the livers of both health and obese mice through comparative hepatic metabolomics analysis. Correlation between serum or adipose L-aspartate level and body weight in obese mice, as well as human body mass index (BMI), was evaluated. In addition, saline or 200 mg/kg L-aspartate was orally administrated to HFC diet mice and HFC diet-induced obese mice for 6-7 weeks. Body weight, adipose tissue weight, glucose tolerance and liver damage were assessed to evaluate the effect on obesity prevention and treatment. Comprehensive lab animal monitoring system (CLAMS) and seahorse assay were employed to investigate the regulatory effect of L-aspartate on energy metabolism in vivo and in vitro, respectively. 3T3-L1 preadipocytes and murine white adipose tissue (WAT) were utilized to examine the impact of L-aspartate on adipocyte adipogenesis and lipogenesis and cellular signalling pathway in vitro and in vivo.
    RESULTS: L-aspartate, an approved drug for liver injury and chronic fatigue, was identified as an endogenous inducer of energy expenditure. Serum or adipose L-aspartate levels were found to be negatively correlated with the severity of obesity in both humans and mice. Administration of L-aspartate to HFC diet mice led to a significant reduction in body weight, with decreases of 14.5% in HFC diet mice and 8.5% in HFC diet-induced obese mice, respectively. In addition, the treatment improved related metabolic syndrome (Figure 2 and Figure S3). These therapeutics were associated with enhancements in whole-body energy expenditure and suppression of adipocyte adipogenesis along with activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway.
    CONCLUSION: L-aspartate may serve as a novel endogenous inducer of energy expenditure and suppressor of adipogenesis and lipogenesis along with activation of AMPK, thereby offering a promising therapeutic strategy for obesity prevention and treatment.
    Keywords:  AMPK signalling pathway; L‐aspartate; energy expenditure; obesity
    DOI:  https://doi.org/10.1111/dom.16053
  34. Mol Med Rep. 2025 Jan;pii: 17. [Epub ahead of print]31(1):
    Peroxisome proliferator‑activated receptor γ coactivator‑1α in heart disease (Review).
    Siyu Sun, Huige Guo, Guohui Chen, Hui Zhang, Zhanrui Zhang, Xiulong Wang, Dongxu Li, Xuefang Li, Guoan Zhao, Fei Lin.
      Heart disease (HD) is a general term for various diseases affecting the heart. An increasing body of evidence suggests that the pathogenesis of HD is closely related to mitochondrial dysfunction. Peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) is a transcriptional coactivator that plays an important role in mitochondrial function by regulating mitochondrial biogenesis, energy metabolism and oxidative stress. The present review shows that PGC‑1α expression and activity in the heart are controlled by multiple signaling pathways, including adenosine monophosphate‑activated protein kinase, sirtuin 1/3 and nuclear factor κB. These can mediate the activation or inhibition of transcription and post‑translational modifications (such as phosphorylation and acetylation) of PGC‑1α. Furthermore, it highlighted the recent progress of PGC‑1α in HD, including heart failure, coronary heart disease, diabetic cardiomyopathy, drug‑induced cardiotoxicity and arrhythmia. Understanding the mechanisms underlying PGC‑1α in response to pathological stimulation may prove to be beneficial in developing new ideas and strategies for preventing and treating HDs. Meanwhile, the present review explored why the opposite results occurred when PGC‑1α was used as a target therapy.
    Keywords:  energy metabolism; heart disease; mitochondrial; oxidative stress; peroxisome proliferator‑activated receptor γ coactivator‑1α
    DOI:  https://doi.org/10.3892/mmr.2024.13382
  35. Circ Heart Fail. 2024 Nov 08. e011729
    IL1RAP Blockade With a Monoclonal Antibody Reduces Cardiac Inflammation and Preserves Heart Function in Viral and Autoimmune Myocarditis.
    Diego A Lema, Gabriel Jakobsson, Abdel Daoud, David Elias, Monica V Talor, Sara Rattik, Caitríona Grönberg, Hannah Kalinoski, Elin Jaensson Gyllenbäck, Nadan Wang, David Liberg, Alexandru Schiopu, Daniela Čiháková.
       BACKGROUND: Currently, there are no therapies targeting specific pathogenic pathways in myocarditis. IL (interleukin)-1 blockade has shown promise in preclinical studies and case reports. We hypothesized that blockade of IL1RAP (IL-1 receptor accessory protein), a shared subunit of the IL-1, IL-33, and IL-36 receptors, could be more efficient than IL-1 blockade alone.
    METHODS: We induced coxsackievirus B3 (CVB3)-mediated or experimental autoimmune myocarditis (EAM) in BALB/c mice, followed by treatment with an Fc (fragment crystallizable)-modified mIgG2a mouse anti-mouse IL1RAP monoclonal antibody (mCAN10). Myocarditis severity and immune infiltration were assessed by histology and flow cytometry. Cardiac function was measured by echocardiography. We used spatial transcriptomics (Visium 10× Genomics) to compare the gene expression landscape in the hearts of mCAN10-treated versus control mice.
    RESULTS: IL1RAP blockade reduced CVB3 and EAM severity. In EAM, the treatment prevented deterioration of cardiac function, measured on day 42 post-disease induction (left ventricular ejection fraction: 56.5% versus 51.0% in isotype controls [P=0.002] and versus 51.4% in mice treated with anti-IL-1β antibodies alone [P=0.003]; n=10-11 mice per group). In the CVB3 model, mCAN10 did not impede viral clearance from the heart and significantly lowered the numbers of CD4+ (cluster of differentiation 4) T cells (P=0.025), inflammatory Ly6C+CCR2+ (lymphocyte antigen 6 complex, locus C/C-C motif chemokine receptor 2) monocytes (P=0.038), neutrophils (P=0.001) and eosinophils (P<0.001) infiltrating the myocardium. The spatial transcriptomic analysis revealed reduced canonical IL-1 signaling and chemokine expression in cardiac immune foci in CVB3-infected mice treated with IL1RAP blockade.
    CONCLUSIONS: Blocking IL1RAP reduces acute CVB3 myocarditis and EAM severity and preserves cardiac function in EAM. We conclude that IL1RAP blockade is a potential therapeutic strategy in viral and autoimmune myocarditis.
    Keywords:  eosinophils; flow cytometry; monocytes; myocarditis; therapeutics
    DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.011729
  36. J Biol Chem. 2024 Nov 05. pii: S0021-9258(24)02474-8. [Epub ahead of print] 107972
    Acute inflammation upregulates FAHFAs in adipose tissue and in co-cultured adipocytes.
    Meric Erikci Ertunc, Srihari Konduri, Zhichen Ma, Antonio F M Pinto, Cynthia J Donaldson, Jeremiah Momper, Dionicio Siegel, Alan Saghatelian.
      Since the discovery of fatty acid hydroxy fatty acids (FAHFAs), significant progress has been made in understanding their regulation, biochemistry, and physiological activities. Here, we contribute to this understanding by revealing that inflammation induces the production of fatty acid hydroxy stearic acids (FAHSAs) and fatty acid hydroxyoctadecadienoic acids (FAHODEs) in white adipose tissue depots and in adipocytes co-cultured with macrophages. In LPS-induced co-culture systems, we confirm that adipose triglyceride lipase (ATGL) is required for inflammation-induced FAHFA generation and demonstrate that inflammation is necessary for producing hydroxy fatty acids. Chemically synthesized FAHODEs show anti-inflammatory activities in vivo, but only at supraphysiological concentrations. While endogenous FAHFAs are unlikely to be anti-inflammatory due to their low concentrations, conversion of pro-inflammatory hydroxy fatty acids into FAHFAs may modulate inflammation. We test this concept by showing the pro-inflammatory lipids-hydroxyeicosatetraenoic acids (HETEs) and leukotriene B4 (LTB4)-are converted into FAHFAs in cell culture, and that two LTB4-derived FAHFAs have are modestly anti- not pro-inflammatory. Further research is needed to establish whether these increased FAFHA levels have a role in inflammation or are simply markers of inflammation, but the discovery of significant increases in FAHFA upon acute inflammation advances our knowledge of FAHFAs.
    Keywords:  ATGL; FAHFA; HETE; HODE; LPS; LTB4; adipose tissue; inflammation; lipid
    DOI:  https://doi.org/10.1016/j.jbc.2024.107972
  37. Prostaglandins Leukot Essent Fatty Acids. 2024 Sep 25. pii: S0952-3278(24)00045-0. [Epub ahead of print]203 102651
    Dose-dependency of a combined EPA:DHA mixture on incorporation, washout, and protein synthesis in C2C12 myotubes.
    M Banic, M van Dijk, F J Dijk, M J W Furber, O C Witard, N Donker, M J A Becker, S D Galloway, N Rodriguez-Sanchez.
      We demonstrate divergent incorporation and washout patterns for EPA and DHA following high and low-dose EPA+DHA incubation in C2C12 myotubes, with higher concentrations favoring n-3 PUFA incorporation. Lower n-3 PUFA concentrations increased MPS without further upregulating the mTORC1 signaling pathway. Our study provides novel insights into the temporal incorporation and washout dynamics of EPA and DHA and, specifically, their combined effect on MPS, thereby advancing knowledge regarding dietary n-3 PUFA prescription to promote skeletal muscle health in humans.
    Keywords:  Dose; Fish oil; Muscle; Time-course; mTORC1 signaling; n-3 PUFA
    DOI:  https://doi.org/10.1016/j.plefa.2024.102651
  38. Mol Biol Rep. 2024 Nov 12. 51(1): 1144
    Methylation of the ESR1 promoters in visceral adipose tissue and its relationship with obesity.
    Filiz Güçlü-Geyik, Turgay Erginel, Çağrı Güleç, Pınar Köseoğlu-Büyükkaya, Nihan Erginel-Ünaltuna.
       BACKGROUND: Obesity is associated with decreased ESR1 expression level in visceral adipose tissue. However, it is unclear exactly what mechanisms are responsible for this decline. The aim of this study was to investigate the impact of aberrant methylation of the ESR1 alternative promoters on decreased ESR1 expression and its connection to obesity.
    METHODS: Visceral adipose tissues and peripheral blood cells were obtained from 21 patients (non-obese and obese) undergoing inguinal hernia or gallbladder removal. Alternative promoter regions, C, E2 and F of the ESR1 gene, were analyzed by Methylation-Specific PCR (MSP) and mRNA levels were measured by quantitative real-time PCR (qPCR) in both visceral adipose tissue and peripheral blood cells. All statistical analyses were performed by SPSS (23.0).
    RESULTS: The methylation percentage in the three promoter regions of ESR1 was not different in obese individuals compared to non-obese individuals. We observed that promoter C had the highest methylation frequency in obese patients, although it was not statistically significant. Additionally, we observed that the hypermethylation of ESR1's promoter C was significantly associated with lower mRNA expression level in obesity (p = 0.020).
    CONCLUSION: This study suggests that methylation of ESR1 promoter C may be a factor in the development of obesity or a consequence of obesity. Further studies with advanced methods and larger study groups are needed to clarify this issue.
    Keywords:   ESR1 ; Adipose tissue; Methylation; Methylation-specific PCR; Obesity
    DOI:  https://doi.org/10.1007/s11033-024-10091-w
  39. Sci Rep. 2024 Nov 15. 14(1): 28193
    Contribution of glucose and glutamine to hypoxia-induced lipid synthesis decreases, while contribution of acetate increases, during 3T3-L1 differentiation.
