bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–02–16
fourteen papers selected by
Xiong Weng, University of Edinburgh
  1. Caloric Restriction and Telomere Preservation in TERT Knockout Adipocyte Progenitors Does Not Rescue Mice From Metabolic Dysfunction due to a TERT Function in Adipocyte Mitochondria.
  2. Adenylate cyclase 10 promotes brown adipose tissue thermogenesis.
  3. Unveiling the Molecular Legacy of Transient Insulin Resistance: Implications for Hepatic Metabolic Adaptability.
  4. Protein phosphatase 6 regulates metabolic dysfunction-associated steatohepatitis via the mTORC1 pathway.
  5. Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.
  6. TRIM56 Promotes White Adipose Tissue Browning to Attenuate Obesity by Degrading TLE3.
  7. Host-microbiome determinants of insulin resistance in obesity: alone we go faster, together we go further!
  8. Isoform usage as a distinct regulatory layer driving nutrient-responsive metabolic adaptation.
  9. Temporal phosphoproteomics reveals circuitry of phased propagation in insulin signaling.
  10. Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis.
  11. Long-read sequencing of 945 Han individuals identifies structural variants associated with phenotypic diversity and disease susceptibility.
  12. Fructose-induced progression of steatohepatitis involves disrupting aldolase B-AMPK signaling in methionine adenosyltransferase 1A deficient mice.
  13. Integration of metabolomic and transcriptomic analyses reveals regulatory functions of the ChREBP transcription factor in energy metabolism.
  14. Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.
  1. Aging Cell. 2025 Feb 11. e14499
    Caloric Restriction and Telomere Preservation in TERT Knockout Adipocyte Progenitors Does Not Rescue Mice From Metabolic Dysfunction due to a TERT Function in Adipocyte Mitochondria.
    Zhanguo Gao, Yongmei Yu, Kristin Eckel-Mahan, Mikhail G Kolonin.
      Inactivation of telomerase (TERT) in adipocyte progenitor cells (APC) expedites telomere attrition, and the onset of diabetes in mice fed high-fat diet (HFD), which promotes APC over-proliferation and replicative senescence. Here, we show that time-restricted feeding or caloric restriction in the postnatal development of mice subsequently subjected to HFD prevents telomere attrition but not glucose intolerance. This metabolic effect of dietary intervention was not observed for mice with TERT KO in endothelial or myeloid cells. To characterize the telomere-independent effects of TERT in the APC lineage, we analyzed mice with TERT knockout in mature adipocytes (AD-TERT-KO), which do not proliferate and avoid telomere attrition. Analysis of adipocytes from AD-TERT-KO mice indicated reliance on glycolysis and decreased mitochondrial oxidative metabolism. We show that AD-TERT-KO mice have reduced cold tolerance and metabolism abnormality indicating a defect in adaptive thermogenesis, characteristic of aging. Conversely, ectopic TERT expression in brown adipocytes-induced mitochondrial oxidation and thermogenic gene expression. We conclude that TERT plays an important non-canonical function in the mitochondria of adipocytes.
    Keywords:  TERT; adipocyte; mitochondria; progenitor; senescence; telomerase; telomere
    DOI:  https://doi.org/10.1111/acel.14499
  2. iScience. 2025 Feb 21. 28(2): 111833
    Adenylate cyclase 10 promotes brown adipose tissue thermogenesis.
    Anupam Das, Christine Mund, Eman Hagag, Ruben Garcia-Martin, Eleftheria Karadima, Anke Witt, Mirko Peitzsch, Andreas Deussen, Triantafyllos Chavakis, Thomas Noll, Vasileia Ismini Alexaki.
