bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–09–29
72 papers selected by
Henver Brunetta, Karolinska Institutet
  1. Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.
  2. Effect of statins on mitochondrial function and contractile force in human skeletal and cardiac muscle.
  3. The age-dependent development of abnormal cardiac metabolism in the peroxisome proliferator-activated receptor α-knockout mouse.
  4. CALHM2 is a mitochondrial protein import channel that regulates fatty acid metabolism.
  5. Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway.
  6. Antidiabetic and Antihyperlipidemic Activities and Molecular Mechanisms of Phyllanthus emblica L. Extract in Mice on a High-Fat Diet.
  7. 6-Gingerol improves lipid metabolism disorders in skeletal muscle by regulating AdipoR1/AMPK signaling pathway.
  8. Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis.
  9. Modulating mitochondrial dynamics ameliorates left ventricular dysfunction by suppressing diverse cell death pathways after diabetic cardiomyopathy.
  10. Melatonin alleviates high glucose-induced cardiomyocyte injury through suppressing mitochondrial FUNDC1-DRP1 axis.
  11. METTL3-mediated m6A modification of OTUD1 aggravates press overload induced myocardial hypertrophy by deubiquitinating PGAM5.
  12. Mitochondrial lipid peroxidation is necessary but not sufficient for induction of ferroptosis.
  13. N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy.
  14. CTRP6-mediated cardiac protection in heart failure via the AMPK/SIRT1/PGC-1α signalling pathway.
  15. CPEB2-activated Prdm16 translation promotes brown adipocyte function and prevents obesity.
  16. The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis.
  17. Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-κB signaling pathways.
  18. Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.
  19. Obesity alters adipose tissue response to fasting and refeeding in women: A study on lipolytic and endocrine dynamics and acute insulin resistance.
  20. NR2F2 Reactivation in Early-life Adipocyte Stem-like Cells Rescues Adipocyte Mitochondrial Oxidation.
  21. Modification of the Diabetes Prevention Program Lifestyle Intervention in Persons with Spinal Cord Injury: Efficacy for Reducing Major Cardiometabolic Risks, Increased Fitness, and Improved Health-Related Quality of Life.
  22. TRIM35 triggers cardiac remodeling by regulating SLC7A5-mediated amino acid transport and mTORC1 activation in fibroblasts.
  23. Altered hepatic metabolic landscape and insulin sensitivity in response to pulmonary tuberculosis.
  24. Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
  25. Cardiac macrophages and fibroblasts: A synergistic partnership without cellular transition.
  26. Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats.
  27. Beyond MitoCarta-expanding the list of candidate proteins involved in mitochondrial functions using a biological network approach.
  28. Machine Learning-Based Plasma Metabolomics in Liraglutide-Treated Type 2 Diabetes Mellitus Patients and Diet-Induced Obese Mice.
  29. Unraveling the nexus of age, epilepsy, and mitochondria: exploring the dynamics of cellular energy and excitability.
  30. NPLOC4 aggravates heart failure by regulating ROS and mitochondrial function.
  31. Setting the curve: the biophysical properties of lipids in mitochondrial form and function.
  32. Comparison of free vs. liposomal naringenin in white adipose tissue browning in C57BL/6j mice.
  33. Unveiling sex differences in skeletal muscle metabolism: the role of HIF1α in normoxia.
  34. A whole-food, plant-based intensive lifestyle intervention improves glycaemic control and reduces medications in individuals with type 2 diabetes: a randomised controlled trial.
  35. Exercise training improves cardiovascular fitness in dilated cardiomyopathy caused by truncating titin variants.
  36. HDAC5 controls a hypothalamic STAT5b-TH axis, the sympathetic activation of ATP-consuming futile cycles and adult-onset obesity in male mice.
  37. Propofol binds and inhibits skeletal muscle ryanodine receptor 1.
  38. GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
  39. Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
  40. Dual ablation of the RyR2-Ser2808 and RyR2-Ser2814 sites increases propensity for pro-arrhythmic spontaneous Ca2+ releases.
  41. Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform.
  42. Effects of Dietary Allitol and D-Allulose on Body Fat Accumulation and Cecal Short-Chain Fatty Acid Production in Rats Fed a High-Fat Diet.
  43. Bile acids acting as a feeding signal and functional foods mimicking bile acid function.
  44. Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway.
  45. Effects of Glucagon-like Peptide-1 Receptor Agonists on Cardiac Function, Exercise Capacity and Quality of Life.
  46. PRDM16 determines specification of ventricular cardiomyocytes by suppressing alternative cell fates.
  47. Evolution of translational control and the emergence of genes and open reading frames in human and non-human primate hearts.
  48. Constipation as a new non-traditional significant contributor to cardiovascular disease.
  49. Melatonin regulates mitochondrial dynamics and mitophagy: Cardiovascular protection.
  50. RNA-Seq analysis of human heart tissue reveals SARS-CoV-2 infection and inappropriate activation of the TNF-NF-κB pathway in cardiomyocytes.
  51. A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
  52. Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy.
  53. Calcitriol/vitamin D receptor system alleviates PM2.5-induced human bronchial epithelial damage through upregulating mitochondrial bioenergetics in association with regulation of HIF-1α/PGC-1α signaling.
  54. Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
  55. Imatinib-cardiotoxicity: biventricular heart failure, thrombi and transmural fibrosis.
  56. Genetic excision of the regulatory cardiac troponin I extension in high-heart rate mammal clades.
  57. Metabolic revitalization: exploring erythrocyte fatty acid profile following laparoscopic sleeve gastrectomy.
  58. GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia.
  59. PUFAs regulate SREBP1c through phosphorylation of Insig2.
  60. Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
  61. SUMOylation of cardiac myosin binding protein-C reduces its phosphorylation and results in impaired relaxation following treatment with isoprenaline.
  62. Ceramides-Emerging Biomarkers of Lipotoxicity in Obesity, Diabetes, Cardiovascular Diseases, and Inflammation.
  63. Metabolomic Fingerprints of Medical Therapy Versus Bariatric Surgery in Patients With Obesity and Type 2 Diabetes: The STAMPEDE Trial.
  64. Body composition in recurrent prostate cancer and the role of steroidogenic genotype.
  65. Effects of glucokinase haploinsufficiency on the pancreatic β-cell mass and function of long-term high-fat, high-sucrose diet-fed mice.
  66. Mitochondria facilitate neuronal differentiation by metabolising nuclear-encoded RNA.
  67. Chronic whole-body heat treatment in obese insulin-resistant C57BL/6J mice.
  68. Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.
  69. Nasal administration of mitochondria relieves depressive- and anxiety-like behaviors in male mice exposed to restraint stress through the suppression ROS/NLRP3/caspase-1/IL-1β signaling pathway.
  70. Effect of Cannabistilbene I in Attenuating Angiotensin II-Induced Cardiac Hypertrophy: Insights into Cytochrome P450s and Arachidonic Acid Metabolites Modulation.
  71. Correlation of serum homocysteine and cystatin C levels with prognosis in heart failure with preserved ejection fraction patients.
  72. Protocol to monitor live-cell, real-time, mitochondrial respiration in mouse muscle cells using the Resipher platform.
  1. Circ Res. 2024 Sep 27.
    Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.
    Akira Yoshii, Timothy S McMillen, Yajun Wang, Bo Zhou, Hongye Chen, Durba Banerjee, Melisa Herrero, Pei Wang, Naoto Muraoka, Wang Wang, Charles E Murry, Rong Tian.
       BACKGROUND: Metabolic remodeling and mitochondrial dysfunction are hallmarks of heart failure with reduced ejection fraction. However, their role in the pathogenesis of HF with preserved ejection fraction (HFpEF) is poorly understood.
    METHODS: In a mouse model of HFpEF, induced by high-fat diet and Nω-nitrol-arginine methyl ester, cardiac energetics was measured by 31P NMR spectroscopy and substrate oxidation profile was assessed by 13C-isotopmer analysis. Mitochondrial functions were assessed in the heart tissue and human induced pluripotent stem cell-derived cardiomyocytes.
    RESULTS: HFpEF hearts presented a lower phosphocreatine content and a reduced phosphocreatine/ATP ratio, similar to that in heart failure with reduced ejection fraction. Decreased respiratory function and increased reactive oxygen species production were observed in mitochondria isolated from HFpEF hearts suggesting mitochondrial dysfunction. Cardiac substrate oxidation profile showed a high dependency on fatty acid oxidation in HFpEF hearts, which is the opposite of heart failure with reduced ejection fraction but similar to that in high-fat diet hearts. However, phosphocreatine/ATP ratio and mitochondrial function were sustained in the high-fat diet hearts. We found that mitophagy was activated in the high-fat diet heart but not in HFpEF hearts despite similar extent of obesity suggesting that mitochondrial quality control response was impaired in HFpEF hearts. Using a human induced pluripotent stem cell-derived cardiomyocyte mitophagy reporter, we found that fatty acid loading stimulated mitophagy, which was obliterated by inhibiting fatty acid oxidation. Enhancing fatty acid oxidation by deleting ACC2 (acetyl-CoA carboxylase 2) in the heart stimulated mitophagy and improved HFpEF phenotypes.
    CONCLUSIONS: Maladaptation to metabolic stress in HFpEF hearts impairs mitochondrial quality control and contributed to the pathogenesis, which can be improved by stimulating fatty acid oxidation.
    Keywords:  arginine methyl ester; fatty acids; heart diseases; mitophagy; ventricular dysfunction, left
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324103
  2. Biomed Pharmacother. 2024 Sep 25. pii: S0753-3322(24)01378-7. [Epub ahead of print]180 117492
    Effect of statins on mitochondrial function and contractile force in human skeletal and cardiac muscle.
    Tim Somers, Sailay Siddiqi, Margit C M Janssen, Wim J Morshuis, Renee G C Maas, Jan W Buikema, Petra H H van den Broek, Tom J J Schirris, Frans G M Russel.
       OBJECTIVES AND BACKGROUND: The success of statin therapy in reducing cardiovascular morbidity and mortality is contrasted by the skeletal muscle complaints, which often leads to nonadherence. Previous studies have shown that inhibition of mitochondrial function plays a key role in statin intolerance. Recently, it was found that statins may also influence energy metabolism in cardiomyocytes. This study assessed the effects of statin use on cardiac muscle ex vivo from patients using atorvastatin, rosuvastatin, simvastatin or pravastatin and controls.
    METHODS: Cardiac tissue and skeletal muscle tissue were harvested during open heart surgery after patients provided written informed consent. Patients included were undergoing cardiac surgery and either taking statins (atorvastatin, rosuvastatin, simvastatin or pravastatin) or without statin therapy (controls). Contractile behaviour of cardiac auricles was tested in an ex vivo set-up and cellular respiration of both cardiac and skeletal muscle tissue samples was measured using an Oxygraph-2k. Finally, statin acid and lactone concentrations were quantified in cardiac and skeletal homogenates by LC-MS/MS.
    RESULTS: Fatty acid oxidation and mitochondrial complex I and II activity were reduced in cardiac muscle, while contractile function remained unaffected. Inhibition of mitochondrial complex III by statins, as previously described, was confirmed in skeletal muscle when compared to control samples, but not observed in cardiac tissue. Statin concentrations determined in skeletal muscle tissue and cardiac muscle tissue were comparable.
    CONCLUSIONS: Statins reduce skeletal and cardiac muscle cell respiration without significantly affecting cardiac contractility.
    Keywords:  Cardiac muscle; Cellular respiration; Contractile force; Heart auricle; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.biopha.2024.117492
  3. Atherosclerosis. 2024 Sep 17. pii: S0021-9150(24)01171-7. [Epub ahead of print] 118599
    The age-dependent development of abnormal cardiac metabolism in the peroxisome proliferator-activated receptor α-knockout mouse.
    Michael S Dodd, Lucy Ambrose, Vicky Ball, Kieran Clarke, Carolyn A Carr, Damian J Tyler.
       BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor α (PPARα) is crucial for regulating cardiac β-oxidation in the heart, liver, and kidney. Ageing can induce cardiac metabolic alterations, but the role of PPARα has not been extensively characterised. The aim of this research was to investigate the role of PPARα in the aged heart.
    METHODS: Hyperpolarized [1-13C]pyruvate was used to evaluate in vivo cardiac carbohydrate metabolism in fed and fasted young (3 months) and old (20-22 months) PPARα knockout (KO) mice versus controls. Cine MRI assessed cardiac structural and functional changes. Cardiac tissue analysis included qRT-PCR and Western blotting for Pparα, medium chain acyl-CoA dehydrenase (MCAD), uncoupling protein (UCP) 3, glucose transporter (GLUT) 4 and PDH kinase (PDK) 1,2, and 4 expression.
    RESULTS: PPARα-KO hearts from both young and old mice showed significantly reduced Pparα mRNA and a 58-59 % decrease in MCAD protein levels compared to controls. Cardiac PDH flux was similar in young control and PPARα-KO mice but 96 % higher in old PPARα-KO mice. Differences between genotypes were consistent in fed and fasted states, with reduced PDH flux when fasted. Increased PDH flux was accompanied by a 179 % rise in myocardial GLUT4 protein. No differences in PDK 1, 2, or 4 protein levels were observed between fed groups, indicating the increased PDH flux in aged PPARα-KO mice was not due to changes in PDH phosphorylation.
    CONCLUSIONS: Aged PPARα-KO mice demonstrated higher cardiac PDH flux compared to controls, facilitated by increased myocardial GLUT4 protein levels, leading to enhanced glucose uptake and glycolysis.
    Keywords:  Ageing; Cardiac metabolism; Hyperpolarized 13C MRS; PPARalpha
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2024.118599
  4. Res Sq. 2024 Sep 13. pii: rs.3.rs-4985689. [Epub ahead of print]
    CALHM2 is a mitochondrial protein import channel that regulates fatty acid metabolism.
    Elizabeth Jonas, Nelli Mnatsakanyan, Felix Rivera-Molina, Andrew Robson, Alexandra MacColl Garfinkel, Amrendra Kumar, Stephen Batter, Valeria Padovano, Kaitlin Webster, Rebecca Cardone, Justin Berg, Derek Toomre, Richard Kibbey Iv, Michael Caplan, Mustafa Khokha.
      For mitochondrial metabolism to occur in the matrix, multiple proteins must be imported across the two (inner and outer) mitochondrial membranes. Classically, two protein import channels, TIM/TOM, are known to perform this function, but whether other protein import channels exist is not known. Here, using super-resolution microscopy, proteomics, and electrophysiological techniques, we identify CALHM2 as the import channel for the ECHA subunit of the mitochondrial trifunctional protein (mTFP), which catalyzes β-oxidation of fatty acids in the mitochondrial matrix. We find that CALHM2 sits specifically at the inner mitochondrial and cristae membranes and is critical for membrane morphology. Depletion of CALHM2 leads to a mislocalization of ECHA outside of the mitochondria leading to severe cellular metabolic defects. These defects include cytosolic accumulation of fatty acids, depletion of tricarboxylic acid cycle enzymes and intermediates, and reduced cellular respiration. Our data identify CALHM2 as an essential protein import channel that is critical for fatty acid- and glucose-dependent aerobic metabolism. .
    DOI:  https://doi.org/10.21203/rs.3.rs-4985689/v1
  5. Cell Rep. 2024 Sep 19. pii: S2211-1247(24)01097-0. [Epub ahead of print]43(10): 114746
    Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway.
    Weiwei Xu, Dongyan Zhang, Yumin Ma, Rafael C Gaspar, Mario Kahn, Ali Nasiri, Sue Murray, Varman T Samuel, Gerald I Shulman.
      Inhibition of the ceramide synthetic pathway with myriocin or an antisense oligonucleotide (ASO) targeting dihydroceramide desaturase (DES1) both improved hepatic insulin sensitivity in rats fed either a saturated or unsaturated fat diet and was associated with reductions in both hepatic ceramide and plasma membrane (PM)-sn-1,2-diacylglycerol (DAG) content. The insulin sensitizing effects of myriocin and Des1 ASO were abrogated by acute treatment with an ASO against DGAT2, which increased hepatic PM-sn-1,2-DAG but not hepatic C16 ceramide content. Increased PM-sn-1,2-DAG content was associated with protein kinase C (PKC)ε activation, increased insulin receptor (INSR)T1150 phosphorylation leading to reduced insulin-stimulated INSRY1152/AktS473 phosphorylation, and impaired insulin-mediated suppression of endogenous glucose production. These results demonstrate that inhibition of de novo ceramide synthesis by either myriocin treatment or DES1 knockdown protects against lipid-induced hepatic insulin resistance through a C16 ceramide-independent mechanism and that they mediate their effects to protect from lipid-induced hepatic insulin resistance via the PM-sn-1,2-DAG-PKCε-INSRT1150 phosphorylation pathway.