    Lucie Ryskova, Katerina Pospisilova, Jiri Vavra, Tomas Wolf, Ales Dvorak, Libor Vitek, Jan Polak.
      The molecular mechanisms linking obstructive sleep apnea syndrome (OSA) to obesity and the development of metabolic diseases are still poorly understood. The role of hypoxia (a characteristic feature of OSA) in excessive fat accumulation has been proposed. The present study investigated the possible effects of hypoxia (4% oxygen) on de novo lipogenesis by tracking the major carbon sources in differentiating 3T3-L1 adipocytes. Gas-permeable cultuware was employed to cultivate 3T3-L1 adipocytes in hypoxia (4%) for 7 or 14 days of differentiation. We investigated the contribution of glutamine, glucose or acetate using 13C or 14C labelled carbons to the newly synthesized lipid pool, changes in intracellular lipid content after inhibiting citrate- or acetate-dependent pathways and gene expression of involved key enzymes. The results demonstrate that, in differentiating adipocytes, hypoxia decreased the synthesis of lipids from glucose (44.1 ± 8.8 to 27.5 ± 3.0 pmol/mg of protein, p < 0.01) and partially decreased the contribution of glutamine metabolized through the reverse tricarboxylic acid cycle (4.6% ± 0.2-4.2% ± 0.1%, p < 0.01). Conversely, the contribution of acetate, a citrate- and mitochondria-independent source of carbons, increased upon hypoxia (356.5 ± 71.4 to 649.8 ± 117.5 pmol/mg of protein, p < 0.01). Further, inhibiting the citrate- or acetate-dependent pathways decreased the intracellular lipid content by 58% and 73%, respectively (p < 0.01) showing the importance of de novo lipogenesis in hypoxia-exposed adipocytes. Altogether, hypoxia modified the utilization of carbon sources, leading to alterations in de novo lipogenesis in differentiating adipocytes and increased intracellular lipid content.
    DOI:  https://doi.org/10.1038/s41598-024-79458-0
  40. Acta Diabetol. 2024 Nov 09.
    A qualitative study of the mental health outcomes in people being treated for obesity and type 2 diabetes with glucagon-like peptide-1 receptor agonists.
    Aureliane C S Pierret, Madeleine Benton, Piya Sen Gupta, Khalida Ismail.
       OBJECTIVE: Obesity and type 2 diabetes (T2D) are associated with increased rates of mental disorders, particularly depression, anxiety and binge-eating disorder. GLP-1 receptor agonists are a novel class of pharmacological agents for obesity and T2D. We aimed to describe participants' experiences of GLP-1 receptor agonists on their mental health.
    METHODS: Qualitative, individual, semi-structured interviews were conducted in nine participants who were prescribed GLP-1 receptor agonists for the treatment of obesity and/or T2D. Mental health status was measured at time of GLP-1 receptor agonist initiation and assessed again at 12-16 weeks when the semi-structured interview took place. Data were analysed using reflexive thematic analysis.
    RESULTS: Three main themes were generated from the analysis: (1) acceptance of negative side effects for long term physical health benefits; (2) reflections on the diverse impact on mental health; (3) reduced appetite and increased control of eating behaviours.
    DISCUSSION: Overall, participants with obesity and/or T2D described a positive impact of GLP-1 receptor agonists on their mental health, especially perception of improved control of eating behaviours. This suggests GLP-1 receptor agonists should be further studied for their potential effectiveness for treatment of binge-eating disorder.
    Keywords:  Binge-eating disorder; Depression; Diabetes; GLP-1 receptor agonist; Obesity; Qualitative
    DOI:  https://doi.org/10.1007/s00592-024-02392-0
  41. Mol Biol Cell. 2024 Nov 13. mbcE24070306
    Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA.
    Brett T Wisniewski, Jason C Casler, Laura L Lackner.
      Mitochondria exist as dynamic tubular networks and the morphology of these networks impacts organelle function and cell health. Mitochondrial morphology is maintained in part by the opposing activities of mitochondrial fission and fusion. Mitochondrial fission and fusion are also required to maintain mitochondrial DNA (mtDNA) integrity. In Saccharomyces cerevisiae, the simultaneous inhibition of mitochondrial fission and fusion results in increased mtDNA mutation and the consequent loss of respiratory competence. The mechanism by which fission and fusion maintain mtDNA integrity is not fully understood. Previous work demonstrates that mtDNA is spatially linked to mitochondrial fission sites. Here, we extend this finding using live-cell imaging to localize mtDNA to mitochondrial fusion sites. While mtDNA is present at sites of mitochondrial fission and fusion, mitochondrial fission and fusion rates are not altered in cells lacking mtDNA. Using alleles that alter mitochondrial fission and fusion rates, we find that mtDNA integrity can be maintained in cells with significantly reduced, but balanced, rates of fission and fusion. In addition, we find that increasing mtDNA copy number reduces the loss of respiratory competence in double mitochondrial fission-fusion mutants. Our findings add novel insights into the relationship between mitochondrial dynamics and mtDNA integrity.
    DOI:  https://doi.org/10.1091/mbc.E24-07-0306
  42. Nat Commun. 2024 Nov 08. 15(1): 9667
    FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice.
    Xin Zhang, Yi-Peng Gao, Wen-Sheng Dong, Kang Li, Yu-Xin Hu, Yun-Jia Ye, Can Hu.
      Fibronectin type III domain-containing (FNDC) proteins play critical roles in cellular homeostasis and cardiac injury, and our recent findings define FNDC5 as a promising cardioprotectant against doxorubicin- and aging-related cardiac injury. FNDC4 displays a high homology with FNDC5; however, its role and mechanism in cardiac ischemia/reperfusion (I/R) injury remain elusive. Here, we show that cardiac and plasma FNDC4 levels are elevated during I/R injury in a hypoxia-inducible factor 1α (HIF1α)-dependent manner. Cardiac-specific FNDC4 overexpression facilitates, while cardiac-specific FNDC4 knockdown inhibits cardiomyocyte survival and angiogenesis in I/R-stressed hearts of male mice through regulating the proteasomal degradation of HIF1α. Interestingly, FNDC4 does not directly stimulate angiogenesis of endothelial cells, but increases the expression and secretion of fibroblast growth factor 1 from cardiomyocytes to enhance angiogenesis in a paracrine manner. Moreover, therapeutic administration of recombinant FNDC4 protein is sufficient to alleviate cardiac I/R injury in male mice, without resulting in significant side effects. In this work, we reveal that FNDC4 alleviates cardiac I/R injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis, and define FNDC4 as a promising predictive and therapeutic target of cardiac I/R injury.
    DOI:  https://doi.org/10.1038/s41467-024-53564-z
  43. Nutr Res. 2024 Sep 28. pii: S0271-5317(24)00132-5. [Epub ahead of print]132 95-111
    Improved metabolic stability in iNOS knockout mice with Lactobacillus supplementation.
    Hobby Aggarwal, Jyoti Gautam, Sonu Kumar Gupta, Bhabatosh Das, Yashwant Kumar, Kumaravelu Jagavelu, Madhu Dikshit.
      Oxidative and nitrosative stress play pivotal roles in normal physiological processes and the pathogenesis of metabolic disorders. Previous studies from our lab demonstrated insulin resistance (IR), and dyslipidemia in iNOS-/- mice, emphasizing the importance of maintaining optimal redox balance. These mice exhibited altered gut microbiota with decreased Lactobacillus. Therefore, we hypothesized that Lactobacillus supplementation could mitigate metabolic disturbances in iNOS-/- mice. To test this hypothesis, iNOS-/- mice and wild-type (WT) mice were divided into four groups: iNOS-/- with or without Lactobacillus supplementation, WT with or without Lactobacillus supplementation and glucose tolerance, insulin resistance, gluconeogenesis, lipids, gene expression related to glucose and lipid metabolism (qPCR), fecal gut microbiota (16S rRNA sequencing), and serum and caecum metabolomics (LC-MS) were monitored. IR and dyslipidemic iNOS-/- mice exhibited reduced microbial diversity, diminished presence of Lactobacillus, and altered serum metabolites, indicating metabolic dysregulation. Lactobacillus supplementation in iNOS-/- mice effectively reversed glucose intolerance, IR, dyslipidemia, and associated metabolic irregularities compared to WT. These improvements correlated with changes in gene expression related to fatty acid synthesis in liver and adipose tissue, lipid oxidation in liver, and lipid efflux in intestinal tissue as compared to untreated iNOS-/- mice. Despite the positive effects on metabolic markers, Lactobacillus supplementation did not reduce body weight or rectify disrupted energy balance, as evidenced by reduced VCO2 production, heat generation, and metabolic rates in iNOS-/- mice. The results suggest that Lactobacillus supplementation ameliorates metabolic disturbances but did not fully restore disrupted energy balance, highlighting complex interactions between the gut microbiome and metabolism.
    Keywords:  Dyslipidemia; Insulin resistance; Lactobacillus; Metabolome analysis; Obesity; iNOS(−/−) mice
    DOI:  https://doi.org/10.1016/j.nutres.2024.09.018
  44. JHEP Rep. 2024 Nov;6(11): 101187
    Palmitoylcarnitine impairs immunity in decompensated cirrhosis.
    Ingrid Wei Zhang, María Belén Sánchez-Rodríguez, Cristina López-Vicario, Mireia Casulleras, Marta Duran-Güell, Roger Flores-Costa, Ferran Aguilar, Michael Rothe, Paula Segalés, Carmen García-Ruiz, José C Fernández-Checa, Jonel Trebicka, Vicente Arroyo, Joan Clària.
       Background & Aims: In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells.
    Methods: Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy individuals. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leucocytes from healthy donors by determining mitochondrial membrane potential (Δψm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox systems were assessed by transmission electron microscopy and gene and protein expression analysis.
    Results: Plasma levels of several acylcarnitine species were significantly elevated in patients with AD cirrhosis compared with healthy individuals, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, p = 0.0059) impaired Δψm and reduced the spare respiratory capacity of peripheral mononuclear leucocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the expression of the antioxidant gene HMOX1, and increased CXCL8 expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into the mitochondria, reversed the suppression of HMOX1. Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced CXCL8 expression. Importantly, oxidative stress and Δψm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis.
    Conclusions: Our findings suggest that long-chain acylcarnitines induce mitochondrial injury in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis.
    Impact and implications: Patients with acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings underline the importance of immunometabolism as a treatment target in patients with acute decompensation of cirrhosis and ACLF.
    Keywords:  Acute decompensation of cirrhosis; Acylcarnitines; Immune cells; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.jhepr.2024.101187
  45. Methods Mol Biol. 2025 ;2878 117-131
    Mitochondrial Membrane Potential (ΔΨ) Fluctuations Associated with the Metabolic States of Mitochondria.
    Ivo F Machado, Raul G Miranda, João S Teodoro, Daniel J Dorta, Anabela P Rolo, Carlos M Palmeira.
      The proton electrochemical gradient generated by the respiratory chain activity accounts for over 90% of the available respiratory energy and, as such, its evaluation and accurate measurement regarding total values and fluctuations are an invaluable component of the understanding of mitochondrial function. Consequently, alterations in electric potential across the inner mitochondrial membrane generated by differential protonic accumulation and transport are known as the mitochondrial membrane potential, or Δψ, and are reflective of the functional metabolic status of mitochondria. There are several experimental approaches to measure Δψ, ranging from fluorometric evaluations to electrochemical probes. In this chapter, we describe how Δψ may be evaluated in isolated mitochondria and live cells using electrochemical and fluorescent methods, such as tetraphenylphosphonium (TPP+) and tetramethylrhodamine methyl ester (TMRM), respectively. These methods are dependent on the accumulation of cationic probes within mitochondria, which are assessed by using a TPP+-selective electrode or instruments that measure fluorescence (microplate reader and flow cytometer).