      Brown adipose tissue (BAT) thermogenesis dissipates energy through heat production and thereby it opposes metabolic disease. It is mediated by mitochondrial membrane uncoupling, yet the mechanisms sustaining the mitochondrial membrane potential (ΔΨm) in brown adipocytes are poorly understood. Here we show that isocitrate dehydrogenase (IDH) activity and the expression of the soluble adenylate cyclase 10 (ADCY10), a CO2/bicarbonate sensor residing in mitochondria, are upregulated in BAT of cold-exposed mice. IDH inhibition or ADCY10 deficiency reduces cold resistance of mice. Mechanistically, IDH increases the ΔΨm in brown adipocytes via ADCY10. ADCY10 sustains complex I activity and the ΔΨm via exchange protein activated by cAMP1 (EPAC1). However, neither IDH nor ADCY10 inhibition affect uncoupling protein 1 (UCP1) expression. Hence, we suggest that ADCY10, acting as a CO2/bicarbonate sensor, mediates the effect of IDH on complex I activity through cAMP-EPAC1 signaling, thereby maintaining the ΔΨm and enabling thermogenesis in brown adipocytes.
    Keywords:  Cell biology; Molecular biology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2025.111833
  3. J Hepatol. 2025 Feb 11. pii: S0168-8278(25)00080-7. [Epub ahead of print]
    Unveiling the Molecular Legacy of Transient Insulin Resistance: Implications for Hepatic Metabolic Adaptability.
    Alexandre Berthier, Céline Gheeraert, Manjula Vinod, Manuel Johanns, Loïc Guille, Joel T Haas, Julie Dubois-Chevalier, Jérôme Eeckhoute, Bart Staels, Philippe Lefebvre.
       BACKGROUND: Metabolic flexibility (MetF) is an organism's ability to adjust to changing metabolic supplies and energy demands. Insulin plays a central role in coordinating MetF through molecular mechanisms such as signaling pathways, transcriptional responses, and circadian regulation. Insulin resistance (IR) can impair MetF, contributing to type 2 diabetes and obesity, often stemming from continuous challenges such as sedentary lifestyles, poor diets, and circadian disruptions. Transient IR episodes, like gestational diabetes or stress-induced hyperglycemia, also heighten the risk of later diabetes development. Yet, the molecular processes post-transient IR remain poorly understood despite their health significance.
    AIMS AND METHODS: Our aims were to characterize the hepatic response to a high fat diet challenge in mice previously exposed to a transient IR episode. We integrated transcriptomic, epigenomic, lipidomic, and molecular clock assessments to provide a molecular basis for the observed dysregulations.
    RESULTS: Our study shows that temporarily blocking the insulin receptor in young mice leads to later-life liver issues hindering PPARα-mediated adaptation to a high-fat diet. This is linked to decreased histone active marks at PPARα sites and reduced endogenous PPARα ligands. Transient insulin receptor blockade also altered the liver's molecular clock, particularly affecting PPARα transcriptional responsiveness.
    CONCLUSIONS: Seemingly reversible and unnoticed metabolic challenges in early adulthood may predispose the liver to exacerbated metabolic dysfunctions when confronted with chronic challenges later in life.
    Keywords:  Liver; PPARα; REV-ERBα; circadian clock; insulin resistance; metabolic flexibility
    DOI:  https://doi.org/10.1016/j.jhep.2025.02.004
  4. J Hepatol. 2025 Feb 11. pii: S0168-8278(25)00079-0. [Epub ahead of print]
    Protein phosphatase 6 regulates metabolic dysfunction-associated steatohepatitis via the mTORC1 pathway.
    Zhengshuai Liu, Shuang Wei, Yang Jiang, Weitong Su, Fengguang Ma, Genxiang Cai, Yuxiao Liu, Xiaoyang Sun, Ling Lu, Wenguang Fu, Yong Xu, Ruijing Huang, Jian Li, Xu Lin, Aoyuan Cui, Mengwei Zang, Aimin Xu, Yu Li.
       BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a serious chronic liver disease with limited therapies. Although fibroblast growth factor 21 (FGF21) analogs have shown promising therapeutic benefits for MASH in multiple preclinical and clinical studies, the underlying mechanisms remain elusive.