    Keywords:  CP: Metabolism; CP: Molecular biology; antisense oligonucleotides; ceramides; diacylglycerols (DAG); fatty acids; insulin resistance; lipid metabolism; metabolic dysfunction-associated steatotic disease (MASLD); protein kinase C epsilon
    DOI:  https://doi.org/10.1016/j.celrep.2024.114746
  6. Curr Issues Mol Biol. 2024 Sep 20. 46(9): 10492-10529
    Antidiabetic and Antihyperlipidemic Activities and Molecular Mechanisms of Phyllanthus emblica L. Extract in Mice on a High-Fat Diet.
    Hsing-Yi Lin, Cheng-Hsiu Lin, Yueh-Hsiung Kuo, Chun-Ching Shih.
      We planned to explore the protective activities of extract of Phyllanthus emblica L. (EPE) on insulin resistance and metabolic disorders including hyperlipidemia, visceral obesity, and renal dysfunction in high-fat diet (HFD)-progressed T2DM mice. Mice treatments included 7 weeks of HFD induction followed by EPE, fenofibrate (Feno), or metformin (Metf) treatment daily for another 4-week HFD in HFD-fed mice. Finally, we harvested blood to analyze some tests on circulating glycemia and blood lipid levels. Western blotting analysis was performed on target gene expressions in peripheral tissues. The present findings indicated that EPE treatment reversed the HFD-induced increases in blood glucose, glycosylated HbA1C, and insulin levels. Our findings proved that treatment with EPE in HFD mice effectively controls hyperglycemia and hyperinsulinemia. Our results showed that EPE reduced blood lipid levels, including a reduction in blood triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA); moreover, EPE reduced blood leptin levels and enhanced adiponectin concentrations. EPE treatment in HFD mice reduced BUN and creatinine in both blood and urine and lowered albumin levels in urine; moreover, EPE decreased circulating concentrations of inflammatory NLR family pyrin domain containing 3 (NLRP3) and kidney injury molecule-1 (KIM-1). These results indicated that EPE displayed antihyperglycemic and antihyperlipidemic activities but alleviated renal dysfunction in HFD mice. The histology examinations indicated that EPE treatment decreased adipose hypertrophy and hepatic ballooning, thus contributing to amelioration of lipid accumulation. EPE treatment decreased visceral fat amounts and led to improved systemic insulin resistance. For target gene expression levels, EPE enhanced AMP-activated protein kinase (AMPK) phosphorylation expressions both in livers and skeletal muscles and elevated the muscular membrane glucose transporter 4 (GLUT4) expressions. Treatment with EPE reduced hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) expressions to suppress glucose production in the livers and decreased phosphorylation of glycogen synthase kinase 3β (GSK3β) expressions to affect hepatic glycogen synthesis, thus convergently contributing to an antidiabetic effect and improving insulin resistance. The mechanism of the antihyperlipidemic activity of EPE involved a decrease in the hepatic phosphorylation of mammalian target of rapamycin complex C1 (mTORC1) and p70 S6 kinase 1 (S6K1) expressions to improve insulin resistance but also a reduction in hepatic sterol regulatory element binding protein (SREBP)-1c expressions, and suppression of ACC activity, thus resulting in the decreased fatty acid synthesis but elevated hepatic peroxisome proliferator-activated receptor (PPAR) α and SREBP-2 expressions, resulting in lowering TG and TC concentrations. Our results demonstrated that EPE improves insulin resistance and ameliorates hyperlipidemia in HFD mice.
    Keywords:  Phyllanthus emblica L.; antihyperlipidemic; insulin resistance
    DOI:  https://doi.org/10.3390/cimb46090623
  7. Biomed Pharmacother. 2024 Sep 23. pii: S0753-3322(24)01348-9. [Epub ahead of print]180 117462
    6-Gingerol improves lipid metabolism disorders in skeletal muscle by regulating AdipoR1/AMPK signaling pathway.
    Ze Peng, Yan Zeng, Xin Zeng, Qi Tan, Qifeng He, Shang Wang, Jianwei Wang.
       BACKGROUND: To delve into the precise mechanisms by which 6-gingerol ameliorates lipid metabolism disorders in skeletal muscle.
    METHODS: The level of triglycerides (TG) was used to evaluate lipid deposition. In skeletal muscle, transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. Additionally, PCR was applied to detect mitochondrial biogenesis, and levels of malondialdehyde (MDA), catalase (CAT), glutathione, r-glutamyl cysteingl+glycine (GSH) and nicotinamide adenine dinucleotide (NADH) were measured to assess mitochondrial oxidative stress levels. In vivo, flow cytometry and immunofluorescence assays were conducted to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Furthermore, the Seahorse XF assays was utilized to assess mitochondrial respiratory capacity. Fluorescence confocal microscopy and molecular docking were applied to analyze the binding of 6-gingerol and adiponectin receptor 1 (AdipoR1). The expression of AdipoR1, AMPK, PGC-1α and SIRT1 were detected by Western Blot.
    RESULTS: In vivo, 6-gingerol could reduce body weight in mice induced by a high-fat diet, enhance metabolic profiles in plasma, decrease lipid accumulation in skeletal muscle and liver, and elevate adiponectin levels. In skeletal muscle, it could restore mitochondrial morphology, boost mitochondrial copy number and biogenesis, and mitigate oxidative stress. In vitro, 6-gingerol may directly interact with AdipoR1 to upregulate the expression of downstream proteins p-AMPK, SIRT1, and PGC-1α, leading to a reduction in lipid deposition, a decrease in ROS production, an increase in mitochondrial membrane potential, and an enhancement of mitochondrial respiratory capacity in C2C12 myotubes.
    CONCLUSION: 6-Gingerol ameliorated lipid metabolism in skeletal muscle by regulating the AdipoR1/AMPK signaling pathway.
    Keywords:  6-gingerol; Ginger; Lipid metabolism disorders; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.biopha.2024.117462
  8. Redox Biol. 2024 Sep 19. pii: S2213-2317(24)00343-4. [Epub ahead of print]77 103365
    Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis.
    Yijie Song, Mengjie Zhu, Md Ariful Islam, Wenyi Gu, Kavsar Alim, Chien-Shan Cheng, Jingxian Chen, Yu Xu, Hongxi Xu.
      Adipose tissue senescence is a precursor to organismal aging and understanding adipose remodelling contributes to discovering novel anti-aging targets. Glutathione peroxidase 3 (GPx3), a critical endogenous antioxidant enzyme, is diminished in the subcutaneous adipose tissue (sWAT) with white adipose expansion. Based on the active role of the antioxidant system in counteracting aging, we investigated the involvement of GPx3 in adipose senescence. We determined that knockdown of GPx3 in adipose tissue by adeno-associated viruses impaired mitochondrial function in mice, increased susceptibility to obesity, and exacerbated adipose tissue senescence. Impairment of GPx3 may cause mitochondrial dysfunction through inner mitochondrial membrane disruption. Adipose reshaping management (cold stimulation and intermittent diet) counteracted the aging of tissues, with an increase in GPx3 expression. Overall metabolic improvement induced by cold stimulation was partially attenuated when GPx3 was depleted. GPx3 may be involved in adipose browning by interacting with UCP1, and GPx3 may be a limiting factor for intracellular reactive oxygen species (ROS) accumulation during stem cell browning. Collectively, these findings emphasise the importance of restoring the imbalanced redox state in adipose tissue to counteract aging and that GPx3 may be a potential target for maintaining mitochondrial homeostasis and longevity.
    Keywords:  Adipose tissue; Anti-Senescence; Glutathione peroxidase 3; Mitochondrial
    DOI:  https://doi.org/10.1016/j.redox.2024.103365
  9. Int J Med Sci. 2024 ;21(12): 2324-2333
    Modulating mitochondrial dynamics ameliorates left ventricular dysfunction by suppressing diverse cell death pathways after diabetic cardiomyopathy.
    Fumin Zhi, Xiangyi Pu, Wei Wei, Li Liu, Chunyan Liu, Ye Chen, Xing Chang, Hongtao Xu.
      Diabetic cardiomyopathy (DCM) triggers a detrimental shift in mitochondrial dynamics, characterized by increased fission and decreased fusion, contributing to cardiomyocyte apoptosis and cardiac dysfunction. This study investigated the impact of modulating mitochondrial dynamics on DCM outcomes and underlying mechanisms in a mouse model. DCM induction led to upregulation of fission genes (Drp1, Mff, Fis1) and downregulation of fusion genes (Mfn1, Mfn2, Opa1). Inhibiting fission with Mdivi-1 or promoting fusion with Ginsenoside Rg1 preserved cardiac function, as evidenced by improved left ventricular ejection fraction (LVEF), fractional shortening (FS), and E/A ratio. Both treatments also reduced infarct size and attenuated cardiomyocyte apoptosis, indicated by decreased caspase-3 activity. Mechanistically, Mdivi-1 enhanced mitochondrial function by improving mitochondrial membrane potential, reducing reactive oxygen species (ROS) production, and increasing ATP generation. Ginsenoside Rg1 also preserved mitochondrial integrity and function under hypoxic conditions in HL-1 cardiomyocytes. These findings suggest that restoring the balance of mitochondrial dynamics through pharmacological interventions targeting either fission or fusion may offer a promising therapeutic strategy for mitigating MI-induced cardiac injury and improving patient outcomes.
    Keywords:  cardiomyocyte apoptosis; diabetic cardiomyopathy; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.7150/ijms.98065
  10. J Pharm Pharmacol. 2024 Sep 22. pii: rgae114. [Epub ahead of print]
    Melatonin alleviates high glucose-induced cardiomyocyte injury through suppressing mitochondrial FUNDC1-DRP1 axis.
    Junyi Zheng, Lili Zhao, Yingying Zhang, Wenbin He, Xukun Guo, Jixiang Wang.
       OBJECTIVES: To use H9c2 cardiomyocytes to establish a diabetic cardiomyopathic model by exposing these cells to high glucose (HG), followed by treating them with melatonin (MEL) or plasmid vectors overexpressing FUN14 Domain Containing 1 (FUNDC1).
    METHODS: We employed quantitative real-time PCR, mitochondrial staining, and biochemical assays to measure the activity of various antioxidant and mitochondrial complex functions under various treatment conditions.
    KEY FINDINGS: Our results showed that HG induced the expression of FUNDC1 and increased mitochondrial oxidative stress and fragmentation, while MEL treatment reversed most of these pathological effects. Moreover, HG exposure activated dynamin-related protein 1 expression and its translocation to mitochondria. Modulation of AMP-activated protein kinase level was found to be another pathological hallmark. In silico molecular docking, analysis revealed that MEL could directly bind the catalytic groove of FUNDC1 through Van der Waal's force and hydrogen bonding. Finally, MEL ameliorated diabetic cardiomyopathy-induced mitochondrial injury through FUNDC1 in vivo.
    CONCLUSIONS: Hyperglycemia induced mitochondrial fragmentation and altered electron transport chain complex functions, which could be ameliorated by MEL treatment, suggesting its potential as a cardiovascular therapeutic.
    Keywords:  FUNDC1; cardiomyocytes; high glucose; hyperglycemia; melatonin; mitochondrial fragmentation
    DOI:  https://doi.org/10.1093/jpp/rgae114
  11. Int J Biol Sci. 2024 ;20(12): 4908-4921
    METTL3-mediated m6A modification of OTUD1 aggravates press overload induced myocardial hypertrophy by deubiquitinating PGAM5.
    Kai Huang, Xiaotian Sun, Xiangyang Xu, Jie Lu, Boyao Zhang, Qin Li, Chuyi Wang, Sufan Ding, Xiaolei Huang, Xiaohong Liu, Zhiyun Xu, Lin Han.
      Background: Pathological cardiac hypertrophy, a condition that contributes to heart failure, is characterized by its intricate pathogenesis. The meticulous regulation of protein function, localization, and degradation is a crucial role played by deubiquitinating enzymes in cardiac pathophysiology. This study clarifies the participation and molecular mechanism of OTUD1 (OTU Deubiquitinase 1) in pathological cardiac hypertrophy. Methods: We generated a cardiac-specific Otud1 knockout mouse line (Otud1-CKO) and adeno-associated virus serotype 9-Otud1 mice to determine the role of Otud1 in cardiac hypertrophy. Its impact on cardiomyocytes enlargement was investigated using the adenovirus. RNA immunoprecipitation was used to validate the specific m6a methyltransferase interacted with OTUD1 transcript. RNA sequencing in conjunction with immunoprecipitation-mass spectrometry analysis was employed to identify the direct targets of OTUD1. A series of depletion mutant plasmids were constructed to detect the interaction domain of OTUD1 and its targets. Results: Ang II-stimulated neonatal rat cardiac myocytes and mice hearts subjected to transverse aortic constriction (TAC) showed increased protein levels of Otud1. Cardiac hypertrophy and dysfunction were less frequent in Otud1-CKO mice during TAC treatment, while Otud1 overexpression worsened cardiac hypertrophy and remodeling. METTL3 mediated m6A modification of OTUD1 transcript promoted mRNA stability and elevated protein expression. In terms of pathogenesis, Otud1 plays a crucial role in cardiac hypertrophy by targeting Pgam5, leading to the robust activation of the Ask1-p38/JNK signal pathway to accelerate cardiac hypertrophy. Significantly, the pro-hypertrophy effects of Otud1 overexpression were largely eliminated when Ask1 knockdown. Conclusion: Our findings confirm that targeting the OTUD1-PGAM5 axis holds significant potential as a therapeutic approach for heart failure associated with pathological hypertrophy.
    DOI:  https://doi.org/10.7150/ijbs.95707
  12. Front Cell Dev Biol. 2024 ;12 1452824
    Mitochondrial lipid peroxidation is necessary but not sufficient for induction of ferroptosis.
    He Huan, Konstantin G Lyamzaev, Alisa A Panteleeva, Boris V Chernyak.
      Ferroptosis, a form of regulated cell death mediated by lipid peroxidation (LPO), has become the subject of intense research due to its potential therapeutic applications in cancer chemotherapy as well as its pathophysiological role in ischemic organ injury. The role of mitochondrial lipid peroxidation (LPO) in ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate (FAC) in combination with buthionine sulfoximine (BSO, an inhibitor of glutathione biosynthesis) induces mitochondrial lipid peroxidation that precedes ferroptosis in normal human fibroblasts. The mitochondrial-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis, but do not affect the cytosolic ROS accumulation. These data indicate that mitochondrial lipid peroxidation is required for ferroptosis induced by exogenous iron. FAC in the absence of BSO stimulates mitochondrial peroxidation without reducing cell viability. Glutathione depletion by BSO does not affect FAC-induced mitochondrial LPO but strongly stimulates the accumulation of ROS in the cytosol. These data allow us to conclude that mitochondrial LPO is not sufficient for ferroptosis and that cytosolic ROS mediates additional oxidative events that stimulate ferroptosis in conjunction with mitochondrial LPO.
    Keywords:  buthionine sulfoximine (BSO); ferric ammonium citrate (FAC); ferroptosis; mitochondrial lipid peroxidation; mitochondrial-targeted antioxidants
    DOI:  https://doi.org/10.3389/fcell.2024.1452824
  13. J Cell Physiol. 2024 Sep 22. e31448
    N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy.
    Pingping Qi, Wei Zhang, Yang Gao, Shengkui Chen, Minghe Jiang, Rong He, Wenzhong Chen, Xiawei Wei, Bingquan Hu, Hao Xu, Minsheng Wu, Rong Tang.
      N6-methyladenosine (m6A) is known to be crucial in various biological processes, but its role in sepsis-induced circulatory and cardiac dysfunction is not well understood. Specifically, mitophagy, a specialized form of autophagy, is excessively activated during lipopolysaccharide (LPS)-induced myocardial injury. This study aimed to investigate the impact of LPS-induced endotoxemia on m6A-RNA methylation and its role in regulating mitophagy in sepsis-induced myocardial dysfunction. Our research demonstrated that FTO (fat mass and obesity-associated protein), an m6A demethylase, significantly affects abnormal m6A modification in the myocardium and cardiomyocytes following LPS treatment. In mice, cardiac dysfunction and cardiomyocyte apoptosis worsened after adeno-associated virus serotype 9 (AAV9)-mediated FTO knockdown. Further analyses to uncover the cellular mechanisms improving cardiac function showed that FTO reduced mitochondrial reactive oxygen species, restored both basal and maximal respiration, and preserved mitochondrial membrane potential. We revealed that FTO plays a critical role in activating mitophagy by targeting BNIP3. Additionally, the cardioprotective effects of AAV-FTO were significantly compromised by mdivi-1, a mitophagy inhibitor. Mechanistically, FTO interacted with BNIP3 transcripts and regulated their expression in an m6A-dependent manner. Following FTO silencing, BNIP3 transcripts with elevated m6A modification levels in their coding regions were bound by YTHDF2 (YT521-B homology m6A RNA-binding protein 2), leading to mRNA destabilization and decreased BNIP3 protein levels. These findings highlight the importance of FTO-dependent cardiac m6A methylation in regulating mitophagy and enhance our understanding of this critical interplay, which is essential for developing therapeutic strategies to protect cardiac mitochondrial function, alleviate cardiac dysfunction, and improve survival during sepsis.