    Keywords:  Flow cytometry; Membrane potential; Metabolic states; Mitochondria; TMRM; TPP+-selective electrode
    DOI:  https://doi.org/10.1007/978-1-0716-4264-1_7
  46. NPJ Sci Food. 2024 Nov 08. 8(1): 90
    High-fiber basil seed flour reduces insulin resistance and hepatic steatosis in high-fat diet mice.
    Camila Farías, Camila Cisternas, Angie Caicedo, Lorena Mercado, Rodrigo Valenzuela, Héctor Calderón, Alejandra Espinosa, L A Videla, Loreto A Muñoz.
      The incidence of insulin resistance (IR) and hepatic steatosis is increasing, with dietary fiber playing a protective role against these disorders. Ocimum basilicum L., widely used in food, pharmaceutical, and cosmetic industries, but their health-promoting properties remain underexplored. This study evaluated the effects of a fiber-rich fraction of partially defatted basil seeds (BSF) on IR, hepatic steatosis, and polyunsaturated fatty acid and short-chain fatty acid (SCFA) profiles in high-fat diet (HFD)-fed C57BL/6 J male mice. Mice were assigned to four groups and fed either a control diet or HFD, supplemented with BSF or oat flour for 4 weeks. HFD induced IR, hepatic steatosis, proinflammatory state, and a significant decreased in SCFA production. In contrast, supplementation with BSF attenuated IR, steatosis, liver damage, oxidative stress, and inflammation, while increasing n-3 polyunsaturated fatty acids in liver, adipocytes, and erythrocytes, and enhancing SCFA production, suggesting potential therapeutic benefits in managing these conditions.
    DOI:  https://doi.org/10.1038/s41538-024-00329-z
  47. Int J Mol Sci. 2024 Oct 27. pii: 11549. [Epub ahead of print]25(21):
    Oligonol®, an Oligomerized Polyphenol from Litchi chinensis, Enhances Branched-Chain Amino Acid Transportation and Catabolism to Alleviate Sarcopenia.
    Yun-Ching Chang, Yu-Chi Chen, Yin-Ching Chan, Cheng Liu, Sue-Joan Chang.
      Branched-chain amino acids (BCAAs) are essential for muscle protein synthesis and are widely acknowledged for mitigating sarcopenia. Oligonol® (Olg), a low-molecular-weight polyphenol from Litchi chinensis, has also been found to attenuate sarcopenia by improving mitochondrial quality and positive protein turnover. This study aims to investigate the effect of Olg on BCAA-stimulated protein synthesis in sarcopenia. In sarcopenic C57BL/6 mice and senescence-accelerated mouse-prone 8 (SAMP8) mice, BCAAs were significantly decreased in skeletal muscle but increased in blood serum. Furthermore, the expressions of membrane L-type amino acid transporter 1 (LAT1) and branched-chain amino acid transaminase 2 (BCAT2) in skeletal muscle were lower in aged mice than in young mice. The administration of Olg for 8 weeks significantly increased the expressions of membrane LAT1 and BCAT2 in the skeletal muscle when compared with non-treated SAMP8 mice. We further found that BCAA deprivation via LAT1-siRNA in C2C12 myotubes inhibited the signaling of protein synthesis and facilitated ubiquitination degradation of BCAT2. In C2C12 cells mimicking sarcopenia, Olg combined with BCAA supplementation enhanced mTOR/p70S6K activity more than BCAA alone. However, blocked LAT1 by JPH203 reversed the synergistic effect of the combination of Olg and BCAAs. Taken together, changes in LAT1 and BCAT2 during aging profoundly alter BCAA availability and nutrient signaling in aged mice. Olg increases BCAA-stimulated protein synthesis via modulating BCAA transportation and BCAA catabolism. Combining Olg and BCAAs may be a useful nutritional strategy for alleviating sarcopenia.
    Keywords:  L-type amino acid transporter 1; branched-chain amino acid transaminase 2; branched-chain amino acids; low-molecular-weight polyphenol; oligonol®; protein synthesis; sarcopenia
    DOI:  https://doi.org/10.3390/ijms252111549
  48. Heart Vessels. 2024 Nov 14.
    Chest-CT-based radiomics feature of epicardial adipose tissue for screening coronary atherosclerosis.
    Qin Wei, Yanling Chen, Deqing Yuan, Fumei Nie, Jian Li, KeBing Yu, Chengwei Zhang.
       BACKGROUND AND AIMS: This study aims to investigate the diagnostic value of chest-CT epicardial adipose tissue (EAT) radiomics feature in coronary atherosclerotic stenosis.
    METHODS: Clinical data from 215 individuals who underwent coronary angiography and chest-CT scan from January to July 2022 at our institution were retrospectively analyzed. Based on the coronary angiography results, the total population, men, and women were divided into the CAD group and non-CAD group. radiomics feature of EAT at the level of the bifurcation of the left-main coronary artery on the transverse level of chest CT were measured. The features contain both first-order feature and shape-order feature.The differences between groups were analyzed using the t test or Chi-square test. The diagnostic efficacy of each parameter in diagnosing atherosclerotic stenosis of coronary arteries was assessed by plotting the receiver operating characteristic (ROC) curve.
    RESULTS: First-order features: Mean, IntDen, Median, and RawIntDen; shape-order features: Area, Perim, Round, and BSA index; and clinical index: HbA1c showed statistical significance between the CAD group and the non-CAD group. The ROC curve analysis demonstrated high diagnostic efficacy, with the best for diagnostic efficacy being Median for the first-order feature parameter (AUC, 0.753; 95% confidence interval [CI], 0.689-0.817; t = 4.785, p < 0.001), Round for the shape-order feature (AUC, 0.775; 95% CI, 0.714-0.836; t = 7.842, p < 0.001), and HbA1c for the clinical index (AUC, 0.797; 95% CI, 0.783-0.856; t = 6.406, p < 0.001). After dividing the participants into male and female subgroups, the best diagnostic efficacy was observed with the BSA index for men (AUC, 0.743; 95% CI, 0.656-0.829; t = 5.128, p < 0.001) and Round for women (AUC, 0.871; 95% CI, 0.793-0.949; t = 7.247, p < 0.001).
    CONCLUSIONS: Median, Round in radiomics feature of EAT on chest CT may play a role in the assessment of coronary atherosclerotic stenosis.
    Keywords:  Coronary atherosclerosis stenosis; Epicardial adipose tissue; Radiomics feature; Subject operating characteristic curves
    DOI:  https://doi.org/10.1007/s00380-024-02479-2
  49. PLoS One. 2024 ;19(11): e0313519
    Proteomic and ubiquitinome analysis reveal that microgravity affects glucose metabolism of mouse hearts by remodeling non-degradative ubiquitination.
    Xin Zhang, Xuemei Zhou, Zhiwei Tu, Lihua Qiang, Zhe Lu, Yuping Xie, Cui Hua Liu, Lingqiang Zhang, Yesheng Fu.
      Long-term exposure to a microgravity environment leads to structural and functional changes in hearts of astronauts. Although several studies have reported mechanisms of cardiac damage under microgravity conditions, comprehensive research on changes at the protein level in these hearts is still lacking. In this study, proteomic analysis of microgravity-exposed hearts identified 156 differentially expressed proteins, and ubiquitinomic analysis of these hearts identified 169 proteins with differential ubiquitination modifications. Integrated ubiquitinomic and proteomic analysis revealed that differential proteomic changes caused by transcription affect the immune response in microgravity-exposed hearts. Additionally, changes in ubiquitination modifications under microgravity conditions excessively activated certain kinases, such as hexokinase and phosphofructokinase, leading to cardiac metabolic disorders. These findings provide new insights into the mechanisms of cardiac damage under microgravity conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0313519
  50. Poult Sci. 2024 Oct 10. pii: S0032-5791(24)00982-9. [Epub ahead of print]103(12): 104403
    Chicken GLUT4 function via enhancing mitochondrial oxidative phosphorylation and inhibiting ribosome pathway in skeletal muscle satellite cells.
    Lin Zhang, Pengna Luo, Huihong Li, Yuxian Pan, Huaiyong Zhang, Xuemeng Si, Wen Chen, Yanqun Huang.
      Glucose Transporter 4 (GLUT4) is a crucial protein facilitating glucose uptake and metabolism across cell membranes in mammals. However, information on GLUT4 in birds has historically been limited. In this study, we investigated the dynamic expression profile of chicken GLUT4 using real-time quantitative PCR (RT-qPCR) and examined its potential effects and mechanisms via GLUT4 overexpression and RNA sequencing (RNA-seq) in chicken primary skeletal muscle satellite cells (CP-SMSCs). Our results demonstrated that chicken GLUT4 is differentially expressed across tissues, with predominant expression in skeletal muscles, and across developmental stages of CP-SMSCs, with notable upregulation during the phases of cell proliferation and early differentiation. Notably, 0.1 μM insulin for 60 min significantly elevated the expression of GLUT4 in CP-SMSCs (P < 0.05). GLUT4 overexpression in CP-SMSCs promoted cell proliferation, as evidenced by Cell Counting Kit-8 (CCK-8) (P < 0.05) and 5-Ethynyl-2'-Deoxyuridine (EDU) assays (P < 0.05), and enhanced glucose consumption following 0.1 μM insulin treatment (P < 0.05). However, it inhibited glucose consumption 12 h after the addition of 5 g/L glucose (P < 0.05). After overexpressing GLUT4, we identified 302 differentially expressed genes (DEGs) in CP-SMSCs, with 134 upregulated and 168 downregulated. These DEGs are primarily enriched in pathways such as oxidative phosphorylation, ribosome, cardiac muscle contraction, ATP metabolic processes, and mitochondrial protein complexes. Specifically, in the enriched oxidative phosphorylation pathway, the upregulated DEGs (12) encode mitochondrial proteins, while the downregulated DEGs (6) are nuclear genome-derived. The ribosomal pathway is predominantly inhibited, accompanying with the downregulation of the translocase of outer mitochondrial membrane 7 (TOMM7)/translocase of inner mitochondrial membrane 8 (TIMM8A) complex responsible for mitochondrial protein transport, and a reduction in 28S (LOC121106978) and 18S (LOC112533601) ribosomal rRNAs. In conclusion, chicken GLUT4 is dynamically modulated during development and acts as an insulin responder that significantly regulates cellular glucose uptake and cell proliferation. This regulation occurs mainly through enhancing the mitochondrial oxidative phosphorylation and inhibiting ribosomal pathway.
    Keywords:  chicken; glucose transporter 4; insulin; mitochondrial oxidative phosphorylation; skeletal muscle satellite cell
    DOI:  https://doi.org/10.1016/j.psj.2024.104403
  51. J Biol Chem. 2024 Nov 13. pii: S0021-9258(24)02497-9. [Epub ahead of print] 107995
    Engineered bacterial lipoate protein ligase A (lplA) restores lipoylation in cell models of lipoylation deficiency.