    METHODS: Liver-specific PPP6C knockout (PPP6C LKO) mice, βKlotho knockout (βKlotho LKO) and their wild-type littermates were fed with Amylin liver NASH (AMLN) diet for 16 weeks or choline-deficient, L-amino acid-defined, high-fat diet (CDA-HFD) for 8 weeks, followed by daily subcutaneous injection of rFGF21 (0.5 mg/kg) or vehicle for 4 weeks. Mass spectrometry assay was used for identification of PPP6C as a βKlotho binding protein. The in vitro phosphatase assay was used to evaluate the effects of FGF21 on PPP6C activity. Human studies shown that deregulation of PPP6C is associated with the progression of MASH.
    RESULTS: We identified serine and threonine phosphatase PPP6C as a direct target of FGF21. Hepatic PPP6C deficiency accelerates MASH progression in mice fed with AMLN diet or CDA-HFD, which blocks FGF21 action on MASH. Mechanistically, PPP6C is sufficient to interact with the coreceptor βKlotho upon FGF21 treatment, directly dephosphorylates tuberous sclerosis complex 2 (TSC2) at Ser939 and Thr1462, thereby inhibiting mTORC1 and promoting nuclear entry of TFE3 and Lipin1. In livers of MASH subjects, expression levels of PPP6C are decreased whereas TSC2 phosphorylation is elevated.
    CONCLUSIONS: These results define a fundamental mechanism underlying FGF21 signals in hepatocytes and demonstrate that targeting PPP6C may have therapeutic potential for treating MASH.
    IMPACT AND IMPLICATIONS: MASH is a severe chronic liver disease that increases susceptibility to more severe cirrhosis and hepatocellular carcinoma, yet currently lacks effective clinical therapeutic strategies. Here we have identified serine and threonine protein phosphatase PPP6C as a key regulator of MASH progression in mice and humans. PPP6C is directly activated by FGF21 via FGFRs/βKlotho and improves MASH features through dephosphorylation of TSC2 in hepatocytes. This study implies that pharmacological approaches, genetic or metabolic factors targeting PPP6C activity may offer attractive prospects for treating liver fibrosis and MASH.
    Keywords:  FGF21; Liver fibrosis; MASH; PPP6C; mTORC1; βKlotho
    DOI:  https://doi.org/10.1016/j.jhep.2025.02.003
  5. Elife. 2025 Feb 12. pii: RP100541. [Epub ahead of print]13
    Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.
    Kelsey R Baron, Samantha Oviedo, Sophia Krasny, Mashiat Zaman, Rama Aldakhlallah, Prerona Bora, Prakhyat Mathur, Gerald Pfeffer, Michael J Bollong, Timothy E Shutt, Danielle A Grotjahn, R Luke Wiseman.
      Excessive mitochondrial fragmentation is associated with the pathologic mitochondrial dysfunction implicated in the pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) - comprising the four eIF2α kinases PERK, GCN2, PKR, and HRI - is a prominent stress-responsive signaling pathway that regulates mitochondrial morphology and function in response to diverse types of pathologic insult. This suggests that pharmacologic activation of the ISR represents a potential strategy to mitigate pathologic mitochondrial fragmentation associated with human disease. Here, we show that pharmacologic activation of the ISR kinases HRI or GCN2 promotes adaptive mitochondrial elongation and prevents mitochondrial fragmentation induced by the calcium ionophore ionomycin. Further, we show that pharmacologic activation of the ISR reduces mitochondrial fragmentation and restores basal mitochondrial morphology in patient fibroblasts expressing the pathogenic D414V variant of the pro-fusion mitochondrial GTPase MFN2 associated with neurological dysfunctions, including ataxia, optic atrophy, and sensorineural hearing loss. These results identify pharmacologic activation of ISR kinases as a potential strategy to prevent pathologic mitochondrial fragmentation induced by disease-relevant chemical and genetic insults, further motivating the pursuit of highly selective ISR kinase-activating compounds as a therapeutic strategy to mitigate mitochondrial dysfunction implicated in diverse human diseases.
