bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–12–07
forty-four papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
  2. Displaced myonuclei are attributable to both resident myonuclear migration and stem cell fusion during mechanical loading in adult skeletal muscle.
  3. Non-muscle myosin IIC predominantly expressed in the slow-twitch skeletal muscles impedes age-related muscle weakness.
  4. Tension to Translation: External to Internal Processes in Muscle Hypertrophy.
  5. Critical role of mitochondrial aconitase in skeletal muscle maturation.
  6. Differential responses to acute endurance exercise-induced signaling protein phosphorylation and abundance alterations in whole murine gastrocnemius muscle and isolated myofibers.
  7. Editorial: Stem cell therapy for hereditary neuromuscular diseases.
  8. Tenascin-C from the tissue microenvironment promotes muscle stem cell maintenance and function through Annexin A2.
  9. Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.
  10. Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle.
  11. Cold-Induced Suppression of Myogenesis in Skeletal Muscle Stem Cells Contributes to Delayed Muscle Regeneration During Hibernation.
  12. Circular RNAs and their emerging roles in muscular immune-related diseases.
  13. Conditional Dmd ablation in muscle and brain causes profound effects on muscle function and neurobehavior.
  14. Divergent alterations in the skeletal muscle and serum proteome in a rodent model of anorexia nervosa and weight recovery.
  15. Juvenile vs. adult skeletal muscle transplants in the treatment of volumetric muscle loss injury.
  16. Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
  17. Precision rewriting of muscle genetics: therapeutic horizons of base and prime editing in skeletal muscle disorders.
  18. C2C12-Derived ApoVs Promote Skeletal Muscle Development and Ameliorate Age-Related Muscle Loss Through Igf1r/PI3K/AKT/mTOR Pathway.
  19. Histone deacetylases in Duchenne muscular dystrophy: a role in the mechanism of disease and a target for inhibition.
  20. Dual role of Macrophages in skeletal muscle Atrophy: Mechanisms and therapeutic strategies.
  21. Beta-nicotinamide mononucleotide attenuates creatine kinase release in Duchenne muscular dystrophy model rats.
  22. Control of quiescence and activation of human muscle stem cells by cytokines.
  23. Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
  24. Decorin Deficiency Promotes D-Galactose-Induced Skeletal Muscle Atrophy and Fibrosis by Regulating ITGB1/Akt/mTOR Signalling Pathway.
  25. The role of cell death in the physiological and pathological processes of skeletal muscle.
  26. Effects of acidosis and inorganic phosphate on Ca2+ sensitivity of young and older adult skeletal muscle fibers.
  27. TAS1R3 regulates GTPase signaling in human skeletal muscle cells for glucose uptake.
  28. Negative Impact of p21-Activated Kinase 4-Mediated AMP-Activated Protein Kinase Inhibition on Sarcopenia in Mice and Humans.
  29. Dystrophin-deficiency stiffens skeletal muscle and impairs elasticity: an in vivo rheological examination.
  30. Skeletal muscle memory: implications for sports, aging and nutrition.
  31. Aging-Associated CD55⁺ Fibroblasts Promote Chronic Inflammation and ECM Dysregulation in Sarcopenia.
  32. Irisin regulates the phosphorylation of glucocorticoid receptor Ser212 and Ser234 and mediates glucocorticoid-induced muscle atrophy in mice.
  33. Chronic circadian misalignment accelerates sarcopenia progression in mice.
  34. Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.
  35. Transcriptomic Analysis of Skeletal Muscle Systems Comparing Bovines, Humans, and Mice Using scRNA-Seq.
  36. The metabolic role of corticotropin-releasing hormone receptor 2 and its UCN peptides: emerging therapeutic potential.
  37. Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
  38. Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle-tumor metabolic competition.
  39. Assaying the myosin super-relaxed state across muscle types, cells and proteins for understanding muscle biology and use in drug discovery.
  40. Postmenopausal sarcopenia and Alzheimer's disease: The interplay of mitochondria, insulin resistance, and myokines.
  41. UQCR10 and TNNT1: novel biomarkers for sarcopenia identified through integrated transcriptomic analysis and machine learning.