    Nolan Bick, Margaret Dreishpoon, Ava Perry, Anna Rogachevskaya, Sylvia S Bottomley, Mark D Fleming, Sarah Ducamp, Peter Tsvetkov.
      Protein lipoylation, a vital lysine posttranslational modification (PTM), plays a crucial role in the function of key mitochondrial TCA cycle enzymatic complexes. In eukaryotes, lipoyl PTM synthesis occurs exclusively through de novo pathways, relying on lipoyl synthesis/transfer enzymes, dependent upon mitochondrial fatty acid and Fe-S cluster biosynthesis. Dysregulation in any of these pathways leads to diminished cellular lipoylation. Efficient restoration of lipoylation in lipoylation deficiency cell states using either chemical or genetic approaches has been challenging due to pathway complexity and multiple upstream regulators. To address this challenge, we explored the possibility that a bacterial lipoate protein ligase (lplA) enzyme, that can salvage free lipoic acid bypassing the dependency on de novo synthesis, could be engineered to be functional in human cells. Overexpression of the engineered lplA in lipoylation null cells restored lipoylation levels, cellular respiration, and growth in low glucose conditions. Engineered lplA restored lipoylation in all tested lipoylation null cell models, mimicking defects in mitochondrial fatty acid synthesis (MECR KO), Fe-S cluster biosynthesis (BOLA3 KO), and specific lipoylation regulating enzymes (FDX1, LIAS and LIPT1 KOs). Furthermore, we describe a patient with a homozygous c.212C>T variant LIPT1 with a previously uncharacterized syndromic congenital sideroblastic anemia. K562 erythroleukemia cells engineered to harbor this missense LIPT1 allele recapitulate the lipoylation deficient phenotype and exhibit impaired proliferation in low glucose that is completely restored by engineered lplA. This synthetic approach offers a potential therapeutic strategy for treating lipoylation disorders.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107995
  52. Int J Biometeorol. 2024 Nov 15.
    Influence of hydrotherapy on change in weight: a narrative review.
    M Y Manju, Geetha B Shetty, K J Sujatha, Prashanth Shetty.
      There is a growing interest in weight loss in today's world. Environmental factors are the main contributor behind the rapidly spreading obesity during pandemic. Exercise and diet are two controllable elements that significantly effect on energy balance., The use of cold application such as cold-water immersion, cold abdominal pack, balneotherapy, cold exposure, water drinking, steam, and sauna sessions, has shown a positive impact in weight management. This review explains the mechanism and various types of hydrotherapy applications managing weight through thermogenesis and non-shivering thermogenic pathways, which involve the brown adipose tissue, and dependent on uncoupling protein 1 (UCP1) in the inner mitochondrial membrane. Hence the present literature provides insight into use of hydrotherapy applications for future direction in weight management.
    DOI:  https://doi.org/10.1007/s00484-024-02823-1
  53. NMR Biomed. 2024 Nov 07. e5290
    Fatty acid composition evaluation of abdominal adipose tissue using chemical shiftencoded MRI: Association with diabetes.
    Dingxia Liu, Minyan Yin, Jiejun Chen, Caixia Fu, Manuel Schneider, Dominik Nickel, Xiuzhong Yao.
      This study investigated the association between the fatty acid composition of abdominal adipose tissue in NAFLD patients using chemical shift-encoded MRI and the development of insulin resistance and T2DM. We enrolled 231 subjects with NAFLD who underwent both abdominal magnetic resonance spectroscopy and chemical shift-encoded MRI: comprising of 49 T2DM patients and 182 subjects without. MRI- and MRS-based liver fat fraction was measured from a circular region of interest on the right lobe of the liver. The abdominal fatty acid compositions were measured at the umbilical level with chemical shift-encoded MRI. Bland-Altman analysis, Student's t test, Mann-Whitney U test, and Spearman correlation analysis were performed. The logistic regression was applied to identify the independent factors for T2DM. Then, the predictive performance was assessed by Receiver operating characteristic curve analyses. An excellent agreement was found between liver fat fraction measured by MRS and MRI. (slope = 0.8; bias =-0.92%). In, patients with T2DM revealed lower fractions of mono-unsaturated fatty acid (Fmufa) (33.68 ± 10.62 vs 38.62 ± 12.21, P =.0089) and higher fractions of saturated fatty acid (Fsfa) (34.11 ± 9.746 vs 31.25 ± 8.66, P =.0351) of visceral fat tissue compared with patients without. BMI, HDL-c, Fmufa and Fsfa of visceral fat were independent factors for T2DM. Furthermore, Fsfa-S% was positively correlated with liver enzyme levels (P =.003 and 0.04). However, Fmufa-V% was negatively correlated with fasting blood glucose, HbA1c and HOMA-IR (P =.004, P =.001 and P =.03 respectively). Hence, the evaluation of fatty acid compositions of abdominal fat tissue using chemical shift-encoded MRI may have a predictive value for T2DM in patients with NAFLD.
    Keywords:  CSE‐MRI; MRS; diabetes; fatty acid composition
    DOI:  https://doi.org/10.1002/nbm.5290
  54. Cell Death Dis. 2024 Nov 08. 15(11): 807
    TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis.
    Niall A Buckley, Andrew Craxton, Xiao-Ming Sun, Emanuele Panatta, Lucia Giraldez Pinon, Sina Beier, Lajos Kalmar, Jaime Llodrá, Nobuhiro Morone, Ivano Amelio, Gerry Melino, L Miguel Martins, Marion MacFarlane.
      Dysregulated mitochondrial fusion and fission has been implicated in the pathogenesis of numerous diseases. We have identified a novel function of the p53 family protein TAp73 in regulating mitochondrial dynamics. TAp73 regulates the expression of Optic Atrophy 1 (OPA1), a protein responsible for controlling mitochondrial fusion, cristae biogenesis and electron transport chain function. Disruption of this axis results in a fragmented mitochondrial network and an impaired capacity for energy production via oxidative phosphorylation. Owing to the role of OPA1 in modulating cytochrome c release, TAp73-/- cells display an increased sensitivity to apoptotic cell death, e.g., via BH3-mimetics. We additionally show that the TAp73/OPA1 axis has functional relevance in the upper airway, where TAp73 expression is essential for multiciliated cell differentiation and function. Consistently, ciliated epithelial cells of Trp73-/- (global p73 knock-out) mice display decreased expression of OPA1 and perturbations of the mitochondrial network, which may drive multiciliated cell loss. In support of this, Trp73 and OPA1 gene expression is decreased in chronic obstructive pulmonary disease (COPD) patients, a disease characterised by alterations in mitochondrial dynamics. We therefore highlight a potential mechanism involving the loss of p73 in COPD pathogenesis. Our findings also add to the growing body of evidence for growth-promoting roles of TAp73 isoforms.
    DOI:  https://doi.org/10.1038/s41419-024-07130-6
  55. Exp Neurol. 2024 Nov 11. pii: S0014-4886(24)00382-0. [Epub ahead of print] 115056
    Sevoflurane aggravates cognitive impairment in OSAS mice through tau phosphorylation and mitochondrial dysfunction.
    Feixiang Li, Dujuan Li, Bingqing Gong, Zichen Song, Yang Yu, Yonghao Yu, Yongyan Yang.
      With an aging population, the incidence of obstructive sleep apnea syndrome (OSAS) is rising, resulting in a growing number of patients undergoing surgery who are also affected by OSAS. The combined impact of anesthetic drugs and OSAS-related neurological damage has drawn significant attention. Here, wild-type (WT) and Tau-knockout (Tau-KO) mice were subjected to intermittent hypoxia and sevoflurane exposure to induce OSAS and sevoflurane-induced neurotoxicity. Protein expression of tau phosphorylation (Tau-Ser202/Thr205 and Tau-Ser422) was measured by Western blotting. Immunofluorescence was used to visualize tau phosphorylation (Tau-Ser202/Thr205) in the hippocampal CA1 region. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP levels. Cognitive functions were assessed using the Morris water maze and Y-maze tests. We found that compared to the WT OSAS group, sevoflurane significantly increased tau phosphorylation and mitochondrial dysfunction in WT OSAS mice, leading to cognitive impairment. Interestingly, idebenone treatment mitigated sevoflurane-induced mitochondrial dysfunction and cognitive impairment in WT OSAS mice, but it did not affect tau phosphorylation. Compared to the Tau-KO control group, Tau-KO OSAS mice exhibited mitochondrial dysfunction and cognitive impairment, but sevoflurane did not exacerbate mitochondrial dysfunction or cognitive impairment in these mice. These findings suggest that sevoflurane exacerbates cognitive impairments in OSAS mice through tau phosphorylation-induced mitochondrial dysfunction, but also uncovered differing mechanisms between cognitive impairments induced by OSAS and those exacerbated by sevoflurane.
    Keywords:  Cognitive impairment; Mitochondrial dysfunction; Obstructive sleep apnea syndrome; Sevoflurane; Tau phosphorylation
    DOI:  https://doi.org/10.1016/j.expneurol.2024.115056
  56. J Physiol. 2024 Nov 09.
    Daily GDF15 treatment has sex-specific effects on body weight and food intake and does not enhance the effects of voluntary physical activity in mice.
    Stewart Jeromson, Michael Akcan, Bradley Baranowski, Meagan Arbeau, Annalaura Bellucci, David C Wright.
      Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that suppresses food intake and causes weight loss. GDF15 also reduces voluntary physical activity and, thus, it is not clear whether combining GDF15 with exercise will be beneficial or if reductions in food intake would be offset by decreases in physical activity. We investigated how GDF15 treatment combined with voluntary wheel running (VWR) would impact weight gain, food intake, adiposity and indices of metabolic health in mice. High-fat fed male and female mice underwent daily GDF15 treatments and were given access to voluntary running wheels, or not, for 11 days. In both sexes, VWR prevented weight gain. In males, GDF15 reduced food intake, as well as attenuated weight gain and the accumulation of adipose tissue, with no additional effect of VWR. In female mice, GDF15 did not impact body weight gain or body composition. GDF15 acutely reduced food intake in female mice but this was followed by a period of rebound hyperphagia and consequently GDF15 did not reduce total food intake in female mice. GDF15 treatment reduced wheel running distance in both sexes. There were main effects of VWR to improve glucose tolerance in female but not male mice. These findings show that GDF15 has sex-specific effects on food intake and consequently weight gain and adiposity. There is no added benefit of combining GDF15 and voluntary physical activity for weight loss. Adaptive responses to acute caloric restriction induced by GDF15 might limit its effectiveness as a weight loss tool in females. KEY POINTS: GDF15 is a stress-induced signalling factor that reduces food intake and voluntary physical activity. It is not known whether combining GDF15 treatment with voluntary wheel running would impart beneficial combined effects in attenuating weight gain and the accumulation of adipose tissue. In the present study, we demonstrate that GDF15 reduces food intake and prevents weight gain in male but not female mice consuming a high-fat diet and also that combining GDF15 with voluntary wheel running (VWR) does not lead to a greater dampening of weight gain. In female mice, GDF15 acutely reduced food intake, but this was followed by a period of rebound hyperphagia resulting in no differences in total food intake. In both sexes, VWR was equivalent, or superior to GDF15 in preventing weight gain.
    Keywords:  GDF15; food intake; mice; obesity; physical activity
    DOI:  https://doi.org/10.1113/JP287256
  57. Front Pharmacol. 2024 ;15 1446300
    CDKN1A as a target of senescence in heart failure: insights from a multiomics study.