    Keywords:  cell biology; human; integrated stress response; mitochondrial fragmentation; mitochondrial morphology; mouse; stress signaling
    DOI:  https://doi.org/10.7554/eLife.100541
  6. Adv Sci (Weinh). 2025 Feb 10. e2414073
    TRIM56 Promotes White Adipose Tissue Browning to Attenuate Obesity by Degrading TLE3.
    Haojie Qin, Yi Zhong, Jinhui Huang, Yanli Miao, Meng Du, Kai Huang.
      In mammals, the activation of thermogenic adipocytes, such as beige and brown adipocytes, can significantly increase overall energy expenditure, offering a promising strategy to combat metabolic diseases. Despite its considerable potential, the regulatory mechanisms governing this activation remain largely elusive. This study bridges this gap by elucidating that tripartite motif 56 (TRIM56), an E3 ubiquitin ligase, is upregulated in response to cold stimuli, thereby promoting the recruitment of beige adipocytes. Notably, the overexpression of TRIM56 in adipocytes is shown to help mice maintain a core temperature under cold conditions, as well as confer protection against diet-induced obesity. Mechanistically, TRIM56 facilitates the degradation of the transducin-like enhancer protein 3 (TLE3) protein by promoting its K48-linked ubiquitination, which subsequently triggers the activation of thermogenic genes in subcutaneousl white adipose tissue and improved the metabolic profiles. These findings unveil a novel function for TRIM56 in adipocyte browning, suggesting its potential as a therapeutic target for the treatment of metabolic disorders.
    Keywords:  Lipolysis; White adipose tissue browning; adaptive thermogenesis; obesity; ubiquitin modifications
    DOI:  https://doi.org/10.1002/advs.202414073
  7. Gut. 2025 Feb 11. pii: gutjnl-2024-333855. [Epub ahead of print]
    Host-microbiome determinants of insulin resistance in obesity: alone we go faster, together we go further!
    Andre Marette, Genevieve Pilon.
      
    Keywords:  DIABETES MELLITUS; LIVER; MICROBIOME; OBESITY; SMALL INTESTINE
    DOI:  https://doi.org/10.1136/gutjnl-2024-333855
  8. Cell Metab. 2025 Feb 05. pii: S1550-4131(25)00009-9. [Epub ahead of print]
    Isoform usage as a distinct regulatory layer driving nutrient-responsive metabolic adaptation.
    Jia Li, Chaoqun Cai, Wei Wen Teo, Kai Shin Chin, Yadanar Than Naing, Shengren Song, Franklin Nelson, Li Qiang, Dan Xu, Lei Sun.
      Transcriptome modulation is essential for metabolic adaptation to nutrient environments. However, the role of isoform usage, a crucial transcriptome component, is not yet fully understood. This study outlines the landscape of isoform-usage modulations across major metabolic organs in both mice and monkeys, spanning diverse metabolic states. Our in-depth analysis identifies numerous isoform-usage events, intricately influenced by nutrient challenges and largely independent of gene expression regulation. Comparative analyses of mice and monkeys highlight hundreds of conserved isoform events that exhibit consistent responses to nutrient challenges across species and correlate with human metabolic traits. When analyzing splicing factor-binding motifs in nutrient-regulated events, HuR emerges as the predominant orchestrator of the isoform network in adipocytes, which is validated using an adipose tissue-specific knockout and an Ap2-promoter-driven transgenic mouse model. In summary, our results offer a comprehensive perspective on isoform usage in metabolic regulation, setting a platform for future functional inquiries.
    Keywords:  Elavl1; HuR; adipose tissue; aging; isoform usage; liver; muscle; nutrient challenge; obesity; splicing
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.009
  9. Nat Commun. 2025 Feb 12. 16(1): 1570
    Temporal phosphoproteomics reveals circuitry of phased propagation in insulin signaling.
    Michael Turewicz, Christine Skagen, Sonja Hartwig, Stephan Majda, Kristina Thedinga, Ralf Herwig, Christian Binsch, Delsi Altenhofen, D Margriet Ouwens, Pia Marlene Förster, Thorsten Wachtmeister, Karl Köhrer, Torben Stermann, Alexandra Chadt, Stefan Lehr, Tobias Marschall, G Hege Thoresen, Hadi Al-Hasani.