  42. Eccentric overload training promotes serial sarcomerogenesis to a greater extent than conventional resistance training.
  43. Autophagy cargo profiles in skeletal muscle during starvation and exercise.
  44. Trends and frontiers in disuse muscle atrophy research.
  1. Nat Metab. 2025 Dec 03.
    Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
    Olaya Santiago-Fernández, Luisa Coletto, Inmaculada Tasset, Susmita Kaushik, Axel R Concepcion, Rizwan Qaisar, Adrián Macho-González, Kristen Lindenau, Antonio Diaz, Rabia R Khawaja, Stefano Donega, Nirad Banskota, Ceereena Ubaida-Mohien, Gavin Pharaoh, Bumsoo Ahn, Lisa M Hartnell, Ignacio Ramírez-Pardo, Bhakti Chavda, Aiara Gazteluiturri, Michael Kinter, Luigi Ferrucci, Julie A Reisz, Angelo D'Alessandro, Holly Van Remmen, Pura Muñoz-Cánoves, Stefan Feske, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.
    DOI:  https://doi.org/10.1038/s42255-025-01412-9
  2. Skelet Muscle. 2025 Dec 05.
    Displaced myonuclei are attributable to both resident myonuclear migration and stem cell fusion during mechanical loading in adult skeletal muscle.
    Nathan Serrano, Pieter Jan Koopmans, Kevin A Murach.
      Non-peripheral (displaced) myonuclei are characteristic of skeletal muscle pathology and severe injury but also appear after exercise and with aging. Displaced myonuclei are typically attributed to the activity of muscle stem cells, or satellite cells. We sought to address whether displaced myonuclei in adult skeletal muscle are exclusively from an exogenous source such as satellite cells or can result from resident myonuclear migration. To address this question, we used a murine recombination-independent muscle fibre-specific doxycycline-inducible fluorescent myonuclear labelling approach, EdU stem cell fate tracking, two durations of plantaris muscle mechanical overload (MOV, 3 days and 7 days), and fluorescent histology. Our findings show that: 1) displaced myonuclei emerge early during MOV in adult mice, 2) resident myonuclear movement occurs rapidly during MOV, and 3) the contribution of resident versus exogenous displaced myonuclei depends on the preferential effects of MOV for specific fibre types or fibre sizes with a given MOV duration. These observations provide fundamental insights on myonuclear motility in response to stress in vivo and reframe our understanding of how a recognized feature of mammalian skeletal muscle can emerge in response to stressors such as mechanical loading.
    DOI:  https://doi.org/10.1186/s13395-025-00407-0
  3. PLoS One. 2025 ;20(12): e0337708
    Non-muscle myosin IIC predominantly expressed in the slow-twitch skeletal muscles impedes age-related muscle weakness.
    Hiroki Hamaguchi, Shino Hiraoka, Kun Tang, Haonan Zhu, Yoshitaka Mita, Yasuro Furuichi, Nobuharu L Fujii, Yasuko Manabe.
      Skeletal muscle expresses three types of non-muscle myosin (NM) II in addition to skeletal type myosin. While immature myoblasts have been reported to express NMIIA and NMIIB, playing roles in cell morphology, the specific localization and function of NMIIC in skeletal muscle cells remain unclear. In this study, we aimed to investigate the expression pattern and the physiological role of NMIIC in skeletal muscle. NMIIC was specifically expressed in the slow-twitch muscles such as soleus, which primarily consists of type I and type IIa fibers, and its expression increased as muscle differentiation progressed. To explore the function of NMIIC in skeletal muscle, we used whole-body NMIIC knockout (KO) mice. Myofiber size was slightly but significantly decreased in the soleus of young (18-20-week-old) NMIIC KO mice. However, contractile force of the isolated soleus muscle in the NMIIC KO mice did not differ from that of wild-type mice, suggesting that the slight reduction in fiber size has limited physiological significance at this age. Interestingly, in 81-week-old NMIIC KO mice, soleus contractile force was significantly reduced despite no difference in fiber size between aged wild-type and NMIIC KO mice. Notably, NMIIC expression levels were higher in aged than young mice. These findings suggest that while NMIIC has minimal impact on skeletal muscle function under young and healthy conditions, it may play a crucial role in maintaining muscle function when muscle is compromised at age.