    Keywords:  BNIP3; FTO; N6‐methyladenosine; mitophagy; sepsis
    DOI:  https://doi.org/10.1002/jcp.31448
  14. Exp Physiol. 2024 Sep 26.
    CTRP6-mediated cardiac protection in heart failure via the AMPK/SIRT1/PGC-1α signalling pathway.
    Tingting Fan, Ningjun Zhu, Mengli Li, Zhen Wang, Xianhe Lin.
      Heart failure (HF) remains a significant global health concern with limited effective treatments available. C1q/TNF-related protein 6 (CTRP6) is a member of the CTRP family analogous to adiponectin and its role in HF pathogenesis remains unclear. Here, we investigated the impact of CTRP6 on HF progression. To mimic heart failure with reduced ejection fraction (HFrEF), we used isoproterenol injection in mice and administered adenovirus vectors expressing CTRP6 (Ad-CTRP6) via tail vein injection. We assessed cardiac function through echocardiography and histology. CTRP6's effects on hypertrophy, fibrosis, apoptosis, oxidative stress and mitochondrial function were analysed. Downstream pathways (phosphorylated AMP-activated protein kinase (p-AMPK), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) were studied in heart tissues. In vitro, isoproterenol-stimulated H9c2 cardiomyocytes were treated with CTRP6 to examine viability, apoptosis, F-actin and signalling proteins. Compound C was used to assess AMPK involvement. CTRP6 expression was lower in the plasma of HF patients. In an isoproterenol-induced HFrEF mouse model, adenovirus-mediated overexpression of CTRP6 ameliorated cardiac dysfunction and reduced cardiomyocyte apoptosis, oxidative stress, inflammation and myocardial injury markers. Mechanistically, CTRP6 activation of the AMPK/SIRT1/PGC-1α signalling pathway restored mitochondrial homeostasis, evidenced by reduced mitochondrial reactive oxygen species levels, increased ATP content, and enhanced mitochondrial complex I/III activities in cardiac tissues. In vitro studies using isoproterenol-stimulated H9c2 cardiomyocytes corroborated these findings, demonstrating that CTRP6 upregulation attenuated hypertrophy, apoptosis, oxidative stress and mitochondrial dysfunction. Furthermore, these effects were partially reversed by the AMPK inhibitor Compound C, implicating the involvement of the AMPK pathway in CTRP6-mediated cardioprotection. CTRP6 alleviates HF progression through the AMPK/SIRT1/PGC-1α signalling pathway.
    Keywords:  AMPK; CTRP6; PGC‐1α; SIRT1; heart failure; mitochondrion
    DOI:  https://doi.org/10.1113/EP092036
  15. Mol Metab. 2024 Sep 19. pii: S2212-8778(24)00165-0. [Epub ahead of print]89 102034
    CPEB2-activated Prdm16 translation promotes brown adipocyte function and prevents obesity.
    Wen-Hsin Lu, Hui-Feng Chen, Pei-Chih King, Chi Peng, Yi-Shuian Huang.
       OBJECTIVE: Brown adipose tissue (BAT) plays an important role in mammalian thermogenesis through the expression of uncoupling protein 1 (UCP1). Our previous study identified cytoplasmic polyadenylation element binding protein 2 (CPEB2) as a key regulator that activates the translation of Ucp1 with a long 3'-untranslated region (Ucp1L) in response to adrenergic signaling. Mice lacking CPEB2 or Ucp1L exhibited reduced UCP1 expression and impaired thermogenesis; however, only CPEB2-null mice displayed obesogenic phenotypes. Hence, this study aims to investigate how CPEB2-controlled translation impacts body weight.
    METHODS: Body weight measurements were conducted on mice with global knockout (KO) of CPEB2, UCP1 or Ucp1L, as well as those with conditional knockout of CPEB2 in neurons or adipose tissues. RNA sequencing coupled with bioinformatics analysis was used to identify dysregulated gene expression in CPEB2-deficient BAT. The role of CPEB2 in regulating PRD1-BF1-RIZ1 homologous-domain containing 16 (PRDM16) expression was subsequently confirmed by RT-qPCR, Western blotting, polysomal profiling and luciferase reporter assays. Adeno-associated viruses (AAV) expressing CPEB2 or PRDM16 were delivered into BAT to assess their efficacy in mitigating weight gain in CPEB2-KO mice.
    RESULTS: We validated that defective BAT function contributed to the increased weight gain in CPEB2-KO mice. Transcriptomic profiling revealed upregulated expression of genes associated with muscle development in CPEB2-KO BAT. Given that both brown adipocytes and myocytes stem from myogenic factor 5-expressing precursors, with their cell-fate differentiation regulated by PRDM16, we identified that Prdm16 was translationally upregulated by CPEB2. Ectopic expression of PRDM16 in CPEB2-deprived BAT restored gene expression profiles and decreased weight gain in CPEB2-KO mice.
    CONCLUSIONS: In addition to Ucp1L, activation of Prdm16 translation by CPEB2 is critical for sustaining brown adipocyte function. These findings unveil a new layer of post-transcriptional regulation governed by CPEB2, fine-tuning thermogenic and metabolic activities of brown adipocytes to control body weight.
    Keywords:  Brown adipose tissue; CPEB2; Obesity; PRDM16; Thermogenesis; Translational control
    DOI:  https://doi.org/10.1016/j.molmet.2024.102034
  16. bioRxiv. 2024 Sep 13. pii: 2024.09.12.612761. [Epub ahead of print]
    The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis.
    Daniel J Pape, Kelly C Falls-Hubert, Ronald A Merrill, Adnan Ahmed, Qingwen Qian, Gavin R McGivney, Paulina Sobieralski, Adam J Rauckhorst, Ling Yang, Eric B Taylor.
      Hepatic gluconeogenesis (GNG) is essential for maintaining euglycemia during prolonged fasting. However, GNG becomes pathologically elevated and drives chronic hyperglycemia in type 2 diabetes (T2D). Lactate/pyruvate is a major GNG substrate known to be imported into mitochondria for GNG. Yet, the subsequent mitochondrial carbon export mechanisms required to supply the extra-mitochondrial canonical GNG pathway have not been genetically delineated. Here, we evaluated the role of the mitochondrial dicarboxylate carrier (DiC) in mediating GNG from lactate/pyruvate. We generated liver-specific DiC knockout (DiC LivKO) mice. During lactate/pyruvate tolerance tests, DiC LivKO decreased plasma glucose excursion and 13 C-lactate/-pyruvate flux into hepatic and plasma glucose. In a Western diet (WD) feeding model of T2D, acute DiC LivKO after induction of obesity decreased lactate/pyruvate-driven GNG, hyperglycemia, and hyperinsulinemia. Our results show that mitochondrial carbon export through the DiC mediates GNG and that the DiC contributes to impaired glucose homeostasis in a mouse model of T2D.
    DOI:  https://doi.org/10.1101/2024.09.12.612761
  17. Pharmacol Res. 2024 Sep 18. pii: S1043-6618(24)00373-6. [Epub ahead of print] 107428
    Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-κB signaling pathways.
    Aneta Stachowicz, Klaudia Czepiel, Anna Wiśniewska, Kamila Stachyra, Magdalena Ulatowska-Białas, Beata Kuśnierz-Cabala, Marcin Surmiak, Grzegorz Majka, Katarzyna Kuś, Mark E Wood, Roberta Torregrossa, Matthew Whiteman, Rafał Olszanecki.
      Metabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem. The pathogenesis of MAFLD includes abnormally increased lipogenesis, chronic inflammation, and mitochondrial dysfunction. Mounting evidence suggests that hydrogen sulfide (H2S) is an important player in the liver, regulating lipid metabolism and mitochondrial function. However, direct delivery of H2S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, our aim was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. Our results demonstrated that AP39 reduced hepatic steatosis in HFD-fed mice, which was corresponded with decreased triglyceride content. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling. It also led to a decrease in hepatic de novo lipogenesis by downregulating mTOR/SREBP-1/SCD1 pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of adipose triglyceride lipase in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of proinflammatory markers (Il1b, Il6, Tnf, Mcp1), which was due to downregulated mTOR/NF-κB pathway. Taken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders.
    Keywords:  AP39; hepatic steatosis; hydrogen sulfide; inflammation; obesity
    DOI:  https://doi.org/10.1016/j.phrs.2024.107428
  18. Circulation. 2024 Sep 24.
    Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.
    Zikun Duan, Zhouqing Huang, Wei Lei, Ke Zhang, Wei Xie, Hua Jin, Maolan Wu, Ningrui Wang, Xiaokun Li, Aimin Xu, Hao Zhou, Fan Wu, Yulin Li, Zhuofeng Lin.
       BACKGROUND: BMP9 (bone morphogenetic protein 9) is a member of the TGF-β (transforming growth factor β) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive.
    METHODS: The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus-mediated BMP9 expression or recombinant human BMP9 protein in mice.
    RESULTS: We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA reductase 1), a rate-limiting enzyme involved in β-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus-mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice.
    CONCLUSIONS: These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart.
    Keywords:  BMP9; DECR1; lymphatic drainage dysfunction; mitochondrial bioenergetics; myocardial infarction
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.065935
  19. Heliyon. 2024 Sep 30. 10(18): e37875
    Obesity alters adipose tissue response to fasting and refeeding in women: A study on lipolytic and endocrine dynamics and acute insulin resistance.
    Lenka Rossmeislová, Eva Krauzová, Michal Koc, Marek Wilhelm, Viktor Šebo, Zuzana Varaliová, Veronika Šrámková, Moniek Schouten, Petr Šedivý, Petr Tůma, Jan Kovář, Dominique Langin, Jan Gojda, Michaela Šiklová.
      Fasting induces significant shifts in substrate utilization with signs of acute insulin resistance (IR), while obesity is associated with chronic IR. Nonetheless, both states substantially influence adipose tissue (AT) function. Therefore, in this interventional study (NCT04260542), we investigated if excessive adiposity in premenopausal women alters insulin sensitivity and AT metabolic and endocrine activity in response to a 60-h fast and a subsequent 48-h refeeding period. Using physiological methods, lipidomics, and AT explants, we showed that obesity partially modified AT endocrine activity and blunted the dynamics of AT insulin resistance in response to the fasting/refeeding challenge compared to that observed in lean women. AT adapted to its own excess by reducing lipolytic activity/free fatty acids (FFA) flux per mass. This adaptation persisted even after a 60-h fast, resulting in lower ketosis in women with obesity. This could be a protective mechanism that limits the lipotoxic effects of FFA; however, it may ultimately impede desirable weight loss induced by caloric restriction in women with obesity.
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37875
  20. bioRxiv. 2024 Sep 09. pii: 2024.09.09.611047. [Epub ahead of print]
    NR2F2 Reactivation in Early-life Adipocyte Stem-like Cells Rescues Adipocyte Mitochondrial Oxidation.
    Snehasis Das, Rohan Varshney, Jacob W Farriester, Gertrude Kyere-Davies, Alexandrea E Martinez, Kaitlyn Hill, Michael Kinter, Gregory P Mullen, Prabhakara R Nagareddy, Michael C Rudolph.
      In humans, perinatal exposure to an elevated omega-6 (n6) relative to omega-3 (n3) Fatty Acid (FA) ratio is associated with the likelihood of childhood obesity. In mice, we show perinatal exposure to excessive n6-FA programs neonatal Adipocyte Stem-like cells (ASCs) to differentiate into adipocytes with lower mitochondrial nutrient oxidation and a propensity for nutrient storage. Omega-6 FA exposure reduced fatty acid oxidation (FAO) capacity, coinciding with impaired induction of beige adipocyte regulatory factors PPARγ, PGC1α, PRDM16, and UCP1. ASCs from n6-FA exposed pups formed adipocytes with increased lipogenic genes in vitro, consistent with an in vivo accelerated adipocyte hypertrophy, greater triacylglyceride accumulation, and increased % body fat. Conversely, n6-FA exposed pups had impaired whole animal 13 C-palmitate oxidation. The metabolic nuclear receptor, NR2F2, was suppressed in ASCs by excess n6-FA intake preceding adipogenesis. ASC deletion of NR2F2, prior to adipogenesis, mimicked the reduced FAO capacity observed in ASCs from n6-FA exposed pups, suggesting that NR2F2 is required in ASCs for robust beige regulator expression and downstream nutrient oxidation in adipocytes. Transiently re-activating NR2F2 with ligand prior to differentiation in ASCs from n6-FA exposed pups, restored their FAO capacity as adipocytes by increasing the PPARγ-PGC1α axis, mitochondrial FA transporter CPT1A, ATP5 family synthases, and NDUF family Complex I proteins. Our findings suggest that excessive n6-FA exposure early in life dampens an NR2F2-mediated induction of beige adipocyte regulators, resulting in metabolic programming that is shifted towards nutrient storage.
    DOI:  https://doi.org/10.1101/2024.09.09.611047
  21. J Spine Res Surg. 2024 ;6(1):
    Modification of the Diabetes Prevention Program Lifestyle Intervention in Persons with Spinal Cord Injury: Efficacy for Reducing Major Cardiometabolic Risks, Increased Fitness, and Improved Health-Related Quality of Life.
    Gregory E Bigford, Doug A Lehmann, Luisa F Betancourt, Jennifer L Maher, Armando J Mendez, Mark S Nash.
      Individuals with chronic spinal cord injury (SCI) face elevated risks of cardiometabolic diseases, including cardiovascular disease and type 2 diabetes, due to factors like physical inactivity, neurogenic obesity, and disrupted glucose and insulin regulation. We conducted a prospective intervention cohort study involving 20 individuals with SCI (aged 28-60) with neurologic injuries at levels C4-T10 and ASIA scale grades A-D, lasting over a year. Our study assessed the impact of a therapeutic lifestyle intervention (TLI) based on the Diabetes Prevention Program (DPP) and its maintenance phase. The TLI comprised circuit resistance training, a Mediterranean-style calorie-restricted diet, and tailored behavioral support. Key outcomes measured included cardiometabolic risks (plasma analytes and disease biomarkers), anthropometrics (body mass, BMI, tissue composition), global metabolism, fitness (aerobic capacity, peak strength), and health-related quality of life (SF36). Results demonstrated a significant reduction in body mass and BMI by 7.5%, a 7% decrease in total fat mass, and substantial improvements in glucose regulation and insulin sensitivity. Lipid profiles improved, with reduced total cholesterol, triglycerides, and LDL-C, and increased HDL-C. Resting energy expenditure and fat oxidation increased by 27.4% and 58.5%, respectively. Aerobic capacity and dynamic strength also improved significantly. The Physical and Mental Composite Scores of the SF36 improved by 22.8% and 30.5%, respectively. Following the maintenance phase, several positive outcomes persisted, indicating a reduction in risk for cardiovascular disease and comorbid disorders. Our findings support the effectiveness of TLI in reducing cardiometabolic risks, enhancing fitness, and improving health-related quality of life in individuals with chronic SCI.
    Trial Registration: ClinicalTrials.gov, ID: NCT02853149 Registered August 2, 2016.
    Keywords:  SCI; cardiometabolic disease; diet and nutrition; exercise and fitness; health; metabolism; quality of life; therapeutic lifestyle intervention
    DOI:  https://doi.org/10.26502/fjsrs0070
  22. Cell Commun Signal. 2024 Sep 20. 22(1): 444
    TRIM35 triggers cardiac remodeling by regulating SLC7A5-mediated amino acid transport and mTORC1 activation in fibroblasts.
    Boshen Yang, Zhixiang Wang, Kaifan Niu, Taixi Li, Tingting Tong, Suiji Li, Liuhang Su, Yan Wang, Chengxing Shen, Xian Jin, Juan Song, Xia Lu.
       BACKGROUND: Cardiac maladaptive remodeling is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase tripartite motif containing 35 (TRIM35) has been identified as a crucial regulator governing cellular growth, immune responses, and metabolism. Nonetheless, the role of TRIM35 in fibroblasts in cardiac remodeling remains elusive.