    Rutao Bian, Li Zhang, Dongyu Li, Xuegong Xu.
       Background: Cardiomyocyte senescence plays a crucial role as a pathological mechanism in heart failure (HF). However, the exact triggering factors and underlying causes of HF onset and progression are still not fully understood.
    Objectives: By integrating multi-omics data, this study aimed to determine the genetic associations between cardiomyocyte and HF using cell senescence-related genes (SRGs).
    Methods: The study utilized the CellAge database and the SenMayo dataset, combined with high-resolution single-cell RNA sequencing (scRNA-seq) data, to identify SRG and examine differences in cardiac cell expression. To explore the causal relationship with HF using Mendelian Randomization (MR). Genetic variations influencing gene expression, DNA methylation, and protein expression (cis-eQTL, cis-mQTL, and cis-pQTL) were analyzed using the two-sample MR (TSMR) and summary-data-based MR (SMR). Additionally, Bayesian colocalization analysis, germline genetic variation, and bulk RNA data were employed to strengthen the reliability of the results. The application potential of therapeutic targets is ultimately assessed by evaluating their druggability.
    Results: The expression of 39 SRGs in cardiomyocytes was identified. In the discovery set revealed that CDKN1A (OR = 1.09, 95% confidence interval (CI) 1.02-1.15, FDR = 0.048) could be causally related to HF, and the results are also replicated in the validation set (OR = 1.20, 95% confidence interval (CI) 1.10-1.30, FDR <0.0001). Based on the SMR method, CDKN1A was confirmed as a candidate pathogenic gene for HF, and its methylation (cg03714916, cg08179530) was associated with HF risk loci. The result is validated by Bayesian colocalization analysis, genetic variations, and bulk RNA data. The druggability analysis identified two potential therapeutic drugs.
    Conclusion: Based on multi-omics data, this study uncovered the reciprocal regulation of cardiomyocyte senescence through CDKN1A, providing potential targets for HF drug development.
    Keywords:  Mendelian randomization; cardiomyocyte; heart failure; omics analysis; senescence
    DOI:  https://doi.org/10.3389/fphar.2024.1446300
  58. Diabet Med. 2024 Nov 09. e15468
    The impact of prolonged walking on fasting plasma glucose in type 2 diabetes: A randomised controlled crossover study.
    Anxious J Niwaha, Beverley M Shields, Lauren R Rodgers, Andrew T Hattersley, Robert C Andrews, Moffat J Nyirenda, Angus G Jones.
       AIMS: In many low-income countries, fasting glucose is the primary measure for monitoring glycaemic control. Many patients in these countries walk long distances to the clinic, but the impact of walking on fasting glucose in type 2 diabetes is unknown. We aimed to determine the impact of walking on fasting glucose in people with type 2 diabetes.
    METHODS: In a randomised crossover trial, the change in glucose from baseline in the fasting state was compared between walking on a treadmill at a predetermined speed of 4.5 km/h for 1 h and not walking (resting) in people with type 2 diabetes.
    RESULTS: In all, 45 participants were enrolled and all completed both visits; 21/45 (46.7%) were women, and the median age was 51. Glucose during and after walking was similar to glucose while at rest; the glucose difference (walking minus rest) was -0.15 (95% CI: -0.55, 0.26) and -0.10 (95% CI: -0.50, 0.31) mmol/L at 1 and 2 h, respectively, p > 0.4 for both.
    CONCLUSIONS: Fasting plasma glucose is not meaningfully affected by prolonged walking in participants with type 2 diabetes; therefore, the reliability of fasting glucose for monitoring glycaemic burden is unlikely to be altered in patients who walk to the clinic.
    Keywords:  exercise; fasting glucose; randomised crossover trial; type 2 diabetes
    DOI:  https://doi.org/10.1111/dme.15468
  59. Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00865-7. [Epub ahead of print]
    Opposing roles for AMPK in regulating distinct mitophagy pathways.
    Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G Ganley.
      Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.
    Keywords:  14-3-3; AMPK; NIX; Parkin; ULK1; autophagy; liver; mito-QC; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.025
  60. Metabol Open. 2024 Dec;24 100326
    Growth hormone attenuates obesity and reshapes gut microbiota in high-fat diet-fed mice.
    Yu Wang, Liyuan Ran, Fang Zhang, Haolin Li, Qianqian Cha, Kun Yang, Haoan Wang, Yingjie Wu, Zichao Yu.
      Growth hormone (GH) and gut microbiota are key regulators of metabolism and have been linked to the development and treatment of obesity. Although variations in GH levels are associated with changes in gut microbiota composition, the specific effects of GH on gut microbiota and its role in obesity remain unclear. This study explored the effects of various GH doses (0.25, 0.75 and 1.5 IU/kg) on adipose tissue mass and gut microbiota in high-fat diet-induced obese mice. Notably, high-dose GH (1.5 IU/kg) significantly reduced the adipose tissue mass. This dose also reversed high-fat diet-induced gut microbiota dysbiosis, restoring microbial diversity and increasing the abundance of beneficial genera such as Ruminococcaceae and Muribaculaceae. Additionally, high-dose GH normalized several obesity-related gut microbiota pathways, including starch and sucrose metabolism, galactose metabolism, and secondary bile acid biosynthesis. GH therapy also improved intestinal barrier function, a key determinant of gut microbial homeostasis. These findings underscore the therapeutic potential of GH in obesity management through its effects on gut microbiota, providing new avenues for obesity interventions.
    Keywords:  Growth hormone; Gut microbiota; Obesity
    DOI:  https://doi.org/10.1016/j.metop.2024.100326
  61. Nat Commun. 2024 Nov 07. 15(1): 9653
    Structures of the multi-domain oxygen sensor DosP: remote control of a c-di-GMP phosphodiesterase by a regulatory PAS domain.
    Wenbi Wu, Pankaj Kumar, Chad A Brautigam, Shih-Chia Tso, Hamid R Baniasadi, Daniel L Kober, Marie-Alda Gilles-Gonzalez.
      The heme-based direct oxygen sensor DosP degrades c-di-GMP, a second messenger nearly unique to bacteria. In stationary phase Escherichia coli, DosP is the most abundant c-di-GMP phosphodiesterase. Ligation of O2 to a heme-binding PAS domain (hPAS) of the protein enhances the phosphodiesterase through an allosteric mechanism that has remained elusive. We determine six structures of full-length DosP in its aerobic or anaerobic conformations, with or without c-di-GMP. DosP is an elongated dimer with the regulatory heme containing domain and phosphodiesterase separated by nearly 180 Å. In the absence of substrate, regardless of the heme status, DosP presents an equilibrium of two distinct conformations. Binding of substrate induces DosP to adopt a single, ON-state or OFF-state conformation depending on its heme status. Structural and biochemical studies of this multi-domain sensor and its mutants provide insights into signal regulation of second-messenger levels.
    DOI:  https://doi.org/10.1038/s41467-024-53942-7
  62. Free Radic Biol Med. 2024 Nov 12. pii: S0891-5849(24)01052-9. [Epub ahead of print]
    TSPO Exacerbates Sepsis-Induced Cardiac Dysfunction by Inhibiting p62-Mediated Autophagic Flux via the ROS-RIP1/RIP3-Exosome Axis.
    Qiao Guo, Haitang Liao, Shuai Hao, Dongyao Hou, Ruixue Liu, Yunting Zhang, Xinhao Tang, Rui Song, Xuxin Tan, Zhenchun Luo, He Huang, Chenyang Duan.
      Septic cardiomyopathy (SCM) is a critical complication of sepsis, primarily attributed to mitochondrial dysfunction and impaired autophagic flux. This study explores the role of translocator protein (TSPO) in SCM pathogenesis and assesses its potential as a therapeutic target. We identified increased TSPO expression in plasma samples from sepsis patients, with further validation in septic rats and LPS-stimulated H9C2 cardiomyocytes. Elevated TSPO disrupted mitochondrial function, leading to increased reactive oxygen species (ROS) production and activation of the RIP1/RIP3 pathway, which hindered p62-positive autophagosome degradation and promoted inflammation. Moreover, exosome release containing TSPO-positive autophagosomes into plasma may exacerbate systemic inflammation. NADH, identified as a TSPO-binding molecule, restored autophagic flux, improved mitochondrial function, and enhanced cardiac performance and survival in septic rats. These findings suggest that targeting TSPO with NADH could alleviate mitochondrial dysfunction and inflammatory responses in SCM, providing a promising therapeutic strategy for sepsis-induced cardiac injury.
    Keywords:  LC3II/I; RIP 1/RIP 3; TSPO; autophagy flux; cardiomyopathy; exosomes; inflammation; p62; reactive oxygen species (ROS); sepsis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.018
  63. Metabolism. 2024 Nov 06. pii: S0026-0495(24)00289-0. [Epub ahead of print] 156061
    Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis.
    Francesca Pontanari, Hadrien Demagny, Adrien Faure, Xiaoxu Li, Giorgia Benegiamo, Antoine Jalil, Alessia Perino, Johan Auwerx, Kristina Schoonjans.
      Several laboratories, including ours, have employed the Slc25a47tm1c(EUCOMM)Hmgu mouse model to investigate the role of SLC25A47, a hepatocyte-specific mitochondrial carrier, in regulating hepatic metabolism and systemic physiology. In this study, we reveal that the hepatic and systemic phenotypes observed following recombination of the Slc25a47-Wars1 locus in hepatocytes are primarily driven by the unexpected downregulation of Wars1, a cytosolic tryptophan aminoacyl-tRNA synthetase located adjacent to Slc25a47. While the downregulation of Wars1 predictably affects cytosolic translation, we also observed a significant impairment in mitochondrial protein synthesis within hepatocytes. This disturbance in mitochondrial function leads to an activation of the mitochondrial unfolded protein response (UPRmt), a critical component of the mitochondrial stress response (MSR). Our findings clarify the distinct roles of Slc25a47 and Wars1 in maintaining both systemic and hepatic metabolic homeostasis. This study sheds new light on the broader implications of aminoacyl-tRNA synthetases in mitochondrial physiology and stress responses.
    Keywords:  Hepatocytes; ISR; MSR; SLC25A47; Translation; UPR(mt); WARS1
    DOI:  https://doi.org/10.1016/j.metabol.2024.156061
  64. Cytoskeleton (Hoboken). 2024 Nov 11.
    Analyses of Off-Target Effects on Cardiac and Skeletal Muscles by Berberine, a Drug Used to Treat Cancers and Induce Weight Loss.
    Jushuo Wang, Yingli Fan, Syamalima Dube, Patricia Benz, Dipak Dube, Jean M Sanger, Joseph W Sanger.