      Insulin is a pleiotropic hormone that elicits its metabolic and mitogenic actions through numerous rapid and reversible protein phosphorylations. The temporal regulation of insulin's intracellular signaling cascade is highly complex and insufficiently understood. We conduct a time-resolved analysis of the global insulin-regulated phosphoproteome of differentiated human primary myotubes derived from satellite cells of healthy donors using high-resolution mass spectrometry. Identification and tracking of ~13,000 phosphopeptides over time reveal a highly complex and coordinated network of transient phosphorylation and dephosphorylation events that can be allocated to time-phased regulation of distinct and non-overlapping subcellular pathways. Advanced network analysis combining protein-protein-interaction (PPI) resources and investigation of donor variability in relative phosphosite occupancy over time identifies novel putative candidates in non-canonical insulin signaling and key regulatory nodes that are likely essential for signal propagation. Lastly, we find that insulin-regulated phosphorylation of the pre-catalytic spliceosome complex is associated with acute alternative splicing events in the transcriptome of human skeletal muscle. Our findings highlight the temporal relevance of protein phosphorylations and suggest that synchronized contributions of multiple signaling pathways form part of the circuitry for propagating information to insulin effector sites.
    DOI:  https://doi.org/10.1038/s41467-025-56335-6
  10. Nat Commun. 2025 Feb 10. 16(1): 1483
    Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis.
    Qingwen Zhao, Xuan Cui, Qi Zhu, Feiyan Li, Ran Bao, Ting Shi, Haojie Liu, Wenjing Lv, Yingjiang Xu, Yue Gao, Qi-Qun Tang, Min Zhang, Dongning Pan.
      Lysine methyltransferase KMT5C catalyzes deposition of trimethylation on histone H4 lysine 20 (H4K20me3), an epigenetic marker usually associated with gene repression and maintenance of heterochromatin. KMT5C is widely expressed in a variety of tissues, however, its functional role in liver has not been explored. Here, we show Kmt5c is a fasting- and glucagon-induced gene in liver which regulates hepatic gluconeogenesis. Loss of KMT5C in hepatocytes results in downregulated gluconeogenic gene expression and compromised glucose output during fasting. KMT5C fosters gluconeogenesis through decreasing ubiquitination-mediated PGC-1α degradation, which is unexpectedly independent of its methyltransferase activity. In fact, KMT5C impedes the E3 ligase RNF34 binding to the C-terminal of PGC-1α and subsequent ubiquitination-associated degradation. The diabetic mice models and patients show elevated KMT5C levels in the livers, and KMT5C knockdown beneficially reduces gluconeogenesis and fasting blood glucose levels. In conclusion, the present study identifies KMT5C as a hepatic gluconeogenesis regulator by affecting PGC-1α stability.
    DOI:  https://doi.org/10.1038/s41467-025-56696-y
  11. Nat Commun. 2025 Feb 10. 16(1): 1494
    Long-read sequencing of 945 Han individuals identifies structural variants associated with phenotypic diversity and disease susceptibility.
    Chinese Pangenome Consortium (CPC)
      Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations.
    DOI:  https://doi.org/10.1038/s41467-025-56661-9
  12. Metabolism. 2025 Feb 06. pii: S0026-0495(25)00023-X. [Epub ahead of print]165 156154
    Fructose-induced progression of steatohepatitis involves disrupting aldolase B-AMPK signaling in methionine adenosyltransferase 1A deficient mice.
    Lucía Barbier-Torres, María Luque-Urbano, Jyoti Chhimwal, Aaron E Robinson, David Fernández-Ramos, Fernando Lopitz-Otsoa, Jennifer E Van Eyk, Oscar Millet, José M Mato, Shelly C Lu.