    METHODS: Heart tissues from human donors were used to verify tissue-specific expression of TRIM35. Fibroblast-specific Trim35 gene knockout mice (Trim35cKO) were used to investigate the function of TRIM35 in fibroblasts. Cardiac function, morphology, and molecular changes in the heart tissues were analyzed after transverse aortic constriction (TAC) surgery. The mechanisms by which TRIM35 regulates fibroblast phenotypes were elucidated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and RNA sequencing (RNA-Seq). These findings were further validated through the use of adenoviral and adeno-associated viral transfection systems, as well as the mTORC1 inhibitor Rapamycin.
    RESULTS: TRIM35 expression is primarily up-regulated in cardiac fibroblasts in both murine and human fibrotic hearts, and responds to TGF-β1 stimulation. Specific deletion of TRIM35 in cardiac fibroblasts significantly improves cardiac fibrosis and hypertrophy. Consistently, the overexpression of TRIM35 promotes fibroblast proliferation, migration, and differentiation. Through paracrine signaling, it induces hypertrophic growth of cardiomyocytes. Mechanistically, we found that TRIM35 interacts with, ubiquitinates, and up-regulates the amino acid transporter SLC7A5, which enhances amino acid transport and activates the mTORC1 signaling pathway. Furthermore, overexpression of SLC7A5 significantly reverses the reduced cardiac fibrosis and hypertrophy caused by conditional knockout of TRIM35.
    CONCLUSION: Our findings demonstrate a novel role of fibroblast-TRIM35 in cardiac remodeling and uncover the mechanism underlying SLC7A5-mediated amino acid transport and mTORC1 activation. These results provide a potential novel therapeutic target for treating cardiac remodeling.
    Keywords:  Amino acid transport; Cardiac remodeling; Fibroblast activation; SLC7A5; TRIM35; mTORC1
    DOI:  https://doi.org/10.1186/s12964-024-01826-0
  23. PLoS Pathog. 2024 Sep 27. 20(9): e1012565
    Altered hepatic metabolic landscape and insulin sensitivity in response to pulmonary tuberculosis.
    Mrinal K Das, Ben Savidge, John E Pearl, Thomas Yates, Gareth Miles, Manish Pareek, Pranabashis Haldar, Andrea M Cooper.
      Chronic inflammation triggers development of metabolic disease, and pulmonary tuberculosis (TB) generates chronic systemic inflammation. Whether TB induced-inflammation impacts metabolic organs and leads to metabolic disorder is ill defined. The liver is the master regulator of metabolism and to determine the impact of pulmonary TB on this organ we undertook an unbiased mRNA and protein analyses of the liver in mice with TB and reanalysed published data on human disease. Pulmonary TB led to upregulation of genes in the liver related to immune signalling and downregulation of genes encoding metabolic processes. In liver, IFN signalling pathway genes were upregulated and this was reflected in increased biochemical evidence of IFN signalling, including nuclear location of phosphorylated Stat-1 in hepatocytes. The liver also exhibited reduced expression of genes encoding the gluconeogenesis rate-limiting enzymes Pck1 and G6pc. Phosphorylation of CREB, a transcription factor controlling gluconeogenesis was drastically reduced in the livers of mice with pulmonary TB as was phosphorylation of other glucose metabolism-related kinases, including GSK3a, AMPK, and p42. In support of the upregulated IFN signalling being linked to the downregulated metabolic functions in the liver, we found suppression of gluconeogenic gene expression and reduced CREB phosphorylation in hepatocyte cell lines treated with interferons. The impact of reduced gluconeogenic gene expression in the liver was seen when infected mice were less able to convert pyruvate, a gluconeogenesis substrate, to the same extent as uninfected mice. Infected mice also showed evidence of reduced systemic and hepatic insulin sensitivity. Similarly, in humans with TB, we found that changes in a metabolite-based signature of insulin resistance correlates temporally with successful treatment of active TB and with progression to active TB following exposure. These data support the hypothesis that TB drives interferon-mediated alteration of hepatic metabolism resulting in reduced gluconeogenesis and drives systemic reduction of insulin sensitivity.
    DOI:  https://doi.org/10.1371/journal.ppat.1012565
  24. FASEB J. 2024 Sep 30. 38(18): e70066
    Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
    Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Joseph M Wider, Thomas H Sanderson.
      Mitochondrial form and function are regulated by the opposing forces of mitochondrial dynamics: fission and fusion. Mitochondrial dynamics are highly active and consequential during neuronal ischemia/reperfusion (I/R) injury. Mitochondrial fusion is executed at the mitochondrial inner membrane by Opa1. The balance of long (L-Opa1) and proteolytically cleaved short (S-Opa1) isoforms is critical for efficient fusion. Oma1 is the predominant stress-responsive protease for Opa1 processing. In neuronal cell models, we assessed Oma1 and Opa1 regulation during mitochondrial stress. In an immortalized mouse hippocampal neuron line (HT22), Oma1 was sensitive to mitochondrial membrane potential depolarization (rotenone, FCCP) and hyperpolarization (oligomycin). Further, oxidative stress was sufficient to increase Oma1 activity and necessary for depolarization-induced proteolysis. We generated Oma1 knockout (KO) HT22 cells that displayed normal mitochondrial morphology and fusion capabilities. FCCP-induced mitochondrial fragmentation was exacerbated in Oma1 KO cells. However, Oma1 KO cells were better equipped to perform restorative fusion after fragmentation, presumably due to preserved L-Opa1. We extended our investigations to a combinatorial stress of neuronal oxygen-glucose deprivation and reoxygenation (OGD/R), where we found that Opa1 processing and Oma1 activation were initiated during OGD in an ROS-dependent manner. These findings highlight a novel dependence of Oma1 on oxidative stress in response to depolarization. Further, we demonstrate contrasting fission/fusion roles for Oma1 in the acute response and recovery stages of mitochondrial stress. Collectively, our results add intersectionality and nuance to the previously proposed models of Oma1 activity.
    Keywords:  membrane fusion; membrane potential; mitochondria; mitochondrial dynamics; proteostasis; reactive oxygen species
    DOI:  https://doi.org/10.1096/fj.202400313R
  25. J Mol Cell Cardiol. 2024 Sep 19. pii: S0022-2828(24)00156-1. [Epub ahead of print]
    Cardiac macrophages and fibroblasts: A synergistic partnership without cellular transition.
    Daniel A Kasprovic, Robert M Jaggers, Michael Tranter, Onur Kanisicak.
      
    Keywords:  Cardiac remodeling; Cellular transition; Fibroblast; Heart; Macrophage
    DOI:  https://doi.org/10.1016/j.yjmcc.2024.09.008
  26. Geroscience. 2024 Sep 23.
    Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats.
    Robert V Musci, Jordan D Fuqua, Frederick F Peelor, Hoang Van Michelle Nguyen, Arlan Richardson, Solbie Choi, Benjamin F Miller, Jonathan Wanagat.
      Mitochondrial genomic integrity is a key element of physiological processes and health. Changes in the half-life of the mitochondrial genome are implicated in the generation and accumulation of age-induced mitochondrial DNA (mtDNA) mutations, which are implicated in skeletal muscle aging and sarcopenia. There are conflicting data on the half-life of mtDNA, and there is limited information on how aging affects half-life in skeletal muscle. We hypothesized that skeletal muscle mtDNA synthesis rates would decrease with age in both female and male rats concomitant with changes in mtDNA integrity reflected in mtDNA copy number and mutation frequency. We measured mitochondrial genome half-life using stable isotope labeling over a period of 14 days and assessed mtDNA copy number and deletion mutation frequency using digital PCR in the quadriceps muscle of 9-month-old and 26-month-old male and female OKC-HET rats. We found a significant age-related increase in mtDNA half-life, from 132 days at 9 months to 216 days at 26 months of age in OKC-HET quadriceps. Concomitant with the increase in mtDNA half-life, we found an age-related increase in mtDNA deletion mutation frequency in both male and female rats. Notably, 26-month-old female rats had a lower mutation frequency than male rats, and there were no changes in mtDNA copy number with sex, age, or mitochondrial genotype. These data reveal several key findings: (1) mtDNA turnover in rat skeletal muscle decreases with age, (2) mtDNA half-lives in skeletal muscle are approximately an order of magnitude longer than what is reported for other tissues, and (3) muscle mtDNA turnover differs significantly from the turnover of other mitochondrial macromolecules including components of the mitochondrial nucleoid. These findings provide insight into the factors driving age-induced mtDNA mutation accumulation, which contribute to losses of mitochondrial genomic integrity and may play a role in skeletal muscle dysfunction.
    Keywords:  Aging; Deuterium oxide; Mitochondrial DNA; Mutation; Rats; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11357-024-01344-4
  27. NAR Genom Bioinform. 2023 Dec;5(4): lqad107
    Beyond MitoCarta-expanding the list of candidate proteins involved in mitochondrial functions using a biological network approach.
    Dmitriy Leyfer, Jessica L Fetterman.
      Mitochondrial diseases are the result of pathogenic variants in genes involved in the diverse functions of the mitochondrion. A comprehensive list of mitochondrial genes is needed to improve gene prioritization in the diagnosis of mitochondrial diseases and development of therapeutics that modulate mitochondrial function. MitoCarta is an experimentally derived catalog of proteins localized to mitochondria. We sought to expand this list of mitochondrial proteins to identify proteins that may not be localized to the mitochondria yet perform important mitochondrial functions. We used a computational approach to assign statistical significance to the overlap between STRING database gene network neighborhoods and MitoCarta proteins. Using a data-driven stringent significance threshold, 2059 proteins that were not located in MitoCarta were identified, which we termed mitochondrial proximal (MitoProximal) proteins. We identified all of the oxidative phosphorylation complex subunits and 90% of 149 genes that contain confirmed oxidative phosphorylation disease causal variants, lending validation to our methodology. Among the MitoProximal proteins, 134 are annotated to be localized to mitochondria but are not in the MitoCarta 3.0 database. We extend MitoCarta nearly 3-fold, generating a more comprehensive list of mitochondrial genes, a resource to facilitate the identification of pathogenic variants in mitochondrial and metabolic diseases.
    DOI:  https://doi.org/10.1093/nargab/lqad107
  28. Metabolites. 2024 Sep 02. pii: 483. [Epub ahead of print]14(9):
    Machine Learning-Based Plasma Metabolomics in Liraglutide-Treated Type 2 Diabetes Mellitus Patients and Diet-Induced Obese Mice.
    Seokjae Park, Eun-Kyoung Kim.
      Liraglutide, a glucagon-like peptide-1 receptor agonist, is effective in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Despite its benefits, including improved glycemic control and weight loss, the common metabolic changes induced by liraglutide and correlations between those in rodents and humans remain unknown. Here, we used advanced machine learning techniques to analyze the plasma metabolomic data in diet-induced obese (DIO) mice and patients with T2DM treated with liraglutide. Among the machine learning models, Support Vector Machine was the most suitable for DIO mice, and Gradient Boosting was the most suitable for patients with T2DM. Through the cross-evaluation of machine learning models, we found that liraglutide promotes metabolic shifts and interspecies correlations in these shifts between DIO mice and patients with T2DM. Our comparative analysis helped identify metabolic correlations influenced by liraglutide between humans and rodents and may guide future therapeutic strategies for T2DM and obesity.
    Keywords:  liraglutide; machine learning; metabolic profiling; metabolomics; obesity; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/metabo14090483
  29. Front Pharmacol. 2024 ;15 1469053
    Unraveling the nexus of age, epilepsy, and mitochondria: exploring the dynamics of cellular energy and excitability.
    Wen Xie, Sushruta Koppula, Mayur B Kale, Lashin S Ali, Nitu L Wankhede, Mohit D Umare, Aman B Upaganlawar, Ahmed Abdeen, Elturabi E Ebrahim, Mohamed El-Sherbiny, Tapan Behl, Bairong Shen, Rajeev K Singla.
      Epilepsy, a complex neurological condition marked by recurring seizures, is increasingly recognized for its intricate relationship with mitochondria, the cellular powerhouses responsible for energy production and calcium regulation. This review offers an in-depth examination of the interplay between epilepsy, mitochondrial function, and aging. Many factors might account for the correlation between epilepsy and aging. Mitochondria, integral to cellular energy dynamics and neuronal excitability, perform a critical role in the pathophysiology of epilepsy. The mechanisms linking epilepsy and mitochondria are multifaceted, involving mitochondrial dysfunction, reactive oxygen species (ROS), and mitochondrial dynamics. Mitochondrial dysfunction can trigger seizures by compromising ATP production, increasing glutamate release, and altering ion channel function. ROS, natural byproducts of mitochondrial respiration, contribute to oxidative stress and neuroinflammation, critical factors in epileptogenesis. Mitochondrial dynamics govern fusion and fission processes, influence seizure threshold and calcium buffering, and impact seizure propagation. Energy demands during seizures highlight the critical role of mitochondrial ATP generation in maintaining neuronal membrane potential. Mitochondrial calcium handling dynamically modulates neuronal excitability, affecting synaptic transmission and action potential generation. Dysregulated mitochondrial calcium handling is a hallmark of epilepsy, contributing to excitotoxicity. Epigenetic modifications in epilepsy influence mitochondrial function through histone modifications, DNA methylation, and non-coding RNA expression. Potential therapeutic avenues targeting mitochondria in epilepsy include mitochondria-targeted antioxidants, ketogenic diets, and metabolic therapies. The review concludes by outlining future directions in epilepsy research, emphasizing integrative approaches, advancements in mitochondrial research, and ethical considerations. Mitochondria emerge as central players in the complex narrative of epilepsy, offering profound insights and therapeutic potential for this challenging neurological disorder.
    Keywords:  ageing; epigenetic modification; epilepsy; ketogenic diet; mitochondria targeted therapy
    DOI:  https://doi.org/10.3389/fphar.2024.1469053
  30. Int Immunopharmacol. 2024 Sep 26. pii: S1567-5769(24)01721-1. [Epub ahead of print]142(Pt B): 113199
    NPLOC4 aggravates heart failure by regulating ROS and mitochondrial function.
    Kaidi Ren, Yi Luan, Yuanyuan Sun, Siyuan Huang, Shuwei Zhang, Yang Yang, Yage Jin, Xing Chen.
      Heart failure (HF) is a leading cause of morbidity and mortality worldwide, necessitating the discovery of new therapeutic targets. NPLOC4 is known as an endoplasmic reticulum protein involved in protein degradation and cellular stress responses. Herein, NPLOC4 was investigated for its role in HF using a transverse aortic constriction (TAC) mouse model and an Angiotensin II (Ang II)-induced H9c2 cardiomyocyte model. Transcriptomic analysis revealed NPLOC4 upregulation in HF. NPLOC4 knockdown in the TAC model inhibited HF progression, as evidenced by reduced cardiac hypertrophy and fibrosis. Subsequent knockdown experiments showed the relievement in heart failure phenotypes, reduced reactive oxygen species (ROS) levels and enhanced mitochondrial function caused by NPLOC4 depletion in Ang II-induced H9c2 cells. STRING analysis predicted ERO1α as a potential NPLOC4 interactor, with further studies identifying that NPLOC4 knockdown increases ERO1α expression and disrupts mitochondria-associated membranes (MAMs). Additionally, NPLOC4 knockdown modulated the β-catenin/GSK3β pathway, enhancing mitochondrial dynamics and mitophagy. These findings suggest NPLOC4 as a promising therapeutic target for HF.
    Keywords:  ERO1α; Heart failure; Mitochondrial function; NPLOC4; β-catenin/GSK3β pathway
    DOI:  https://doi.org/10.1016/j.intimp.2024.113199
  31. J Lipid Res. 2024 Sep 18. pii: S0022-2275(24)00148-2. [Epub ahead of print] 100643
    Setting the curve: the biophysical properties of lipids in mitochondrial form and function.
    Kailash Venkatraman, Christopher T Lee, Itay Budin.
      Mitochondrial membranes are defined by their diverse functions, complex geometries, and unique lipidomes. In the inner mitochondrial membrane (IMM), highly-curved membrane folds known as cristae house the electron transport chain and are the primary sites of cellular energy production. The outer mitochondrial membrane (OMM) is flat by contrast, but is critical for the initiation and mediation of processes key to mitochondrial physiology: mitophagy, inter-organelle contacts, fission and fusion dynamics and metabolite transport. While the lipid composition of both the IMM and OMM have been characterized across a variety of cell types, a mechanistic understanding for how individual lipid classes contribute to mitochondrial structure and function remains nebulous. In this review, we address the biophysical properties of mitochondrial lipids and their related functional roles. We highlight the intrinsic curvature of the bulk mitochondrial phospholipid pool, with an emphasis on the nuances surrounding the mitochondrially-synthesized cardiolipin. We also outline emerging questions about other lipid classes, ether lipids and sterols, with potential roles in mitochondrial physiology. We propose that further investigation is warranted to elucidate the specific properties of these lipids and their influence on mitochondrial architecture and function.