      Previous reports from our laboratory describing the formation of myofibrils in cultured embryonic cardiac and skeletal muscle cells have proposed that myofibrillogenesis occurs in three steps of increasing protein organization: beginning with premyofibrils, followed by nascent myofibrils, and ending in mature myofibrils. Inhibitors of the ubiquitin proteasome system (UPS) prevented nascent myofibrils from progressing directly to mature myofibrils in cultured cardiac and skeletal muscle cells, supporting a three-step model of assembly in which some of the proteins in nascent myofibrils are proteolyzed to allow the assembly of mature myofibrils. Application of UPS inhibitors on cultured muscle cells suggests possible explanations for the off-target cardiac and skeletal muscle adverse effects of UPS drugs, which are used on cancer patients. Berberine, a plant derivative, has been used to treat various cancers, including multiple myelomas. In contrast to the use of UPS drugs, success was reported with Berberine in multiple myeloma patients with no off-target effects on their hearts. We have exposed cultured cardiac and skeletal muscle cells to Berberine, a ligase inhibitor of UHRF1 (ubiquitin-like with PHD and RING finger domains). Berberine inhibited myofibril assembly at the nascent myofibril stage in embryonic skeletal muscle cells but had no effect in the assembly of mature myofibrils in embryonic heart cells. RT-PCR experiments demonstrated Berberine inhibition of mRNA for muscle myosin II heavy chains but not for muscle actin mRNA in skeletal muscle cells. Berberine is also being used as a popular weight losing compound, because it is much cheaper and available without a prescription than the semaglutide containing weight losing drugs (Wegovy and Ozempic). In contrast to Berberine, semaglutide had no effects on myofibril assembly in culture assays for both cardiac and skeletal muscle cells. We postulate that analyses of cultured embryonic cardiac and skeletal muscle cells will provide a preclinical assay for the testing of novel cancer drugs with improved outcomes for patients, an important goal for cancer therapeutics.
    Keywords:  Berberine; cardiomyocytes; mature myofibril; myofibrillogenesis; nascent myofibril; semaglutide; skeletal muscles
    DOI:  https://doi.org/10.1002/cm.21950
  65. J Inflamm Res. 2024 ;17 8135-8146
    ZLN005 Reduces Neuroinflammation and Improves Mitochondrial Function in Mice with Perioperative Neurocognitive Disorders.
    Xiaofan Wu, Sheng Ding, Guizhi Wang, Wei Zhang, Keqiang He.
       Background: The decrease expression of PGC-1α contributes to perioperative neurocognitive disorders (PND). This study aimed to investigate the effects of the PGC-1α agonist ZLN005 in preventing PND and to explore the potential mechanism.
    Methods: C57BL/6 mice were randomly divided into four groups: the control group (Group C), the surgery group (Group S), the surgery and ZLN005 (5 mg/(kg⋅d)) group (Group L), and the surgery and ZLN005 (7.5 mg/(kg⋅d)) group (Group H). Except for Group C, the other three groups received intraperitoneal injections of vehicle or ZLN005 once a day from 3 days before surgery to 3 days after surgery. The open field test, novel object recognition test and fear conditioning test were performed to measure anxiety behaviors, locomotor activity and memory. The levels of IL-6 and IL-1β were measured at 24 hours after surgery. ATP and ROS levels were measured at 3 days post-surgery. PGC-1α, NRF-1, Atp5d, Atp5k and Cox5a were measured at one day or three days post-surgery.
    Results: ZLN005 treatment improved the cognitive function of mice in Group L and Group H compared with Group S. The expression of IL-6 and IL-1β in the hippocampus of the S group was increased after surgery, and ZLN005 reduced the expression of IL-6 and IL-1β in the hippocampus of mice one day after surgery. There were parallel decreases in the expression of PGC-1α/NRF-1 and mitochondrial function in the hippocampus of the Group S mice compared with the Group C mice. The expression of PGC-1α/NRF-1 and mitochondrial function were upregulated after ZLN005 treatment.
    Conclusion: Neuroinflammation and mitochondrial damage are involved in the occurrence of PND. ZLN005 activates PGC-1α to increase the expression of mitochondrial proteins, improve mitochondrial function, and ultimately ameliorate the cognitive status of mice after surgery.
    Keywords:  PGC-1α; ZLN005; mitochondrial respiratory chain complex; neuroinflammation; perioperative neurocognitive disorders; respiratory function
    DOI:  https://doi.org/10.2147/JIR.S482051
  66. Int J Cardiol. 2024 Nov 10. pii: S0167-5273(24)01319-6. [Epub ahead of print] 132697
    Prognostic utility of dynamic changes in epicardial adipose tissue in patients undergoing transcatheter aortic valve replacement.
    Shuangxiang Lin, Yao Zhang, Shuyue Wang, Xingfa Ding, Jiaxing Wu, Xinhong Wang, Jianzhong Sun.
       BACKGROUND: Epicardial Adipose Tissue (EAT) volume is associated with the risk of cardiovascular events, which can be assessed by cardiac computed tomography. However, he optimal method and their prognostic utility in patients following transcatheter aortic valve replacement (TAVR) is unknown.
    METHODS: We evaluated 258 participants, focusing on changes in EAT volume using cardiac CT enhancement. EAT volume was automatically computed as three-dimensional voxels between -190 to -30 HU on contrast-enhanced slices. Univariate and multivariable Cox regression analyses were conducted to assess the association of various clinical parameters and EAT volume indices with major adverse cardiovascular events (MACE).
    RESULTS: During a median follow-up of 2.0 years [IQR, 1.8-2.3 years], 34 participants (median age 73 [IQR: -13.1 to -8.3) years, 55.4 % male) experiencing MACE. The optimal cutoff values for EAT volume change fraction (EATVCF) was 15.2 %, determined by the Youden-index. Kaplan-Meier curve analysis revealed that patients with high EATVCF were at higher risk (p < .01). In Cox regression, EATVCF (hazard ratio [HR]: 0.92, 95 % CI: 0.87 to 0.97, p = .001) remained significantly associated with MACE after adjusting for clinical factors. The addition of EATVCF to the clinical model increased the net Reclassification Improvement (NRI) by 30.1 % (95 % CI: 0.07-1.16).
    CONCLUSION: EAT volume change fraction emerged as a significant predictor of MACE post-TAVR, highlighting the clinical value of EAT volume assessment in cardiovascular risk stratification.
    Keywords:  Aortic valve disease; Cardiac CT enhancement; Epicardial adipose tissues; Transcatheter aortic valve replacement
    DOI:  https://doi.org/10.1016/j.ijcard.2024.132697
  67. J Hepatol. 2024 Nov 08. pii: S0168-8278(24)02699-0. [Epub ahead of print]
    Dysglycemia and liver lipid content influence the link between insulin resistance and liver mitochondrial function in obesity - Author's reply.
    Sabine Kahl, Michael Roden.
      
    Keywords:  Dysglycemia; insulin resistance; liver lipids; mitochondria
    DOI:  https://doi.org/10.1016/j.jhep.2024.11.003
  68. Biosci Rep. 2024 11 27. pii: BSR-2019-0229_EOC. [Epub ahead of print]44(11):
    Expression of Concern: Punicalagin protects H9c2 cardiomyocytes from doxorubicin-induced toxicity through activation of Nrf2/HO-1 signaling.
      
    Keywords:  Nrf2/HO-1 signaling; cardiotoxicity; doxorubicin; mitochondrial dysfunction; punicalagin
    DOI:  https://doi.org/10.1042/BSR-2019-0229_EOC
  69. Cancers (Basel). 2024 Oct 29. pii: 3640. [Epub ahead of print]16(21):
    Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts.
    Stuart A Clayton, Alan D Mizener, Marcella A Whetsell, Lauren E Rentz, Ethan M Meadows, Werner J Geldenhuys, Emidio E Pistilli.
      Background/Objectives: Breast cancer (BC) is the second most commonly diagnosed cancer worldwide and is accompanied by fatigue during both active disease and remission in the majority of cases. Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle. Methods: The pioglitazone and vehicle groups were treated orally for 4 weeks upon reaching a tumor volume of 600 mm3. Whole-animal indirect calorimetry was used to evaluate systemic metabolic states. The transcriptome was profiled using short-read bulk RNA sequencing (RNA-seq). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to profile the metabolome and lipidome. Fast and slow skeletal muscle function were evaluated using isolated ex vivo testing. Results: Pioglitazone was associated with a 16.634% lower average O2 consumption (mL∙h-1, p = 0.035), 16.309% lower average CO2 production (mL∙h-1, p = 0.022), and 16.4% lower cumulative energy expenditure (EE) (kcal∙h-1, p = 0.035), with no changes in substrate utilization. RNA-seq supported the downstream effects of pioglitazone on target genes and displayed considerable upregulation of mitochondrial bioenergetic pathways. K-means cluster 5 showed enrichment of the PPAR signaling pathway (adj. p < 0.05, Log2FC = 2.58). Skeletal muscle metabolomic and lipidomic profiles exhibited dysregulation in response to BC, which was partially restored in pioglitazone-treated mice compared to vehicle-treated BC-PDOX mice. In particular, the overall abundance of total ceramide levels was significantly lower in the PioTx group (-46.327%, p = 0.048). Despite molecular support for pioglitazone's efficacy, isolated muscle function was not affected by pioglitazone treatment. No significant difference in the area under the fatigue curve (AUC) was found between the pioglitazone and vehicle groups (p = 0.596). Conclusions: BC induces multi-omic dysregulation in skeletal muscle, which pioglitazone partially ameliorates. Future research should focus on profiling systemic metabolic dysfunction, identifying molecular biomarkers of fatigue, and testing alternative pioglitazone treatment regimens.
    Keywords:  RNA-seq; cachexia; fatigue; lipidomics; metabolomics; peroxisome proliferator-activated receptor (PPAR); transcriptomics
    DOI:  https://doi.org/10.3390/cancers16213640
  70. Annu Rev Physiol. 2024 Nov 12.
    Protein Tyrosine Phosphatases in Metabolism: A New Frontier for Therapeutics.
    Anton M Bennett, Tony Tiganis.
      The increased prevalence of chronic metabolic disorders, including obesity and type 2 diabetes and their associated comorbidities, are among the world's greatest health and economic challenges. Metabolic homeostasis involves a complex interplay between hormones that act on different tissues to elicit changes in the storage and utilization of energy. Such processes are mediated by tyrosine phosphorylation-dependent signaling, which is coordinated by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Perturbations in the functions of PTPs can be instrumental in the pathophysiology of metabolic diseases. The goal of this review is to highlight key advances in our understanding of how PTPs control body weight and glucose metabolism, as well as their contributions to obesity and type 2 diabetes. The emerging appreciation of the integrated functions of PTPs in metabolism, coupled with significant advances in pharmaceutical strategies aimed at targeting this class of enzymes, marks the advent of a new frontier in combating metabolic disorders.
    DOI:  https://doi.org/10.1146/annurev-physiol-022724-105540
  71. Sci Rep. 2024 11 12. 14(1): 27649
    Effects of sodium-glucose cotransporter-2 inhibitor on atrial high-rate episodes in patients with cardiovascular implantable electronic device: a randomized controlled trial.
    Teerapat Nantsupawat, Nattayaporn Apaijai, Arintaya Phrommintikul, Narawudt Prasertwitayakij, Siriporn C Chattipakorn, Nipon Chattipakorn, Wanwarang Wongcharoen.