       OBJECTIVE: Aldolases (ALDO) are sensors that regulate AMPK via binding to fructose 1,6-biphosphate (FBP), an intermediate of glucose and fructose metabolism. Fructose consumption is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) progression but whether ALDO-AMPK signaling is involved is unknown. Methionine adenosyltransferase alpha 1 (Mat1a) knockout (KO) mice have low hepatic S-adenosylmethionine (SAMe) level and spontaneously develop steatohepatitis. ALDOB methylation has not been reported and here we investigated whether SAMe level regulates ALDOB and ALDOB-AMPK signaling and whether fructose feeding accelerates MASLD progression by disrupting ALDOB-AMPK signaling.
    METHODS: Mass spectrometry identified ALDOB methylation sites and recombinant in vitro approaches assessed how methylation at those sites affects ALDOB oligomerization and activity. Primary hepatocytes cultured with high/low glucose and/or fructose and wild type (WT) and Mat1a KO mice fed with a high-fructose diet examined AMPK-ALDOB signaling and MASLD progression.
    RESULTS: In Mat1a KO livers ALDOB R173 is hypomethylated while ALDOB activity is enhanced. Recombinant ALDOB is methylated at R173 and R304 by protein arginine methyltransferase 1. Low hepatic SAMe level results in hypomethylated ALDOB, which favors the tetrameric form that has higher enzymatic activity, and higher capacity to signal to activate AMPK. Fructose, independently of glucose levels, inhibited AMPK activity and induced lipid accumulation in hepatocytes. Mat1a KO mice have hyperactivated AMPK and fructose feeding inhibits it, enhancing the accumulation of fat in the liver and the progression of MASLD.
    CONCLUSION: Hepatic SAMe levels regulate ALDOB oligomeric state and enzymatic activity impacting on AMPK signaling and fructose-induced MASLD progression.
    Keywords:  AMPK; Aldolase B; Fructose; Liver; MASLD
    DOI:  https://doi.org/10.1016/j.metabol.2025.156154
  13. Cell Rep. 2025 Feb 07. pii: S2211-1247(25)00049-X. [Epub ahead of print]44(2): 115278
    Integration of metabolomic and transcriptomic analyses reveals regulatory functions of the ChREBP transcription factor in energy metabolism.
    Jie An, Inna Astapova, Guofang Zhang, Andrew L Cangelosi, Olga Ilkayeva, Hannah Marchuk, Michael J Muehlbauer, Tabitha George, Joseph Brozinick, Mark A Herman, Christopher B Newgard.
      The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomic and metabolomic analyses in rats with GalNac-siRNA-mediated suppression of ChREBP expression in liver reveal other ChREBP functions. GalNac-siChREBP treatment reduces expression of genes involved in coenzyme A (CoA) biosynthesis, with lowering of CoA and short-chain acyl-CoA levels. Despite suppression of pyruvate kinase, pyruvate levels are maintained, possibly via increased expression of pyruvate and amino acid transporters. In addition, expression of multiple anaplerotic enzymes is decreased by GalNac-siChREBP treatment, affecting TCA cycle intermediates. Finally, GalNAc-siChREBP treatment suppresses late steps in purine and NAD synthesis, with increases in precursors and lowering of end products in both pathways. In sum, our study reveals functions of ChREBP beyond its canonical roles in carbohydrate and lipid metabolism to include regulation of substrate transport, mitochondrial function, and energy balance.
    Keywords:  CP: Metabolism; ChREBP; CoA; amino acids; lipids; metabolic regulation; nucleotides
    DOI:  https://doi.org/10.1016/j.celrep.2025.115278
  14. Cell Rep Med. 2025 Feb 06. pii: S2666-3791(25)00041-2. [Epub ahead of print] 101968
    Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.
    Marina Cefis, Vincent Marcangeli, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Caroline Trumpff, Qiuhan Huang, Martin Picard, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou.
      Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.
    Keywords:  calcium retention capacity; functional capacities; intermuscular fat accumulation; mitochondria; mitochondrial permeability transition pore; muscle atrophy and weakness; physical performance; reactive oxygen species; sarcopenia; skeletal muscle aging
    DOI:  https://doi.org/10.1016/j.xcrm.2025.101968
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