    Keywords:  Cardiolipin; Curvature; Mitochondria; Phospholipids; Plasmalogens; Sterols
    DOI:  https://doi.org/10.1016/j.jlr.2024.100643
  32. J Liposome Res. 2024 Sep 19. 1-11
    Comparison of free vs. liposomal naringenin in white adipose tissue browning in C57BL/6j mice.
    Kübra Uçar Baş, Aslıhan Ağaçdiken, Elif Didem Örs Demet, Dilem Tuğal Aslan, Tuba Reçber, Süleyman Can Öztürk, Tugba Gulsun, Mustafa Çelebier, Zeynep Göktaş.
      Naringenin may play a role in browning by increasing thermogenic gene expression. In this study, we encapsulated naringenin using a liposomal formulation and examined the effects of both free and liposomal naringenin on white adipose tissue browning in C57BL6/J mice. In the first phase of the study, naringenin was encapsulated by the liposome method, which is biocompatible and biodegradable. The physical and chemical properties of liposomal naringenin were tested. In the second phase, a total of 48 six-week-old mice were divided into two main groups: prevention and recovery. Each main group was divided into four subgroups: nano-naringenin, void, free-naringenin, and control. The prevention group received a high-fat diet for 10 weeks along with weekly intravenous injections of 20 µM naringenin. On the other hand, the recovery group was first subjected to a high-fat diet for 10 weeks, followed by an additional 10 weeks of the same diet, along with weekly intravenous injections of 20 µM naringenin. Body weight was measured once per week, and brown adipose tissue, inguinal white adipose tissue, and serum samples were collected from each mouse. The mean particle size, polydispersity index and zeta potential values of liposomal naringenin were ∼207 nm, 0.35, and -27 mV, respectively. The encapsulation and loading efficiencies of liposomal naringenin were 94.6 and 19.2%, respectively. Liposomal naringenin exhibited sustained-release behavior, while free naringenin showed a burst-release profile. Liposomal naringenin showed the best physical stability in light and at 4 °C, while free naringenin was more chemically stable in light and at 4 and 22 °C. Free and liposomal naringenin did not significantly reduce weight gain. In the prevention group, liposomal naringenin increased PRDM16 gene expression in inguinal white adipose tissue 4.29 times more than free naringenin (p = 0.010). However, neither formulation significantly altered the expression levels of other browning or adipogenesis markers in the tissues. The results suggest that free naringenin can be efficiently encapsulated in biocompatible and biodegradable nanoparticles. Further research is needed to better understand the physiological effects of liposomal naringenin.
    Keywords:  Naringenin; browning; liposome; obesity
    DOI:  https://doi.org/10.1080/08982104.2024.2405131
  33. J Physiol. 2024 Sep 27.
    Unveiling sex differences in skeletal muscle metabolism: the role of HIF1α in normoxia.
    Ashlyn Ro, Dorota Kaminska.
      
    Keywords:  HIF1A; mitochondria; normoxia; sex differences; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287250
  34. Diabetologia. 2024 Sep 21.
    A whole-food, plant-based intensive lifestyle intervention improves glycaemic control and reduces medications in individuals with type 2 diabetes: a randomised controlled trial.
    Cody J Hanick, Courtney M Peterson, Brenda C Davis, Joan Sabaté, John H Kelly.
       AIMS/HYPOTHESIS: We conducted the largest and longest clinical trial comparing a whole-food, plant-based intervention with standard medical care (SMC) in individuals with type 2 diabetes.
    METHODS: We randomised (parallel-arm; computerised 1:1 randomisation ratio) 169 adults aged 18-75 years with type 2 diabetes in the Marshall Islands to an intensive whole-food, plant-based intervention with moderate exercise (PB+Ex) or SMC for 24 weeks. The PB+Ex intervention included 12 weeks of meals, exercise sessions and group classes. Primary outcomes were glycaemic control (HbA1c, glucose, insulin and HOMA-IR) and glucose-lowering medication use. Secondary outcomes included lipids, blood pressure, heart rate and C-reactive protein. Only lab analysts were blinded.
    RESULTS: Compared with SMC (n=90 randomised; n=70 analysed), the PB+Ex (n=79 randomised; n=66 analysed) intervention decreased HbA1c by an additional 14 mmol/mol (1.3%) at week 12 (-22 vs -7 mmol/mol [-2.0% vs -0.7%]; p<0.0001) and 8 mmol/mol (0.7%) at week 24 (-16 vs -8 mmol/mol [-1.4% vs -0.7%]; p=0.01). Concomitantly, 63% of medicated PB+Ex participants reduced their glucose-lowering medications (vs 24%; p=0.006), and 23% of PB+Ex participants with a baseline HbA1c <75 mmol/mol (<9%) achieved remission. Additionally, the PB+Ex intervention reduced weight (-2.7 kg; p<0.0001), C-reactive protein (-11 nmol/l; p=0.005) and cardiovascular medication use compared with SMC. At intermediate timepoints, it improved glucose, insulin, HOMA-IR, cholesterol, triglycerides and heart rate, but not at week 24.
    CONCLUSIONS/INTERPRETATION: A whole-food, plant-based lifestyle intervention was more effective for improving glycaemic control than SMC. It also reduced the need for diabetes and cardiovascular medications and induced diabetes remission in some participants. Therefore, it is an effective, evidence-based lifestyle option for individuals with type 2 diabetes.
    TRIAL REGISTRATION: ClinicalTrials.gov NCT03862963 FUNDING: This research was funded by the Department of the Army (W81XWH-05-1-0547). CJH received support through a National Institutes of Health Predoctoral T32 Obesity Fellowship (T32 HL105349).
    Keywords:  Cardiovascular disease; Diabetes remission; Diet; Dietary intervention; Glycaemic control; Lifestyle intervention; Nutrition; Plant-based diet; Randomised controlled trial; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s00125-024-06272-8
  35. Heart. 2024 Sep 24. pii: heartjnl-2024-323995. [Epub ahead of print]
    Exercise training improves cardiovascular fitness in dilated cardiomyopathy caused by truncating titin variants.
    Ida Finsen Flensted, Mads Godtfeldt Stemmerik, Sofie Vinther Skriver, Kasper Holst Axelsen, Alex Hørby Christensen, Carsten Lundby, Henning Bundgaard, John Vissing, Christoffer Rasmus Vissing.
       BACKGROUND: Participation in regular exercise activities is recommended for patients with chronic heart failure. However, less is known about the effect of exercise in patients with genetic dilated cardiomyopathy (DCM). We sought to examine the effect of vigorousintensity training on physical capacity in patients with DCM caused by truncating titin variants (TTNtv).
    TRIAL DESIGN: Non-randomised clinical pre-post trial of exercise training.
    METHODS: Individuals with DCM-TTNtv were included from outpatient clinics for inherited cardiac diseases. The trial consisted of 8 weeks of usual care followed by 8 weeks of regular vigorous-intensity cycling exercise, enclosed by three test days. The primary outcome was change in peak oxygen uptake (VO2). Secondary outcomes included change in blood volume, total haemoglobin mass, measures of systolic function and cardiac output/stroke volume during exercise.
    RESULTS: Thirteen out of 14 included participants (43% women, age 48±11 years, body mass index: 30±6 kg/m2) completed the trial. In the exercise training period, peak VO2 increased by +1.9 mL/kg/min (95% CI +0.9 to +2.9, p=0.002). Compared with usual care, exercise training improved peak VO2 by +2.9 mL/kg/min (95% CI +1.2 to +4.5, p=0.002), corresponding to a 10% increase. Adaptations to exercise training included an increase in resting cardiac output (+0.8 L/min, p=0.042), total blood volume (+713 mL, p<0.001), total haemoglobin mass (+73 g, p<0.001), and improved left ventricular (LV) systolic function (LV ejection fraction: +3.2% (p=0.053) and global longitudinal strain: -2.0% (p=0.044)). No exercise-related adverse events or change in plasma biomarkers of cardiac or skeletal muscle damage were observed.
    CONCLUSIONS: Our study shows that vigorous intensity exercise training improved peak VO2 in patients with DCM-TTNtv. Exercise training was associated with improved LV systolic function and increased blood volume and oxygen carrying capacity. Future research should investigate the effect of long-term exercise in this group.
    TRIAL REGISTRATION NUMBER: NCT05180188.
    Keywords:  Cardiac Rehabilitation; Cardiomyopathy, Dilated; Heart Failure
    DOI:  https://doi.org/10.1136/heartjnl-2024-323995
  36. Mol Metab. 2024 Sep 19. pii: S2212-8778(24)00164-9. [Epub ahead of print] 102033
    HDAC5 controls a hypothalamic STAT5b-TH axis, the sympathetic activation of ATP-consuming futile cycles and adult-onset obesity in male mice.
    Raian E Contreras, Tim Gruber, Ismael González-García, Sonja C Schriever, Meri De Angelis, Noemi Mallet, Miriam Bernecker, Beata Legutko, Dhiraj Kabra, Mathias Schmidt, Matthias H Tschöp, Ruth Gutierrez-Aguilar, Jane Mellor, Cristina Garcia-Caceres, Paul T Pfluger.
      With age, metabolic perturbations accumulate to elevate our obesity burden. While age-onset obesity is mostly driven by a sedentary lifestyle and high calorie intake, genetic and epigenetic factors also play a role. Among these, members of the large histone deacetylase (HDAC) family are of particular importance as key metabolic determinants for healthy ageing, or metabolic dysfunction. Here, we aimed to interrogate the role of class 2 family member HDAC5 in controlling systemic metabolism and age-related obesity under non-obesogenic conditions. Starting at 6 months of age, we observed adult-onset obesity in chow-fed male global HDAC5-KO mice, that was accompanied by marked reductions in adrenergic-stimulated ATP-consuming futile cycles, including BAT activity and UCP1 levels, WAT-lipolysis, skeletal muscle, WAT and liver futile creatine and calcium cycles, and ultimately energy expenditure. Female mice did not differ between genotypes. The lower peripheral sympathetic nervous system (SNS) activity in mature male KO mice was linked to higher dopaminergic neuronal activity within the dorsomedial arcuate nucleus (dmARC) and elevated hypothalamic dopamine levels. Mechanistically, we reveal that hypothalamic HDAC5 acts as co-repressor of STAT5b over the control of Tyrosine hydroxylase (TH) gene transactivation, which ultimately orchestrates the activity of dmARH dopaminergic neurons and energy metabolism in male mice under non-obesogenic conditions.
    Keywords:  Adult-onset obesity; Brown fat thermogenesis; Dopamine; Histone deacetylase 5; Hypothalamus
    DOI:  https://doi.org/10.1016/j.molmet.2024.102033
  37. Br J Anaesth. 2024 Sep 19. pii: S0007-0912(24)00469-0. [Epub ahead of print]
    Propofol binds and inhibits skeletal muscle ryanodine receptor 1.
    Thomas T Joseph, Weiming Bu, Omid Haji-Ghassemi, Yu S Chen, Kellie Woll, Paul D Allen, Grace Brannigan, Filip van Petegem, Roderic G Eckenhoff.
       BACKGROUND: As the primary Ca2+ release channel in skeletal muscle sarcoplasmic reticulum (SR), mutations in type 1 ryanodine receptor (RyR1) or its binding partners underlie a constellation of muscle disorders, including malignant hyperthermia (MH). In patients with MH mutations, triggering agents including halogenated volatile anaesthetics bias RyR1 to an open state resulting in uncontrolled Ca2+ release, increased sarcomere tension, and heat production. Propofol does not trigger MH and is commonly used for patients at risk of MH. The atomic-level interactions of any anaesthetic with RyR1 are unknown.
    METHODS: RyR1 opening was measured by [3H]ryanodine binding in heavy SR vesicles (wild type) and single-channel recordings of MH mutant R615C RyR1 in planar lipid bilayers, each exposed to propofol or the photoaffinity ligand analogue m-azipropofol (AziPm). Activator-mediated wild-type RyR1 opening as a function of propofol concentration was measured by Fura-2 Ca2+ imaging of human skeletal myotubes. AziPm binding sites, reflecting propofol binding, were identified on RyR1 using photoaffinity labelling. Propofol binding affinity to a photoadducted site was predicted using molecular dynamics (MD) simulation.
    RESULTS: Both propofol and AziPm decreased RyR1 opening in planar lipid bilayers (P<0.01) and heavy SR vesicles, and inhibited activator-induced Ca2+ release from human skeletal myotube SR. Several putative propofol binding sites on RyR1 were photoadducted by AziPm. MD simulation predicted propofol KD values of 55.8 μM and 1.4 μM in the V4828 pocket in open and closed RyR1, respectively.
    CONCLUSIONS: Propofol demonstrated direct binding and inhibition of RyR1 at clinically plausible concentrations, consistent with the hypothesis that propofol partially mitigates MH by inhibition of induced Ca2+ flux through RyR1.
    Keywords:  free energy perturbation; malignant hyperthermia; photoaffinity labelling; propofol; ryanodine receptor 1; skeletal muscle
    DOI:  https://doi.org/10.1016/j.bja.2024.06.048
  38. Cardiovasc Res. 2024 Sep 23. pii: cvae214. [Epub ahead of print]
    GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
    Minoru Takaoka, John A Tadross, Ali B A K Al-Hadithi, Xiaohui Zhao, Rocío Villena-Gutiérrez, Jasper Tromp, Shazia Absar, Marcus Au, James Harrison, Anthony P Coll, Stefan J Marciniak, Debra Rimmington, Eduardo Oliver, Borja Ibáñez, Adriaan A Voors, Stephen O'Rahilly, Ziad Mallat, Jane C Goodall.
       AIMS: Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A.
    METHODS AND RESULTS: Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure.
    CONCLUSION: Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
    Keywords:  GDF15; Heart Failure; Integrated stress response; PPP1R15A; cachexia
    DOI:  https://doi.org/10.1093/cvr/cvae214
  39. Nat Commun. 2024 Sep 27. 15(1): 8274
    Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
    Abdul Haseeb Khan, Xuefang Gu, Rutvik J Patel, Prabha Chuphal, Matheus P Viana, Aidan I Brown, Brian M Zid, Tatsuhisa Tsuboi.
      A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.
    DOI:  https://doi.org/10.1038/s41467-024-52183-y
  40. J Physiol. 2024 Sep 24.
    Dual ablation of the RyR2-Ser2808 and RyR2-Ser2814 sites increases propensity for pro-arrhythmic spontaneous Ca2+ releases.
    Radoslav Janicek, Emmanuel M Camors, Duilio M Potenza, Miguel Fernandez-Tenorio, Yanting Zhao, Holly C Dooge, Randall Loaiza, Francisco J Alvarado, Marcel Egger, Hector H Valdivia, Ernst Niggli.
      During exercise or stress, the sympathetic system stimulates cardiac contractility via β-adrenergic receptor (β-AR) activation, resulting in phosphorylation of the cardiac ryanodine receptor (RyR2). Three RyR2 phosphorylation sites have taken prominence in excitation-contraction coupling: S2808 and S2030 are described as protein kinase A specific and S2814 as a Ca2+/calmodulin kinase type-2-specific site. To examine the contribution of these phosphosites to Ca2+ signalling, we generated double knock-in (DKI) mice in which Ser2808 and Ser2814 phosphorylation sites have both been replaced by alanine (RyR2-S2808A/S2814A). These mice did not exhibit an overt phenotype. Heart morphology and haemodynamic parameters were not altered. However, they had a higher susceptibility to arrhythmias. We performed confocal Ca2+ imaging and electrophysiology experiments. Isoprenaline was used to stimulate β-ARs. Measurements of Ca2+ waves and latencies in myocytes revealed an increased propensity for spontaneous Ca2+ releases in DKI myocytes, both in control conditions and during β-AR stimulation. In DKI cells, waves were initiated from a lower threshold concentration of Ca2+ inside the sarcoplasmic reticulum, suggesting higher Ca2+ sensitivity of the RyRs. The refractoriness of Ca2+ spark triggering depends on the Ca2+ sensitivity of the RyR2. We found that RyR2-S2808A/S2814A channels were more Ca2+ sensitive in control conditions. Isoprenaline further shortened RyR refractoriness in DKI cardiomyocytes. Together, our results suggest that ablation of both the RyR2-Ser2808 and RyR2-S2814 sites increases the propensity for pro-arrhythmic spontaneous Ca2+ releases, as previously suggested for hyperphosphorylated RyRs. Given that the DKI cells present a full response to isoprenaline, the data suggest that phosphorylation of Ser2030 might be sufficient for β-AR-mediated sensitization of RyRs. KEY POINTS: Phosphorylation of cardiac sarcoplasmic reticulum Ca2+-release channels (ryanodine receptors, RyRs) is involved in the regulation of cardiac function. Ablation of both the RyR2-Ser2808 and RyR2-Ser2814 sites increases the propensity for pro-arrhythmic spontaneous Ca2+ releases, as previously suggested for hyperphosphorylated RyRs. The intra-sarcoplasmic reticulum Ca2+ threshold for spontaneous Ca2+ wave generation is lower in RyR2-double-knock-in cells. The RyR2 from double-knock-in cells exhibits increased Ca2+ sensitivity. Phosphorylation of Ser2808 and Ser2814 might be important for basal activity of the channel. Phosphorylation of Ser2030 might be sufficient for a β-adrenergic response.