      Prior research has demonstrated an association between sodium-glucose cotransporter 2 (SGLT2) inhibitor and a reduced incidence of atrial fibrillation (AF). Given the established link between mitochondrial dysfunction and AF, this study aimed to explore the impact of SGLT2 inhibitors on AF burden and plausible antiarrhythmic mechanisms in patients with cardiovascular implantable electronic devices (CIEDs). Patients with atrial high-rate episodes (AHREs) detected by CIEDs were randomized to receive either 10 mg of dapagliflozin or a placebo for 3 months. AF burdens were quantified via CIEDs interrogations as AHREs duration, percentage, and number of episodes at baseline and after 3 months of treatment. Mitochondrial parameters, cellular oxidative stress, and norepinephrine levels were measured in peripheral blood mononuclear cells (PBMCs). A total of 54 patients with CIEDs were enrolled in the study. Among them, 36 patients (66.7%) had a history of clinical AF, and 9 patients (16.7%) had diabetes mellitus. After 3 months of the assigned treatment, the median longest AHRE duration decreased similarly in both the dapagliflozin and placebo groups (-77.0 vs. -162.0 min, p = 0.442). Clinical AF, as opposed to subclinical AF, was independently linked to decreased basal respiration and adenosine triphosphate (ATP) production. Although the changes in AHREs burden over the 3 months did not significantly differ between the dapagliflozin and placebo groups, dapagliflozin significantly decreased the number of AHREs per month by 2.2 episodes among patients with clinical AF, whereas the placebo group experienced an increase of 0.6 episodes (p = 0.048). Additionally, dapagliflozin significantly reduced cellular oxidative stress (from 26840 to 18164 arbitrary units, p = 0.049) and improved mitochondrial spare respiratory capacity (SRC) percentage (from 166 to 202%, p = 0.016) in patients with clinical AF. Dapagliflozin did not significantly reduce the longest AHRE duration in patients with CIED. However, in the subgroup of patients with clinical AF, dapagliflozin reduced the number of AHREs potentially via reduction of cellular oxidative stress and enhancement of mitochondrial function.The study protocol was registered at the Thai Clinical Trials Registry (TCTR identification number TCTR20210315003) on March 15, 2021.
    Keywords:  Arrhythmias; Atrial fibrillation; Cardiovascular Implantable Electronic device; Sodium-glucose Cotransporter-2 inhibitor
    DOI:  https://doi.org/10.1038/s41598-024-74631-x
  72. Methods Mol Biol. 2025 ;2878 133-162
    The Relation Between Mitochondrial Membrane Potential and Reactive Oxygen Species Formation.
    Magdalena Lebiedzinska-Arciszewska, Jan Suski, Massimo Bonora, Barbara Pakula, Paolo Pinton, Jerzy Duszynski, Patrycja Jakubek-Olszewska, Mariusz R Wieckowski.
      Mitochondria are considered one of the main sites of reactive oxygen species (ROS) production in the eukaryotic cells. For this reason, mitochondrial dysfunction associated with increased ROS production underlies various pathological conditions as well as promotes aging. Chronically increased rates of ROS production contribute to oxidative damage to macromolecules, i.e., DNA, proteins, and lipids. Accumulation of unrepaired oxidative damage may result in progressive cell dysfunction, which can finally trigger cell death. The main by-product of mitochondrial oxidative phosphorylation is superoxide, which is generated by the leak of electrons from the mitochondrial respiratory chain complexes leading to one-electron reduction of oxygen. Mitochondrial superoxide dismutase (MnSOD, SOD2) as well as cytosolic superoxide dismutase (Cu/ZnSOD, SOD1), whose smaller pool is localized in the mitochondrial intermembrane space, converts superoxide to H2O2, which can be then degraded by the catalase to harmless H2O.In this chapter, we focus on the relationship between one of the bioenergetic parameters, which is mitochondrial membrane potential, and the rate of ROS formation. We present a set of various methods enabling the characterization of these parameters applicable to isolated mitochondria or intact cells. We also present examples of experimental data demonstrating that the magnitude and direction (increase or decrease) of a change in mitochondrial ROS production depend on the mitochondrial metabolic state.
    Keywords:  Confocal microscopy; Hydrogen peroxide; Mitochondria; Oxygen consumption; Resazurin; Superoxide
    DOI:  https://doi.org/10.1007/978-1-0716-4264-1_8
  73. Circulation. 2024 Nov 08.
    Exercise Training in Patients With Hypertrophic Cardiomyopathy Without Left Ventricular Outflow Tract Obstruction: A Randomized Clinical Trial.
    Helga Gudmundsdottir, Anna Axelsson Raja, Kasper Rossing, Hanne Rasmusen, Martin Snoer, Lars Juel Andersen, Rikke Gottlieb, Alex Hørby Christensen, Henning Bundgaard, Finn Gustafsson, Jens Jakob Thune.
       BACKGROUND: Patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction commonly experience reduced exercise capacity. Physical training improves exercise capacity in these patients, but whether the underlying effects of exercise are a result of central hemodynamic or peripheral improvement is unclear. This study assessed whether exercise training reduces left ventricular filling pressure measured during exercise in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction.
    METHODS: Between March 2019 and June 2022, patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction were randomly assigned (1:1) to a 12-week (3 h/wk) supervised, moderate-intensity exercise training program or continued usual activity. The primary outcome was the change in invasively measured pulmonary capillary wedge pressure during mild exercise (25 W) from baseline to week 12. Pressure tracings were analyzed offline by a blinded investigator. Secondary outcomes included changes in peak oxygen consumption, cardiac index, quality of life, echocardiographic indices of diastolic function, and natriuretic peptides.
    RESULTS: Of 59 patients randomized (mean age, 58.1±12.2 years; 27% women), 51 (86%) completed all follow-up assessments. At week 12, the change in 25-W pulmonary capillary wedge pressure was -2.8±6.8 mm Hg in the exercise group, compared with +1.2±4.9 mm Hg in the usual-activity group (between-group difference, 4.0 mm Hg [95% CI, 0.7-7.3]; P=0.018). Peak oxygen consumption improved by +1.8±2.0 mL/kg/min in the exercise group versus -0.3±3.1 mL/kg/min in the usual-activity group (P=0.005). Exercise training improved the ventilatory efficiency (VE/VCO2) slope compared with usual activity (between-group difference, 2.0 [95% CI, 0.6-3.5]; P=0.006). Peak cardiac index improved by +0.38±1.38 L/min/m2 in exercise versus -0.85±1.20 L/min/m2 in the usual-activity group (P=0.002). Change in overall Kansas City Cardiomyopathy Questionnaire score was similar between groups. However, the change in physical limitation scores (+8.4±12.0 points in exercise versus +0.7±6.8 points in usual-activity group; P=0.034) and quality-of-life scores (+8.7±18.0 points in exercise versus 0.7±4.0 points in usual-activity group; P=0.01) differed significantly. There were no significant changes in diastolic function assessed by echocardiography or in natriuretic peptides.
    CONCLUSIONS: In patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction, a 12-week moderate-intensity exercise training program resulted in reduced left ventricular filling pressures at mild exertion and improved exercise performance.
    REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03537183.
    Keywords:  exercise; hypertrophic cardiomyopathy; pulmonary capillary wedge pressure; quality of life
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.070064
  74. Neuroscience. 2024 Nov 12. pii: S0306-4522(24)00609-2. [Epub ahead of print]
    Dopamine-D2-agonist targets mitochondrial dysfunction via diminishing Drp1 mediated fission and normalizing PGC1-α/SIRT3 pathways in a rodent model of Subarachnoid haemorrhage.
    Ahmed Shaney Rehman, Pravir Kumar, Suhel Parvez.
      The adverse impact of disturbmitochondrialbiogenesis onearly brain injury (EBI) following Subarachnoid Haemorrhage (SAH) has been broadly recognized and is closely associated with oxidative stress and neuronal apoptosis. Previous studies have indicated the therapeutic potential of Ropinirole in Ischemic Stroke. However, there is a lack of evidence regarding the ability of Ropinirole to enhance mitochondrial biogenesis and quality control after Subarachnoid Haemorrhage. The objective of this study is to investigate the effects of Ropinirole specific doses (10 & 20 mg/kg b. wt.) on mitochondria dysfunction in endovascular perforation SAH model in male Wistar rat. An endovascular perforation model was established using male Wistar rats that had sustained SAH injury. After the SAH injury, SAH grading on blood clot, Nissl staining, and neurobehavioral assessment were used to determine the severity. ROS and MMP, which are indicators of oxidative stress, were examined using flow cytometry. The findings demonstrated that the use of Ropinirole improved neurobehavioral outcomes, decreased brain edema, and reduced oxidative stress and mitochondrial based apoptosis. Further research showed that, Ropinirole therapy inhibit Drp1-mediated fission by accelerating the activity of fusion protein Mfn2/OPA1 along with regulating the translocation of PGC1-α and SIRT3 through restricting cytochrome C inside mitochondria to maintain mitochondrial metabolism. Ropinirole exerted neuroprotective effects by improving mitochondrial activity in a PGC1-α/SIRT3-dependent way via regulating Drp1 mediated fission. The effective treatment for SAH-induced EBI may involve increasing biogenesis and inhibiting excessive mitochondrial fission with Ropinirole.
    Keywords:  Apoptosis; Drp1; Mitochondrial Biogenesis; Neuroinflammation; Ropinirole; Subarachnoid Haemorrhage
    DOI:  https://doi.org/10.1016/j.neuroscience.2024.11.028
  75. Nan Fang Yi Ke Da Xue Xue Bao. 2024 Oct 20. 44(10): 1955-1964
    [Activation of ALDH2 alleviates hypoxic pulmonary hypertension in mice by upregulating the SIRT1/PGC-1α signaling pathway].
    L Wang, F Bian, F Ma, S Fang, Z Ling, M Liu, H Sun, C Fu, S Ni, X Zhao, X Feng, Z Sun, G Lu, P Kang, S Wu.
       OBJECTIVE: To investigate whether activation of mitochondrial acetal dehydrogenase 2 (ALDH2) alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.
    METHODS: Thirty 8-week-old C57 BL/6 mice were randomized into control, hypoxia, and hypoxia +Alda-1 (an ALDH2 activator) group (n=10), and the mice in the latter two groups, along with 10 ALDH2 knockout (ALDH2-/-) mice, were exposed to hypoxia (10% O2, 90% N2) with or without daily intraperitoneal injection of Alda-1 for 4 weeks. The changes in right ventricular function and pressure (RVSP) of the mice were evaluated by echocardiography and right ventricular catheter test, and pulmonary artery pressure was estimated based on RVSP. Pulmonary vascular remodeling, right ventricular injury, myocardial α -SMA expression, distal pulmonary arteriole muscle normalization, right ventricular cross-sectional area, myocardial cell hypertrophy, and right cardiac hypertrophy index were assessed with HE staining, immunofluorescence staining and WGA staining, and the expressions of ALDH2, SIRT1, PGC-1α, P16INK4A and P21CIP1 were detected. In pulmonary artery smooth muscle cells with hypoxic exposure, the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.
    RESULTS: The wild-type mice with hypoxic exposure showed significantly increased RVSP, right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1, which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/- mice. In cultured pulmonary artery smooth muscle cells, hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1, which were all lowered by treatment with Alda-1, but its effect was obviously attenuated by EX527 treatment.
    CONCLUSION: ALDH2 alleviates hypoxiainduced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.
    Keywords:  ALDH2; PGC-1α; SIRT1; pulmonary hypertension; smooth muscle cell senescence
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2024.10.14
  76. Physiol Res. 2024 Nov 15. 73(5): 801-808
    POLG p.A962T Mutation Leads to Neuronal Mitochondrial Dysfunction That is Restored After Mitochondrial Transplantation.
    W Hu, C Shi, H Guo, B Zhang.