    Keywords:  Ca2+‐induced Ca2+ release; cardiac muscle; dephosphorylation; excitation–contraction coupling; protein phosphatase; ryanodine receptor 2
    DOI:  https://doi.org/10.1113/JP286453
  41. Proc Natl Acad Sci U S A. 2024 Oct;121(40): e2404644121
    Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform.
    Devin B Mair, Jonathan H Tsui, Ty Higashi, Paul Koenig, Zhipeng Dong, Jeffrey F Chen, Jessica U Meir, Alec S T Smith, Peter H U Lee, Eun Hyun Ahn, Stefanie Countryman, Nathan J Sniadecki, Deok-Ho Kim.
      With current plans for manned missions to Mars and beyond, the need to better understand, prevent, and counteract the harmful effects of long-duration spaceflight on the body is becoming increasingly important. In this study, an automated heart-on-a-chip platform was flown to the International Space Station on a 1-mo mission during which contractile cardiac function was monitored in real-time. Upon return to Earth, engineered human heart tissues (EHTs) were further analyzed with ultrastructural imaging and RNA sequencing to investigate the impact of prolonged microgravity on cardiomyocyte function and health. Spaceflight EHTs exhibited significantly reduced twitch forces, increased incidences of arrhythmias, and increased signs of sarcomere disruption and mitochondrial damage. Transcriptomic analyses showed an up-regulation of genes and pathways associated with metabolic disorders, heart failure, oxidative stress, and inflammation, while genes related to contractility and calcium signaling showed significant down-regulation. Finally, in silico modeling revealed a potential link between oxidative stress and mitochondrial dysfunction that corresponded with RNA sequencing results. This represents an in vitro model to faithfully reproduce the adverse effects of spaceflight on three-dimensional (3D)-engineered heart tissue.
    Keywords:  heart-on-a-chip; microgravity; mitochondrial dysfunction; oxidative stress; spaceflight
    DOI:  https://doi.org/10.1073/pnas.2404644121
  42. J Oleo Sci. 2024 Sep 20.
    Effects of Dietary Allitol and D-Allulose on Body Fat Accumulation and Cecal Short-Chain Fatty Acid Production in Rats Fed a High-Fat Diet.
    Tatsuhiro Matsuo, Shunsuke Higaki, Reiko Inai, Goro Takata, Susumu Mochizuki, Akihide Yoshihara, Kazuya Akimitsu.
      We investigated the effects of a single and simultaneous intake of allitol and d-allulose on body fat accumulation and cecal short-chain fatty acid (SCFA) production and accurately assessed the contribution of rare sugars to body fat in rats fed a high-fat diet that led to obesity. Thirty-two male 3-week-old Wistar rats were randomly divided into four groups: control, allitol, d-allulose, and allitol + d-allulose. The rats were fed experimental diets and water ad libitum for 11 weeks. High doses of allitol or d-allulose can induce diarrhea in rat; hence, each group of rats was acclimated to 1-5% allitol and d-allulose incrementally for the initial 20 days. After the feeding period, all rats were euthanized and collected tissues. Perirenal, mesenteric, and total intra-abdominal adipose tissue weights were significantly reduced by dietary d-allulose, whereas dietary allitol tended to decrease these adipose tissue weights. Both allitol and d-allulose significantly decreased carcass and total body fat mass. We confirmed that both dietary allitol and d-allulose inhibited body fat accumulation; however, d-allulose did not inhibit hepatic lipogenesis and no synergy was observed between dietary allitol and d-allulose in terms of anti-obesity effects. Dietary allitol significantly increased cecal SCFA levels and these effects were more potent than those of dietary d-allulose. The antiobesity effect of allitol may be due to the action of SCFAs, especially butyric acid, produced by the gut microbiota. Many of the effects of allitol as an alternative sweetener remain unknown, and further research is required.
    Keywords:  D-allulose; allitol; anti-obesity; butyric acid; short-chain fatty acids
    DOI:  https://doi.org/10.5650/jos.ess24099
  43. Biosci Biotechnol Biochem. 2024 Sep 23. pii: zbae133. [Epub ahead of print]
    Bile acids acting as a feeding signal and functional foods mimicking bile acid function.
    Ryuichiro Sato.
      To elucidate the function of the bile acid-binding receptor TGR5 in skeletal muscle, we developed transgenic mice expressing human TGR5 in the skeletal muscle tissue. A significant increase in muscle mass was observed in these transgenic mice, whereas a decrease in muscle mass was observed in the TGR5-deficient mice. Following treadmill exercise, TGR5 gene expression increased in response to ER stress induced in skeletal muscle via an ER stress response motif present in its promoter region. Exercise and rapid postprandial elevation in blood bile acid concentrations can be considered the primary stimuli for the TGR5-mediated increase in skeletal muscle mass. We developed a scoring system to identify food ingredients with TGR5 agonist activity, and identified the citrus limonoid nomilin. Similar effects were observed for other triterpenoids in addition to nomilin. Cell culture and in vivo experiments demonstrated that these food factors increase protein synthesis and muscle mass.
    Keywords:  Bile acid; Nomilin; TGR5; functional foods
    DOI:  https://doi.org/10.1093/bbb/zbae133
  44. Open Med (Wars). 2024 ;19(1): 20241018
    Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway.
    Xueyuan Long, Yanpeng Yang, Ke Zhou.
       Background: Sepsis triggers myocardial injury and dysfunction, leading to a high mortality rate in patients. Cardiomyocyte apoptosis plays a positive regulatory role in septic myocardial injury and dysfunction. However, the mechanism is unclear.
    Methods: Bioinformatics analysis was used to identify differentially expressed genes in septic mice heart and validate key genes and pathways. The correlation of protein-protein and protein-pathway was analyzed. Sequentially, the cecal ligament and puncture (CLP) was used to induce septic mice, followed by Serpine1 inhibitor treatment. Finally, the regulatory relationship of Yes-associated protein1 (YAP1), Serpine1, and caspase-3 was verified in LPS-exposed mouse cardiomyocytes.
    Results: Bioinformatic analysis found that Serpine1 expression is decreased in septic mice heart tissue and closely related to the HIPPO signaling pathway, while YAP1 is negatively correlated with apoptosis. In vivo, CLP induced a reduction of survival rate, cardiac dysfunction, and an increase in Serpine1 and Cleaved Caspase-3 expression, which could be reversed by a Serpine1 inhibitor. In vitro, LPS induced the mouse cardiomyocytes apoptosis, which could be reversed by Serpine1 inhibitor. Silencing YAP1 and Serpine1 reversed the LPS-induced increase in Serpine1 and Cleaved Caspase-3 expression, but silencing Serpine1 did not affect the LPS-induced YAP1 expression.
    Conclusion: Sepsis induced mouse cardiomyocytes apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway.
    Keywords:  Serpine1; YAP1; cardiac dysfunction; cardiomyocyte apoptosis; caspase-3; sepsis
    DOI:  https://doi.org/10.1515/med-2024-1018
  45. Card Fail Rev. 2024 ;10 e10
    Effects of Glucagon-like Peptide-1 Receptor Agonists on Cardiac Function, Exercise Capacity and Quality of Life.
    Anastasia Shchendrygina, Amina Rakisheva, Ilya Giverts, Yasmin Rustamova, Anzhela Soloveva.
      Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are emerging glucose-lowering agents primarily used in managing diabetes and obesity. Recently, GLP-1 RAs have garnered attention for their cardiovascular benefits beyond glycaemic control in patients with type 2 diabetes, exhibiting patterns previously seen in cardiovascular outcomes trials on sodium-glucose cotransporter 2 inhibitors, which now receive a high level of recommendation for the treatment of heart failure (HF). GLP-1 RAs have been increasingly investigated in HF cohorts, but mainly in small-scale studies reporting inconclusive findings regarding clinical outcomes and different safety profiles in HF patients with reduced and preserved ejection fractions. This review discusses the effects of GLP-1 RAs on surrogate HF outcomes, such as cardiac structure and function, exercise capacity and quality of life, in HF patients across the spectrum of left ventricular ejection fraction, to provide insights into the potential of these agents to be investigated in large clinical trials to evaluate clinical outcomes.
    Keywords:  Glucagon-like peptide-1 receptor agonists; cardiac function; exercise capacity; heart failure; quality of life
    DOI:  https://doi.org/10.15420/cfr.2024.05
  46. Life Sci Alliance. 2024 Dec;pii: e202402719. [Epub ahead of print]7(12):
    PRDM16 determines specification of ventricular cardiomyocytes by suppressing alternative cell fates.
    Jore Van Wauwe, Alexia Mahy, Sander Craps, Samaneh Ekhteraei-Tousi, Pieter Vrancaert, Hannelore Kemps, Wouter Dheedene, Rosa Doñate Puertas, Sander Trenson, H Llewelyn Roderick, Manu Beerens, Aernout Luttun.
      PRDM16 is a transcription factor with histone methyltransferase activity expressed at the earliest stages of cardiac development. Pathogenic mutations in humans lead to cardiomyopathy, conduction abnormalities, and heart failure. PRDM16 is specifically expressed in ventricular but not atrial cardiomyocytes, and its expression declines postnatally. Because in other tissues PRDM16 is best known for its role in binary cell fate decisions, we hypothesized a similar decision-making function in cardiomyocytes. Here, we demonstrated that cardiomyocyte-specific deletion of Prdm16 during cardiac development results in contractile dysfunction and abnormal electrophysiology of the postnatal heart, resulting in premature death. By combined RNA+ATAC single-cell sequencing, we found that PRDM16 favors ventricular working cardiomyocyte identity, by opposing the activity of master regulators of ventricular conduction and atrial fate. Myocardial loss of PRDM16 during development resulted in hyperplasia of the (distal) ventricular conduction system. Hence, PRDM16 plays an indispensable role during cardiac development by driving ventricular working cardiomyocyte identity.
    DOI:  https://doi.org/10.26508/lsa.202402719
  47. Nat Cardiovasc Res. 2024 Sep 24.
    Evolution of translational control and the emergence of genes and open reading frames in human and non-human primate hearts.
    Jorge Ruiz-Orera, Duncan C Miller, Johannes Greiner, Carolin Genehr, Aliki Grammatikaki, Susanne Blachut, Jeanne Mbebi, Giannino Patone, Anna Myronova, Eleonora Adami, Nikita Dewani, Ning Liang, Oliver Hummel, Michael B Muecke, Thomas B Hildebrandt, Guido Fritsch, Lisa Schrade, Wolfram H Zimmermann, Ivanela Kondova, Sebastian Diecke, Sebastiaan van Heesch, Norbert Hübner.
      Evolutionary innovations can be driven by changes in the rates of RNA translation and the emergence of new genes and small open reading frames (sORFs). In this study, we characterized the transcriptional and translational landscape of the hearts of four primate and two rodent species through integrative ribosome and transcriptomic profiling, including adult left ventricle tissues and induced pluripotent stem cell-derived cardiomyocyte cell cultures. We show here that the translational efficiencies of subunits of the mitochondrial oxidative phosphorylation chain complexes IV and V evolved rapidly across mammalian evolution. Moreover, we discovered hundreds of species-specific and lineage-specific genomic innovations that emerged during primate evolution in the heart, including 551 genes, 504 sORFs and 76 evolutionarily conserved genes displaying human-specific cardiac-enriched expression. Overall, our work describes the evolutionary processes and mechanisms that have shaped cardiac transcription and translation in recent primate evolution and sheds light on how these can contribute to cardiac development and disease.
    DOI:  https://doi.org/10.1038/s44161-024-00544-7
  48. Am J Physiol Heart Circ Physiol. 2024 Sep 27.
    Constipation as a new non-traditional significant contributor to cardiovascular disease.
    Carmen De Miguel.
      
    Keywords:  Constipation; Major cardiac events; UK BioBank
    DOI:  https://doi.org/10.1152/ajpheart.00660.2024
  49. J Cell Mol Med. 2024 Sep;28(18): e70074
    Melatonin regulates mitochondrial dynamics and mitophagy: Cardiovascular protection.
    Sohrab Rahmani, Ali Roohbakhsh, Vahid Pourbarkhordar, A Wallace Hayes, Gholamreza Karimi.
      Despite extensive progress in the knowledge and understanding of cardiovascular diseases and significant advances in pharmacological treatments and procedural interventions, cardiovascular diseases (CVD) remain the leading cause of death globally. Mitochondrial dynamics refers to the repetitive cycle of fission and fusion of the mitochondrial network. Fission and fusion balance regulate mitochondrial shape and influence physiology, quality and homeostasis. Mitophagy is a process that eliminates aberrant mitochondria. Melatonin (Mel) is a pineal-synthesized hormone with a range of pharmacological properties. Numerous nonclinical trials have demonstrated that Mel provides cardioprotection against ischemia/reperfusion, cardiomyopathies, atherosclerosis and cardiotoxicity. Recently, interest has grown in how mitochondrial dynamics contribute to melatonin cardioprotective effects. This review assesses the literature on the protective effects of Mel against CVD via the regulation of mitochondrial dynamics and mitophagy in both in-vivo and in-vitro studies. The signalling pathways underlying its cardioprotective effects were reviewed. Mel modulated mitochondrial dynamics and mitophagy proteins by upregulation of mitofusin, inhibition of DRP1 and regulation of mitophagy-related proteins. The evidence supports a significant role of Mel in mitochondrial dynamics and mitophagy quality control in CVD.
    Keywords:  cardiovascular disease; dynamin‐related protein 1; heart; melatonin; mitochondrial fission; mitochondrial fusion; mitophagy
    DOI:  https://doi.org/10.1111/jcmm.70074
  50. Sci Rep. 2024 Sep 27. 14(1): 22044
    RNA-Seq analysis of human heart tissue reveals SARS-CoV-2 infection and inappropriate activation of the TNF-NF-κB pathway in cardiomyocytes.
    Kirtan Dave, Mukul Jain, Meenakshi Sharma, Anil Kumar Delta, Chittaranjan Kole, Prashant Kaushik.
      The negative impact of SARS-CoV-2 virus infection on cardiovascular disease (CVD) patients is well established. This research article explores the cellular pathways involved in underlying heart diseases after infection. The systemic inflammatory response to SARS-CoV-2 infection likely exacerbates this increased cardiovascular risk; however, whether the virus directly infects cardiomyocytes remains unknown due to limited multi-omics data. While public transcriptome data exists for COVID-19 infection in different cell types (including cardiomyocytes), infection times vary between studies. We used available RNA-seq data from human heart tissue to delineate SARS-CoV-2 infection and heart failure aetiology specific gene expression signatures. A total of fifty-four samples from four studies were analysed. Our aim was to investigate specific transcriptome changes occurring in cardiac tissue with SARS-CoV-2 infection compared to non-infected controls. Our data establish that SARS-CoV-2 infects cardiomyocytes by the TNF-NF-κB pathway, potentially triggering acute cardiovascular complications and increasing the long-term cardiovascular risk in COVID-19 patients.
    Keywords:  Bioinformatics; COVID-19; Cardiomyocytes; Gene; Heart failure; RNA-seq; TNF-NF-κB
    DOI:  https://doi.org/10.1038/s41598-024-69635-6
  51. Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]
    A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
    Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.
      Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.
    Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt
    DOI:  https://doi.org/10.1016/j.cell.2024.08.045
  52. J Cell Physiol. 2024 Sep 26. e31441
    Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy.
    Monika Komza, Jerry Edward Chipuk.
      Mitochondria are pivotal contributors to cancer mechanisms due to their homeostatic and pathological roles in cellular bioenergetics, biosynthesis, metabolism, signaling, and survival. During transformation and tumor initiation, mitochondrial function is often disrupted by oncogenic mutations, leading to a metabolic profile distinct from precursor cells. In this review, we focus on hepatocellular carcinoma, a cancer arising from metabolically robust and nutrient rich hepatocytes, and discuss the mechanistic impact of altered metabolism in this setting. We provide distinctions between normal mitochondrial activity versus disease-related function which yielded therapeutic opportunities, along with highlighting recent preclinical and clinical efforts focused on targeting mitochondrial metabolism. Finally, several novel strategies for exploiting mitochondrial programs to eliminate hepatocellular carcinoma cells in metabolism-specific contexts are presented to integrate these concepts and gain foresight into the future of mitochondria-focused therapeutics.
    Keywords:  cancer; hepatocytes; metabolism; mitochondria; oncogenes; therapeutics
    DOI:  https://doi.org/10.1002/jcp.31441
  53. Environ Toxicol Pharmacol. 2024 Sep 21. pii: S1382-6689(24)00208-4. [Epub ahead of print]111 104568
    Calcitriol/vitamin D receptor system alleviates PM2.5-induced human bronchial epithelial damage through upregulating mitochondrial bioenergetics in association with regulation of HIF-1α/PGC-1α signaling.
    Anyamanee Chatsirisupachai, Phetthinee Muanjumpon, Saowanee Jeayeng, Tasanee Onkoksong, Mutita Pluempreecha, Tanyapohn Soingam, Uraiwan Panich.
      PM2.5 exposure causes lung injury by triggering oxidative stress, mitochondrial dysfunction, and modulating HIF-1α signaling. Calcitriol activates VDR, which regulates cellular homeostasis. This study evaluated the protective role of the calcitriol/VDR system in PM2.5-induced damage to BEAS-2B bronchial epithelial cells by reducing oxidative stress, upregulating mitochondrial bioenergetics, and downregulating HIF-1α. We found that the calcitriol/VDR system decreased ROS formation and restored mitochondrial bioenergetics in PM2.5-treated cells. This improvement correlated with reduced HIF-1α nuclear translocation and increased PGC-1α protein and mitochondrial gene expressions. This study is the first to suggest that targeting the calcitriol/VDR system could be a promising pharmacological strategy for mitigating PM2.5-induced lung epithelial damage by promoting mitochondrial bioenergetics and regulating PGC-1α and HIF-1α signaling.
    Keywords:  Calcitriol; Human bronchial epithelial cells; Hypoxia-inducible factor 1-alpha (HIF-1α); Mitochondrial bioenergetics; Particulate matter ≤ 2.5 μm (PM 2.5)
    DOI:  https://doi.org/10.1016/j.etap.2024.104568
  54. Free Radic Biol Med. 2024 Sep 25. pii: S0891-5849(24)00675-0. [Epub ahead of print]
    Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
    N Moradi, V C Sanfrancesco, S Champsi, D A Hood.
      Lysosomes play a critical role as a terminal organelle in autophagy flux and in regulating protein degradation, but their function and adaptability in skeletal muscle is understudied. Lysosome functions include both housekeeping and signaling functions essential for cellular homeostasis. This review focuses on the regulation of lysosomes in skeletal muscle during exercise, disuse, and aging, with a consideration of sex differences as well as the role of lysosomes in mediating the degradation of mitochondria, termed mitophagy. Exercise enhances mitophagy during elevated mitochondrial stress and energy demand. A critical response to this deviation from homeostasis is the activation of transcription factors TFEB and TFE3, which drive the expression of lysosomal and autophagic genes. Conversely, during muscle disuse, the suppression of lysosomal activity contributes to the accumulation of defective mitochondria and other cellular debris, impairing muscle function. Aging further exacerbates these effects by diminishing lysosomal efficacy, leading to the accumulation of damaged cellular components. mTORC1, a key nutrient sensor, modulates lysosomal activity by inhibiting TFEB/TFE3 translocation to the nucleus under nutrient-rich conditions, thereby suppressing autophagy. During nutrient deprivation or exercise, AMPK activation inhibits mTORC1, facilitating TFEB/TFE3 nuclear translocation and promoting lysosomal biogenesis and autophagy. TRPML1 activation by mitochondrial ROS enhances lysosomal calcium release, which is essential for autophagy and maintaining mitochondrial quality. Overall, the intricate regulation of lysosomal functions and signaling pathways in skeletal muscle is crucial for adaptation to physiological demands, and disruptions in these processes during disuse and aging underscore the ubiquitous power of exercise-induced adaptations, and also highlight the potential for targeted therapeutic interventions to preserve muscle health.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.028
  55. Acta Cardiol. 2024 Sep 24. 1-2
    Imatinib-cardiotoxicity: biventricular heart failure, thrombi and transmural fibrosis.
    Victor Eduardo Vallejo Garcia, Óscar Fabregat-Andrés, Maria Del Carmen Leon Del Pino.
      
    Keywords:  Cardiovascular diseases; cardiac MRI; cardiomyopathy; cardiotoxicity; clinical cardiology; heart failure
    DOI:  https://doi.org/10.1080/00015385.2024.2408040
  56. Science. 2024 Sep 27. 385(6716): 1466-1471
    Genetic excision of the regulatory cardiac troponin I extension in high-heart rate mammal clades.
    William Joyce, Kai He, Mengdie Zhang, Samuel Ogunsola, Xini Wu, Kelvin T Joseph, David Bogomolny, Wenhua Yu, Mark S Springer, Jiuyong Xie, Anthony V Signore, Kevin L Campbell.
      Mammalian cardiac troponin I (cTnI) contains a highly conserved amino-terminal extension harboring protein kinase A targets [serine-23 and -24 (Ser23/24)] that are phosphorylated during β-adrenergic stimulation to defend diastolic filling by means of an increased cardiomyocyte relaxation rate. In this work, we show that the Ser23/24-encoding exon 3 of TNNI3 was pseudoexonized multiple times in shrews and moles to mimic Ser23/24 phosphorylation without adrenergic stimulation, facilitating the evolution of exceptionally high resting heart rates (~1000 beats per minute). We further reveal alternative exon 3 splicing in distantly related bat families and confirm that both cTnI splice variants are incorporated into cardiac myofibrils. Because exon 3 of human TNNI3 exhibits a relatively low splice strength score, our findings offer an evolutionarily informed strategy to excise this exon to improve diastolic function during heart failure.
    DOI:  https://doi.org/10.1126/science.adi8146
  57. Pol Arch Intern Med. 2024 Sep 17. pii: 16841. [Epub ahead of print]
    Metabolic revitalization: exploring erythrocyte fatty acid profile following laparoscopic sleeve gastrectomy.
    Jan Bylica, Joanna Gdula-Argasińska, Piotr Major, Tomasz Grodzicki, Maria Fornal.
       INTRODUCTION: Obesity is linked to metabolic disorders. Bariatric surgery offers a promising therapeutic approach, but its impact on fatty acid (FA) profiles within erythrocytes and the associated clinical implications remain underexplored.
    OBJECTIVES: This study aimed to assess changes in erythrocytes' membranes FA after Laparoscopic Sleeve Gastrectomy (LSG) and to correlate these alterations with clinical parameters.
    PATIENTS AND METHODS: Sixty-one patients with morbid obesity undergoing LSG and 32 healthy controls were enrolled. Erythrocytes' membranes FA were analyzed using gas chromatography. Clinical parameters were assessed, including BMI, blood pressure, and multiple biochemistry markers.
    RESULTS: Bariatric intervention reduced BMI (41.1 to 32.0) and fat mass (54.1 to 35.2kg). Also, other anthropometric parameters improved significantly. Favorable changes in FA metabolism post LSG, potentially leading to a reduction in cardiovascular disease (CVD) risk, were observed. The OMEGA-3 Index (1.8 vs 3.0), and the eicosapentaenoic/arachidonic (0.1 vs 0.2) FA ratio increased after surgery. The dynamics of metabolism post-LSG, assessed by exploring the ratios of erythrocytes' FA concentration in baseline and 6 months after the surgery, with the corresponding ratios calculated for clinical parameters, evidenced the impact of linoleic (LA) on obesity reduction. The LA ratios increased along with the reduction of BMI (r=-0.32), fat mass (r=-0.39), and waist circumference (r=-0.33) proportions. The opposite relations of LA were held with Excess Weight Loss percentage (r=0.49), and Excess BMI Loss percentage (r=0.5).
    CONCLUSIONS: The study underscores distinct post-LSG changes in erythrocytes' FA profiles potentially associated with reduced weight and BMI, improved inflammatory status, and lowered CVD risk.
    DOI:  https://doi.org/10.20452/pamw.16841
  58. Signal Transduct Target Ther. 2024 Sep 26. 9(1): 253
    GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia.
    Xu Chen, Qingnan Wu, Wei Gong, Shaolong Ju, Jiawen Fan, Xiaohan Gao, Xingyang Liu, Xiao Lei, Siqi Liu, Xiangdong Ming, Qianyu Wang, Ming Fu, Yongmei Song, Yan Wang, Qimin Zhan.
      Cachexia, which affects 50-80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75-ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with withanone, a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.
    DOI:  https://doi.org/10.1038/s41392-024-01950-w
  59. Proc Natl Acad Sci U S A. 2024 Oct;121(40): e2416363121
    PUFAs regulate SREBP1c through phosphorylation of Insig2.
    Xu Xiao, Peter Tontonoz.
      
    DOI:  https://doi.org/10.1073/pnas.2416363121
  60. Cell Rep. 2024 Sep 25. pii: S2211-1247(24)01131-8. [Epub ahead of print]43(10): 114780
    Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
    Jiawei Yan, Xin Zhang, Huiying Wang, Xinglong Jia, Ruohong Wang, Shuangyang Wu, Zheng-Jiang Zhu, Minjia Tan, Tiffany Horng.
      Macrophage elaboration of inflammatory responses is dynamically regulated, shifting from acute induction to delayed suppression during the course of infection. Here, we show that such regulation of inflammation is modulated by dynamic shifts in metabolism. In macrophages exposed to the bacterial product lipopolysaccharide (LPS), an initial induction of protein biosynthesis is followed by compensatory induction of the transcription factor nuclear factor erythroid 2-like 1 (NRF1), leading to increased flux through the ubiquitin proteasome system (UPS). A major target of NRF1-mediated UPS flux is the mitochondrial proteome, and in the absence of NRF1, ubiquitinated mitochondrial proteins accumulate to trigger severe mitochondrial stress. Such mitochondrial stress engages the integrated stress response-ATF4 axis, which limits mitochondrial translation to attenuate mitochondrial stress but amplifies inflammatory responses to augment susceptibility to septic shock. Therefore, NRF1 mediates a dynamic regulation of mitochondrial proteostasis in inflammatory macrophages that contributes to curbing inflammatory responses.
    Keywords:  CP: Metabolism; CP: Molecular biology; NRF1; immunometabolism; inflammation; integrated stress response; macrophage; mitochondria; proteostasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114780
  61. Int J Biochem Cell Biol. 2024 Sep 24. pii: S1357-2725(24)00160-2. [Epub ahead of print]176 106668
    SUMOylation of cardiac myosin binding protein-C reduces its phosphorylation and results in impaired relaxation following treatment with isoprenaline.
    Alice Main, Sheon Mary, Yuan Yan Sin, Tom A Wright, Jiayue Ling, Connor M Blair, Godfrey L Smith, Will Fuller, George S Baillie.
      Systolic and diastolic functions are coordinated in the heart by myofilament proteins that influence force of contraction and calcium sensitivity. Fine control of these processes is afforded by a variety of post-translation modifications that occur on specific proteins at different times during each heartbeat. Cardiac myosin binding protein-C is a sarcomeric accessory protein whose function is to interact transiently with actin, tropomyosin and myosin. Previously many different types of post-translational modification have been shown to influence the action of myosin binding protein-C and we present the first report that the protein can be modified covalently by the small ubiquitin like modifier protein tag. Analysis by mass spectrometry suggests that there are multiple modification sites on myosin binding protein-C for this tag and single point mutations did not serve to abolish the covalent addition of the small ubiquitin like modifier protein. Functionally, our data from both model human embryonic kidney cells and transfected neonatal cardiac myocytes suggests that the modification reduces phosphorylation of the filament protein on serine 282. In cardiac myocytes, the hypo-phosphorylation coincided with a significantly slower relaxation response following isoprenaline induced contraction. We hypothesise that this novel modification of myosin binding protein-C represents a new level of control that acts to alter the relaxation kinetics of cardiac myocytes.
    Keywords:  Cardiac myosin binding protein-C; Neonatal rat ventricular myocytes; Post translational modification; SUMO
    DOI:  https://doi.org/10.1016/j.biocel.2024.106668
  62. Diseases. 2024 Aug 23. pii: 195. [Epub ahead of print]12(9):
    Ceramides-Emerging Biomarkers of Lipotoxicity in Obesity, Diabetes, Cardiovascular Diseases, and Inflammation.
    Ginka Delcheva, Katya Stefanova, Teodora Stankova.
      Abnormalities in lipid homeostasis have been associated with many human diseases, and the interrelation between lipotoxicity and cellular dysfunction has received significant attention in the past two decades. Ceramides (Cers) are bioactive lipid molecules that serve as precursors of all complex sphingolipids. Besides their function as structural components in cell and mitochondrial membranes, Cers play a significant role as key mediators in cell metabolism and are involved in numerous cellular processes, such as proliferation, differentiation, inflammation, and induction of apoptosis. The accumulation of various ceramides in tissues causes metabolic and cellular disturbances. Recent studies suggest that Cer lipotoxicity has an important role in obesity, metabolic syndrome, type 2 diabetes, atherosclerosis, and cardiovascular diseases (CVDs). In humans, elevated plasma ceramide levels are associated with insulin resistance and impaired cardiovascular and metabolic health. In this review, we summarize the role of ceramides as key mediators of lipotoxicity in obesity, diabetes, cardiovascular diseases, and inflammation and their potential as a promising diagnostic tool.
    Keywords:  cardiovascular diseases; ceramides; diabetes; inflammation; lipotoxicity
    DOI:  https://doi.org/10.3390/diseases12090195
  63. Diabetes Care. 2024 Sep 23. pii: dc240859. [Epub ahead of print]
    Metabolomic Fingerprints of Medical Therapy Versus Bariatric Surgery in Patients With Obesity and Type 2 Diabetes: The STAMPEDE Trial.
    Christopher L Axelrod, Adithya Hari, Wagner S Dantas, Sangeeta R Kashyap, Philip R Schauer, John P Kirwan.
       OBJECTIVE: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective procedures to treat and manage type 2 diabetes (T2D). However, the underlying metabolic adaptations that mediate improvements in glucose homeostasis remain largely elusive. The purpose of this study was to identify metabolic signatures associated with biochemical resolution of T2D after medical therapy (MT) or bariatric surgery.
    RESEARCH DESIGN AND METHODS: Plasma samples from 90 patients (age 49.9 ± 7.6 years; 57.7% female) randomly assigned to MT (n = 30), RYGB (n = 30), or SG (n = 30) were retrospectively subjected to untargeted metabolomic analysis using ultra performance liquid chromatography with tandem mass spectrometry at baseline and 24 months of treatment. Phenotypic importance was determined by supervised machine learning. Associations between change in glucose homeostasis and circulating metabolites were assessed using a linear mixed effects model.
    RESULTS: The circulating metabolome was dramatically remodeled after SG and RYGB, with largely overlapping signatures after MT. Compared with MT, SG and RYGB profoundly enhanced the concentration of metabolites associated with lipid and amino acid signaling, while limiting xenobiotic metabolites, a function of decreased medication use. Random forest analysis revealed 2-hydroxydecanoate as having selective importance to RYGB and as the most distinguishing feature between MT, SG, and RYGB. To this end, change in 2-hydroxydecanoate correlated with reductions in fasting glucose after RYGB but not SG or MT.
    CONCLUSIONS: We identified a novel metabolomic fingerprint characterizing the longer-term adaptations to MT, RYGB, and SG. Notably, the metabolomic profiles of RYGB and SG procedures were distinct, indicating equivalent weight loss may be achieved by divergent effects on metabolism.
    DOI:  https://doi.org/10.2337/dc24-0859
  64. Endocr Relat Cancer. 2024 Sep 01. pii: ERC-24-0195. [Epub ahead of print]
    Body composition in recurrent prostate cancer and the role of steroidogenic genotype.
    Neha Venkatesh, Rebecca S Tidwell, Yao Yu, Ana Aparicio, Amado J Zurita, Sumit K Subudhi, Bilal A Siddiqui, Sagar S Mukhida, Justin R Gregg, Paul G Corn, Efstratios Koutroumpakis, Jennifer L McQuade, Daniel E Frigo, Patrick G Pilie, Chad Huff, Christopher J Logothetis, Andrew W Hahn.