      Mutations in DNA polymerase gamma (POLG) are known as the predominant cause of inherited mitochondrial disorders. But how these POLG mutations disturb mitochondrial function remains to be determined. Furthermore, no effective therapy, to date, has been reported for POLG diseases. Using differentiated SH-SY5Y cells, a human neuronal model cell line, the current study investigated whether the novel POLG variant p.A962T impairs mitochondrial function. This involved quantifying mitochondrial DNA (mtDNA) content using PCR and assessing the expression levels of the subunits of complex IV (COXI-IV), a complex I subunit NDUFV1 and Cytochrome C (Cyto C) release using Western blotting. Activities of mitochondrial complex I, II, and IV were measured using colorimetric assays. Mitochondrial membrane potential (delta Psim) and ATP were evaluated using fluorescence assays and luminescent assays, respectively. In addition, we investigated whether mitochondrial transplantation (MT) using Pep-1-conjugated mitochondria could compensate for mitochondrial defects caused by the variant in cells carrying mutant POLG. The results of this study showed that POLG p.A962T mutation resulted in mitochondrial defects, including mitochondrial DNA (mtDNA) depletion, membrane potential (delta Psim) depolarization and adenosine triphosphate (ATP) reduction. Mechanistically, POLG mutation-caused mtDNA depletion led to the loss of mtDNA-encoded subunits of complex I and IV and thus compromised their activities. POLG p.A962T mutation is a pathogenic mutation leading to mitochondrial malfunction and mtDNA depletion in neurons. Cell-penetrating peptide Pep-1-mediated MT treatment compensated for mitochondrial defects induced by these POLG variants, suggesting the therapeutic application of this method in POLG diseases.
  77. J Colloid Interface Sci. 2024 Oct 30. pii: S0021-9797(24)02535-9. [Epub ahead of print]680(Pt A): 429-440
    Mitochondrial dynamics and energy metabolism interference therapy for promoting photothermal sensitization.
    Cuimei Liu, Sihang Cheng, Xue Zhou, Lu Li, Chungang Wang, Lingyu Zhang.
      Photothermal therapy (PTT) is minimally invasive, precisely controlled, and therapeutically effective treatment method. However, its efficacy is limited by the overexpression of heat shock proteins (HSP), which leads to cellular thermal blockade. Targeting mitochondria with PTT can enhance anticancer efficacy, as mitochondria encode genes related to HSP and provide energy for their production. Nevertheless, mitochondrial dynamics confer resistance to damage from external stimuli. Therefore, disrupting the balance of mitochondrial dynamics is essential to impede HSP production. Herein, we synthesized degradable Cu3BiS3 (CBS) nanosheets (NSs) with one face modified by carboxylated triphenylphosphonium (TPP) to target mitochondria. This modification increases the production of exogenous reactive oxygen species (ROS) and induces the overexpression of dynamin-related protein 1 (Drp1), disrupting mitochondrial dynamic homeostasis. The other face was modified with carboxylated β-cyclodextrin (CD) to load the glycolysis inhibitor (2-deoxyglucose, 2DG), thereby reducing adenosine triphosphate (ATP) production in the extra-mitochondrial space, as glycolysis also occurs in the cytoplasm. The resulting TPP-CBS-2DG Janus NSs (JNSs) not only disrupt mitochondrial energy production, leading to cell starvation, but also inhibit HSP production. Consequently, TPP-CBS-2DG JNSs can enhance tumor thermal sensitivity in PTT, improving its efficacy. This work holds great promise for overcoming tumor heat resistance in PTT and provides a feasible method for fabricating selectively modified multifunctional NSs.
    Keywords:  Degradation; Energy metabolism; Janus nanosheets; Mitochondrial dynamics; Sensitized photothermal therapy; Targeting mitochondria
    DOI:  https://doi.org/10.1016/j.jcis.2024.10.180
  78. Circulation. 2024 Nov 12. 150(20): 1563-1566
    Cardiac Resynchronization Therapy: New Perspectives.
    Claude Daubert, Cecilia Linde.
      
    Keywords:  bundle branch block; cardiac resynchronization therapy; heart failure; ventricular function, left
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.070105
  79. ESC Heart Fail. 2024 Nov 11.
    Dapagliflozin alleviates high-fat-induced obesity cardiomyopathy by inhibiting ferroptosis.
    Di Chen, Jiahao Shi, Yue Wu, Lizhu Miao, Zilin Wang, Yixuan Wang, Siwei Xu, Yu Lou.
       AIM: Dapagliflozin (Dapa) is a novel hypoglycaemic agent with multiple cardiovascular protective effects, and it is widely used in treatment of heart failure patients, but whether it can improve obese phenotype of heart failure and its mechanism is still unclear. Ferroptosis is an iron dependent form of cell death and has been proved to be an important role in heart failure. The aim of this study is to determine whether Dapa improves obesity-related heart failure by regulating ferroptosis in high-fat diet rats.
    METHODS AND RESULTS: Male SD rats were fed a high-fat diet for 12 weeks and confirmed of obese heart failure by metabolic parameters and cardiac ultrasound. Being overweight by 20% compared with the normal group, with elevated systolic blood pressure and abnormal levels of insulin and blood lipid (TG and LDL-c), is recognized as obesity. The obese rats with reduced EF, FS, and E/A shown on ultrasound are defined as the obese heart failure (OHF) group. Histological tests confirmed the more pronounced cardiac fibrosis, mitochondrial volume and collagen deposition in OHF group. Dapa treatment effectively reduced body weight, INS, ISI/IRI index, TG and HDL-C levels (P < 0.05). Also, Dapa administration can slightly decrease the SBP and DBP levels; however, there was no statistical difference among those four groups. Furthermore, Dapa treatment can significantly improve high-fat induced systolic and diastolic dysfunction via regulating cardiac histological abnormalities, including less obvious mitochondrial swelling, muscle fibre dissolution and collagen deposition. Additionally, genes from the OHF group were used by GO enrichment analysis, and it shows that ferroptosis metabolic pathway participated in the development of obese phenotype of heart failure. More importantly, Dapa significantly inhibited Fe2+ and MDA levels (P < 0.05), but augmented GSH content (P < 0.05). In addition, the mRNAs and protein expression of some important regulators of ferroptosis, like GPX4, SLC7A11, FTH1 and FPN1, were all decreased after Dapa intervention.
    CONCLUSION: Dapa improved high-fat induced obese cardiac dysfunction via regulating ferroptosis pathway.
    Keywords:  Dapagliflozin; Ferroptosis; Obesity‐related cardiomyopathy; SGLT2i
    DOI:  https://doi.org/10.1002/ehf2.15150
  80. Clin Anat. 2024 Nov 13.
    Relating normal human cardiac development to the anatomical findings in the congenitally malformed heart.
    Jill P J M Hikspoors, Wouter H Lamers, Janet Kerwin, Zihan Hu, Deborah J Henderson, Robert H Anderson.
      A proper appreciation of cardiac development can now provide the necessary background to understand the anatomical findings in the congenitally malformed heart. We recently presented an account of human cardiac development based on reconstructions of histological datasets from human embryos aged between 3.5 and 8 weeks subsequent to conception. In this review, we summarize the changes observed relative to the findings when the heart is congenitally malformed. Beginning at the stage when it is first possible to recognize the primary heart tube, we describe the looping of its ventricular component, which occurs in the 5th week. We proceed with discussion of the formation of the atrial and ventricular chambers in the 6th week. The phases are successive, albeit partially overlapping. Separation of the circulations at the venous pole is completed at stage 17, equivalent to almost 6 weeks of development. During stages representing the 7th week of development, we concentrate on the remodeling of the outflow tract. This involves initially septation, but then separation of the developing circulations. The changes involve incorporation of the proximal outflow tract into the ventricles, with formation of the arterial roots in its middle part, and addition of a distal non-myocardial component to produce the intrapericardial arterial trunks. We pay particular attention to the changes occurring during remodeling of the interventricular foramen. We show that an understanding of this process provides the basis for understanding the functionally univentricular heart, as well as the arrangement found in double outlet right ventricle.
    Keywords:  cardiac compartment; cardiac loop; cardiac septation; developmental timing; embryonic ventricle; growth; staging
    DOI:  https://doi.org/10.1002/ca.24240
  81. Environ Int. 2024 Nov 05. pii: S0160-4120(24)00712-8. [Epub ahead of print]193 109126
    Mitigating environmental toxicity with hydrogen nanobubbles: A mitochondrial function-based approach to ecological restoration.
    Han Bao, You Zhang, Shuang Lv, Shu Liu, Wenhong Fan.
      In biological systems, nanobubbles (NBs) effectively enhance hydrogen molecule retention and scavenging reactive oxygen species (ROS), but the underlying mechanisms remain elusive. To investigate this, we prepared hydrogen NB water samples with consistent dissolved hydrogen levels but varying NB densities to explore their physicochemical properties and effects on green algae (Chlorella vulgaris) under oxidative stress induced by copper ions (Cu2+) and cadmium ions (Cd2+). The results indicated a strong correlation between the hydrogen NB number density and the 25 % inhibitory concentration of Cu2+ over 24 h, with ROS removal efficiency increased with the NB number density. Gas chromatography showed that the hydrogen NBs in the solution had a high gas density that enhanced hydrogen transport into C. vulgaris. With regard to mitochondrial activity, hydrogen NBs were observed to enhance the function of mitochondrial complexes I and V and increase the mitochondrial membrane potential. Experiments with C. vulgaris mitochondrial electrodes showed that the electron transfer rates increased significantly in the presence of hydrogen NBs. We concluded that the high gas density of hydrogen NBs augments intracellular hydrogen delivery and strengthens mitochondrial functions.
    Keywords:  Algae; Copper; Hydrogen content; Mitochondrial; Nanobubble number density; Oxidative stress
    DOI:  https://doi.org/10.1016/j.envint.2024.109126
  82. J Biol Chem. 2024 Nov 12. pii: S0021-9258(24)02481-5. [Epub ahead of print] 107979
    Cap-independent translation directs stress-induced differentiation of the protozoan parasite Toxoplasma gondii.
    Vishakha Dey, Michael J Holmes, Matheus S Bastos, Ronald C Wek, William J Sullivan.
      Translational control mechanisms modulate microbial latency of eukaryotic pathogens, enabling them to evade immunity and drug treatments. The protozoan parasite Toxoplasma gondii persists in hosts by differentiating from proliferative tachyzoites to latent bradyzoites, which are housed inside tissue cysts. Transcriptional changes facilitating bradyzoite conversion are mediated by a Myb domain transcription factor called BFD1, whose mRNA is present in tachyzoites but not translated into protein until stress is applied to induce differentiation. We addressed the mechanisms by which translational control drives BFD1 synthesis in response to stress-induced parasite differentiation. Using biochemical and molecular approaches, we show that the 5'-leader of BFD1 mRNA is sufficient for preferential translation upon stress. The translational control of BFD1 mRNA is maintained when ribosome assembly near its 5'-cap is impaired by insertion of a 5'-proximal stem-loop and upon knockdown of the Toxoplasma cap-binding protein, eIF4E1. Moreover, we determined that a trans-acting RNA-binding protein called BFD2/ROCY1 is necessary for cap-independent translation of BFD1 through its binding to the 5'-leader. Translation of BFD2 mRNA is also suggested to be preferentially induced under stress, but by a cap-dependent mechanism. These results show that translational control and differentiation in Toxoplasma proceed through cap-independent mechanisms in addition to canonical cap-dependent translation. Our identification of cap-independent translation in protozoa underscores the antiquity of this mode of gene regulation in cellular evolution and its central role in stress-induced life-cycle events.
    Keywords:  Toxoplasma; gene expression; parasite; stress response; translation
    DOI:  https://doi.org/10.1016/j.jbc.2024.107979
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