      Hormone therapy (HT) to treat prostate cancer is reported to cause adverse changes in body composition. Clinically, interpatient body composition changes are heterogeneous, but the biologic and clinical determinants of body composition toxicity are unknown. Herein, we test the hypothesis that inherited polymorphisms in steroidogenic genes are associated with differential change in body composition after HT. Men with biochemically recurrent prostate cancer (BCR) who received 8 months of LHRH analog (LHRHa) +/- abiraterone acetate (AAP) were eligible if they had: 1) CT imaging of L3 prior to and after treatment, and 2) nucleated cells collected. Cardiometabolic co-morbidities were retrospectively extracted. Body composition was measured using an AI-based segmentation tool. Germline DNA whole exome or genome sequencing was performed. In 162 men treated with 8 months of HT, median skeletal muscle mass (SMMi) loss was 6.6% and subcutaneous adipose gain was 12.3%. Men with type 2 diabetes had higher loss of SMMi after treatment (-11.1% vs. -6.3%, p = 0.003). For the 150 men with germline NGS, SRD5A2 rs523349 genotype was associated with differential loss in skeletal muscle density after HT, (-1.3% vs. -7.1%, p=0.04). In addition, HSD3B1 rs104703 genotype was associated with decreased baseline visceral adipose tissue (63.0 cm2/m2 vs. 77.9, p=0.05). In men with BCR, HT induced notable loss of skeletal muscle and increased subcutaneous adipose tissue. An inherited polymorphism in SRD5A2 and T2DM were associated with differential skeletal muscle toxicity. These findings suggest that inherited polymorphisms may contribute to the body composition toxicity observed with HT.
    DOI:  https://doi.org/10.1530/ERC-24-0195
  65. J Diabetes Investig. 2024 Sep 21.
    Effects of glucokinase haploinsufficiency on the pancreatic β-cell mass and function of long-term high-fat, high-sucrose diet-fed mice.
    Ikumi Shigesawa, Akinobu Nakamura, Yuki Yamauchi, Shinichiro Kawata, Asuka Miyazaki, Hiroshi Nomoto, Hiraku Kameda, Yasuo Terauchi, Tatsuya Atsumi.
       AIMS/INTRODUCTION: We previously showed that glucokinase haploinsufficiency improves the glucose tolerance of db/db mice by preserving pancreatic β-cell mass and function. In the present study, we aimed to determine the effects of glucokinase haploinsufficiency on the β-cell mass and function of long-term high-fat, high-sucrose (HFHS) diet-fed mice.
    MATERIALS AND METHODS: Four-week-old male glucokinase haploinsufficient (Gck+/-) mice and 4-week-old male wild-type (Gck+/+) mice (controls) were each divided into two groups: an HFHS diet-fed group and a normal chow-fed group, and the four groups were followed until 16, 40 or 60 weeks-of-age. Their glucose tolerance, glucose-stimulated insulin secretion and β-cell mass were evaluated. In addition, islets were isolated from 40-week-old mice, and the expression of key genes was compared.
    RESULTS: Gck+/-HFHS mice had smaller compensatory increases in β-cell mass and glucose-stimulated insulin secretion than Gck+/+HFHS mice, and their glucose tolerance deteriorated from 16 to 40 weeks-of-age. However, their β-cell mass and glucose-stimulated insulin secretion did not decrease between 40 and 60 weeks-of-age, but rather, tended to increase, and there was no progressive deterioration in glucose tolerance. The expression of Aldh1a3 in pancreatic islets, which is high in several models of diabetes and is associated with an impairment in β-cell function, was high in Gck+/+HFHS mice, but not in Gck+/-HFHS mice.
    CONCLUSIONS: Glucokinase haploinsufficiency prevents the progressive deterioration of pancreatic β-cell mass/function and glucose tolerance in long-term HFHS diet-fed mice.
    Keywords:  Glucokinase; Glucose‐stimulated insulin secretion; β‐cell mass
    DOI:  https://doi.org/10.1111/jdi.14307
  66. Cell Commun Signal. 2024 Sep 26. 22(1): 450
    Mitochondria facilitate neuronal differentiation by metabolising nuclear-encoded RNA.
    Filip Vujovic, Mary Simonian, William E Hughes, Claire E Shepherd, Neil Hunter, Ramin M Farahani.
      Mitochondrial activity directs neuronal differentiation dynamics during brain development. In this context, the long-established metabolic coupling of mitochondria and the eukaryotic host falls short of a satisfactory mechanistic explanation, hinting at an undisclosed facet of mitochondrial function. Here, we reveal an RNA-based inter-organellar communication mode that complements metabolic coupling of host-mitochondria and underpins neuronal differentiation. We show that within minutes of exposure to differentiation cues and activation of the electron transport chain, the mitochondrial outer membrane transiently fuses with the nuclear membrane of neural progenitors, leading to efflux of nuclear-encoded RNAs (neRNA) into the positively charged mitochondrial intermembrane space. Subsequent degradation of mitochondrial neRNAs by Polynucleotide phosphorylase 1 (PNPase) located in the intermembrane space curbs the transcriptomic memory of progenitor cells. Further, acquisition of neRNA by mitochondria leads to a collapse of proton motive force, suppression of ATP production, and a resultant amplification of autophagic flux that attenuates proteomic memory. Collectively, these events force the progenitor cells towards a "tipping point" characterised by emergence of a competing neuronal differentiation program. It appears that neuronal differentiation is a consequence of reprogrammed coupling of metabolomic and transcriptomic landscapes of progenitor cells, with mitochondria emerging as key "reprogrammers" that operate by acquiring and metabolising neRNAs. However, the documented role of mitochondria as "reprogrammers" of differentiation remains to be validated in other neuronal lineages and in vivo.
    DOI:  https://doi.org/10.1186/s12964-024-01825-1
  67. Arch Physiol Biochem. 2024 Sep 26. 1-18
    Chronic whole-body heat treatment in obese insulin-resistant C57BL/6J mice.
    Helena Trevisan Schroeder, Carlos Henrique de Lemos Muller, Maria Inês Lavina Rodrigues, Marcela Alves de Azevedo, Victor de Souza Borges, Cristiana Maria Sponchiado, Paulo Ivo Homem de Bittencourt.
       AIM: This study examined the effects of hyperthermic therapy (HT) on mice fed normal chow or a high-fat diet (HFD) for 18 or 22 weeks, undergoing four or eight weekly HT sessions.
    METHODS: Mice were housed within their thermoneutral zone (TNZ) to simulate a physiological response. HFD-induced obesity-related changes, including weight gain, visceral fat accumulation, muscle loss (indicative of obesity sarcopenia), glucose intolerance, and hepatic triglyceride buildup.
    MAIN RESULTS: HT upregulated HSP70 expression in muscles, mitigated weight gain, normalised QUICK index, and reduced plasma HSP70 concentrations. It also lowered the H-index of HSP70 balance, indicating improved immunoinflammatory status, and decreased activated caspase-1 and proliferative senescence in adipose tissue, both linked to insulin resistance.
    CONCLUSION: The findings suggest that even animals on a "control" diet but with insufficient physical activity and within their TNZ may experience impaired glycaemic homeostasis.
    Keywords:  HSP70; Heat shock response; diabetes; high-fat diet; insulin resistance; low-grade inflammation; obesity
    DOI:  https://doi.org/10.1080/13813455.2024.2406904
  68. Metabolism. 2024 Sep 19. pii: S0026-0495(24)00266-X. [Epub ahead of print]161 156038
    Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.
    Zeyu Xie, Guimei Zheng, Zhuoru Liang, Mengting Li, Weishang Deng, Weiling Cao.
       PURPOSE: This study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis.
    METHODS: Relevant randomized controlled trials (RCTs) with an intervention duration of at least 16 weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5 mg; retatrutide, 12 or 8 mg; tirzepatide, 15 or 10 mg; liraglutide, 3.0 mg; semaglutide, 2.4 mg; orforglipron, 45 or 36 mg; and beinaglutide, 0.2 mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software.
    RESULTS: Twenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12 mg (-22.10 % in body weight and - 17.00 cm in waist circumference), retatrutide 8 mg (-20.70 % and - 15.90 cm), and tirzepatide 15 mg (-16.53 % and - 13.23 cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (˂54 mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable.
    CONCLUSION: Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.
    Keywords:  Efficacy; Glucagon-like peptide-1 receptor agonists; Obesity or overweight; Polyagonists; Safety; Weight loss
    DOI:  https://doi.org/10.1016/j.metabol.2024.156038
  69. Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep 28.
    Nasal administration of mitochondria relieves depressive- and anxiety-like behaviors in male mice exposed to restraint stress through the suppression ROS/NLRP3/caspase-1/IL-1β signaling pathway.
    Vida Mafikandi, Fatemehsadat Seyedaghamiri, Naeimeh Hosseinzadeh, Parviz Shahabi, Ali Reza Shafiee-Kandjani, Soraya Babaie, Leila Maghsoumi-Norouzabad, Fereshteh Farajdokht, Leila Hosseini.
      Neuroinflammation and oxidative stress are known to be implicated in the pathogenesis of depression. Exogenous mitochondrial transplantation has exhibited beneficial effects for treating neurological disorders. Hence, this research aimed to evaluate the impact of nasal administration of mitochondria on neuroinflammation and oxidative stress in mouse models displaying depressive- and anxiety-like behaviors caused by restraint stress (RS). Thirty male BALB/c mice were divided into control, RS, and RS + 340 µg of mitochondrial. Mice were subjected to RS using an immobilization falcon tube (2 h/day) for 2 weeks except for the control group. We conducted two behavioral tests to evaluate anxiety-like behaviors: elevated plus maze (EPM) and open field test (OFT). Tail suspension test (TST) was implemented to assess depressive-like behavior. ATP and reactive oxygen species (ROS) levels were measured in the hippocampus. Besides, serum corticosterone (CORT) levels were evaluated using the ELISA method. The expression of NLRP3 inflammasome, caspase-1 (Cas-1), and IL-1β was tested by western blot. We found that mitotherapy increased the time spent in the center of OFT and open arms of the EPM, while it diminished immobility time in TST. Mitochondrial administration considerably attenuated ROS generation and CORT levels and restored ATP levels. Additionally, mitotherapy prevented RS-induced upregulation of IL-1β, cleaved Cas1/Pro Cas1 ratio, and NLRP3/1 in the hippocampus of mice. These findings suggested that the beneficial effects of intranasal mitochondria on depression and anxiety may be attributed to suppression of the ROS/NLRP3/IL-1β/caspase-1 signaling pathway.
    Keywords:  Anxiety; Depression; Mitotherapy; Neuroinflammation; Restraint stress
    DOI:  https://doi.org/10.1007/s00210-024-03487-9
  70. Cannabis Cannabinoid Res. 2024 Sep 26.
    Effect of Cannabistilbene I in Attenuating Angiotensin II-Induced Cardiac Hypertrophy: Insights into Cytochrome P450s and Arachidonic Acid Metabolites Modulation.
    Ahmad H Alammari, Fadumo Ahmed Isse, Conor O'Croinin, Neal M Davies, Ayman O S El-Kadi.
      Introduction: This research investigated the impact of Cannabistilbene I on Angiotensin II (Ang II)-induced cardiac hypertrophy and its potential role in cytochrome P450 (CYP) enzymes and arachidonic acid (AA) metabolic pathways. Cardiac hypertrophy, a response to increased stress on the heart, can lead to severe cardiovascular diseases if not managed effectively. CYP enzymes and AA metabolites play critical roles in cardiac function and hypertrophy, making them important targets for therapeutic intervention. Methods: Adult human ventricular cardiomyocyte cell line (AC16) was cultured and treated with Cannabistilbene I in the presence and absence of Ang II. The effects on mRNA expression related to cardiac hypertrophic markers and CYP were analyzed using real-time polymerase chain reaction, while CYP protein levels were measured by Western blot analysis. AA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Results showed that Ang II triggered hypertrophy, as evidenced by the increase in hypertrophic marker expression, and enlarged the cell surface area, effects that were alleviated by Cannabistilbene I. Gene expression analysis indicated that Cannabistilbene I upregulated CYP1A1, leading to increased enzymatic activity, as evidenced by 7-ethoxyresorufin-O-deethylase assay. Furthermore, LC-MS/MS analysis of AA metabolites revealed that Ang II elevated midchain (R/S)-hydroxyeicosatetraenoic acid (HETE) concentrations, which were reduced by Cannabistilbene I. Notably, Cannabistilbene I selectively increased 19(S)-HETE concentration and reversed the Ang II-induced decline in 19(S)-HETE, suggesting a unique protective role. Conclusion: This study provides new insights into the potential of Cannabistilbene I in modulating AA metabolites and reducing Ang II-induced cardiac hypertrophy, revealing a new candidate as a therapeutic agent for cardiac hypertrophy.
    Keywords:  19-HETE; CYP; Cannabistilbene I; arachidonic acid; hypertrophy; midchain-HETEs
    DOI:  https://doi.org/10.1089/can.2024.0148
  71. BMC Cardiovasc Disord. 2024 Sep 27. 24(1): 510
    Correlation of serum homocysteine and cystatin C levels with prognosis in heart failure with preserved ejection fraction patients.
    Zhi-Heng Chen, Xue-Tao Zhu, Ze-Ping Hu, Jun-Xi Ni, Hou-Liang Chen.
       OBJECTIVE: This study investigated the relationship of serum homocysteine (Hcy) and cystatin C (Cys C) levels with the prognosis of patients with heart failure with preserved ejection fraction (HFpEF).
    METHODS: A total of 178 patients with HFpEF who were admitted to our hospital between December 2019 and November 2020 were included. Patients were grouped based on their serum Hcy and Cys C levels: high Hcy level, normal Hcy level, high Cys C level, and normal Cys C level. Cardiac function, ventricular remodeling indices, and prognosis were compared among patients in these groups. Additionally, the predictive value of serum Hcy and Cys C levels for adverse cardiovascular events in HFpEF patients was analyzed.
    RESULTS: Patients' mean age in the high Hcy level, normal Hcy level, high Cys C level, and normal Cys C level groups was 69.21 ± 4.17,67.74 ± 4.28,69.95 ± 4.98, and 67.06 ± 4.13 years old, respectively. The high Hcy level group exhibited a lower proportion of class II cardiac function according to the New York Heart Association (NYHA) classification and a higher proportion of class IV cardiac function than the normal Hcy level group, with statistically significant differences. Similarly, the high Cys C level group had a lower proportion of class II cardiac function and a higher proportion of class IV cardiac function compared with the normal Cys C level group, with statistically significant differences. Left ventricular end-diastolic internal diameter (LVEDD), left ventricular end-systolic internal diameter (LVESD), and left ventricular mass index (LVMI) were significantly higher in both the high Hcy level and high Cys C level groups compared with the normal group, with statistically significant differences. The rates of all-cause mortality and class I endpoint events were significantly higher in the high Hcy level and high Cys C level groups than in the normal group. Multifactorial logistic regression analysis demonstrated that adverse cardiovascular events were significantly associated with cardiac function class, LVEDD, LVESD, LVMI, Hcy, and Cys C in patients with HFpEF. The area under the curve (AUC) values for Hcy and Cys C, determined using receiver operating characteristic (ROC) curve analysis, were 0.778 (optimal critical value, 25.38) and 0.681 (optimal critical value, 1.56), respectively, for predicting adverse cardiovascular events. Both Hcy and Cys C serum levels were positively correlated with LVEDD, LVESD, LVMI, and NYHA classification.
    CONCLUSION: Serum levels of Hcy and Cys C were closely associated with cardiac function, ventricular remodeling indices, and prognosis in patients with HFpEF. These levels may serve as valuable indices for assessing HFpEF patients' health status and prognosis, providing important insights into their potential role as biomarkers for HFpEF management and prognosis.
    Keywords:  Cardiac function; Cystatin C; Ejection fraction preserved heart failure; Homocysteine; Prognosis; Ventricular remodeling
    DOI:  https://doi.org/10.1186/s12872-024-04058-9
  72. STAR Protoc. 2024 Sep 20. pii: S2666-1667(24)00495-7. [Epub ahead of print]5(4): 103330
    Protocol to monitor live-cell, real-time, mitochondrial respiration in mouse muscle cells using the Resipher platform.
    Matthew Triolo, Mireille Khacho.
      Mitochondrial function is typically assessed by measuring oxygen consumption at a given time point. However, this approach cannot monitor respiratory changes that occur over time. Here, we present a protocol to measure mitochondrial respiration in freshly isolated muscle stem cells, primary skeletal muscle, and immortalized C2C12 myoblasts in real time using the Resipher platform. We describe steps for preparing and plating cells, performing media changes, setting up the software and device, and analyzing data. This method can be adapted to other cell types. For complete details on the use and execution of this protocol, please refer to Triolo et al.1.
    Keywords:  Cell Biology; Metabolism; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2024.103330
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