    DOI:  https://doi.org/10.1371/journal.pone.0337708
  4. Physiology (Bethesda). 2025 Dec 01.
    Tension to Translation: External to Internal Processes in Muscle Hypertrophy.
    Dominique Greyvenstein, James P Newbold, Stuart M Phillips.
      Skeletal muscle is a highly adaptable tissue that plays a central role in overall health. The dynamic balance between muscle protein synthesis and breakdown governs skeletal muscle mass maintenance. Increased loading and hyperaminoacidemia (via protein ingestion) are positive drivers of skeletal muscle protein accretion, which, when combined, drive a hypertrophic phenotypic adaptation. In contrast, unloading (disuse) results in skeletal muscle atrophy and metabolic dysregulation. Hypertrophy enhances metabolic health and functional capacity, underscoring the importance of understanding the mechanisms that regulate this process. External variables, such as resistance exercise and dietary protein, influence hypertrophy; however, resistance exercise is the primary driver, with protein playing a minor supporting role. Signals from external inputs - loading (resistance exercise) and nutritional manipulation (protein ingestion) - are sensed and transduced into intracellular pathways that promote muscle protein synthesis, yet the precise mechanisms underlying their integration remain incompletely understood. This review summarizes current knowledge on how resistance exercise and dietary protein converge on the intracellular level to regulate skeletal muscle hypertrophy in humans.
    Keywords:  amino acid; loading; mechanotransduction; protein
    DOI:  https://doi.org/10.1152/physiol.00034.2025
  5. Sci Rep. 2025 Dec 02. 15(1): 42957
    Critical role of mitochondrial aconitase in skeletal muscle maturation.
    Tomoya Fukawa, Miho Takata, Kota Kishida, Kosuke Sugiura, Minori Suzuki, Haruka Tsuda, Iori Sakakibara, Takayuki Uchida, Md Mizanur Rahman, Anayt Ulla, Koichi Sairyo, Takahiko Sato, Madoka Ikemoto-Uezumi, Akiyoshi Uezumi, Takeshi Nikawa.
      Skeletal muscle dynamically regulates protein synthesis and degradation through metabolic responses to external stimuli. In the absence of mechanical load, this normal metabolic response is impaired, leading to muscle atrophy. Previous studies have suggested that mitochondrial dysfunction occurs under unloaded conditions. In this study, we focused on aconitase 2 (Aco2), a mitochondrial protein known to contain an iron-sulfur cluster and function as a metabolic sensor. We generated skeletal muscle-specific Aco2 knockout (cKO) mice to investigate its role in muscle function. Although these mice appeared grossly normal, they died shortly after birth. Analysis of the diaphragm muscle revealed signs of muscle fiber atrophy and impaired muscle maturation. Besides these signs of immaturity, abnormal muscle cells exhibiting disrupted sarcomere structures were frequently observed. Furthermore, these cells showed a marked increase in the apoptotic marker Active Caspase-3, indicating that Aco2 deficiency induces muscle cell death. These findings suggest that Aco2 plays a critical role in skeletal muscle maturation and maintenance of muscle homeostasis. Moreover, these findings highlighted the potential involvement of Aco2 in disuse muscle atrophy and its utility as a therapeutic target.
    Keywords:  Aconitase 2-knockout mice; Apoptosis; Mitochondrial dysfunction; Sarcomere disruption; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-025-25560-w
  6. Curr Res Physiol. 2025 ;8 100173
    Differential responses to acute endurance exercise-induced signaling protein phosphorylation and abundance alterations in whole murine gastrocnemius muscle and isolated myofibers.
    Kazuki Uemichi, Takanaga Shirai, Shunsuke Sugiyama, Tohru Takemasa.
      Skeletal muscle is composed of diverse cell types, including myofibers. In this study, we investigated how acute endurance exercise could induce signaling protein phosphorylation and abundance alterations using protein lysate extracted from whole-muscle tissue or isolated myofibers. We subjected 8-week-old male Institute Cancer Research mice to a single bout of treadmill running-based endurance exercise, and evaluated the signaling protein expression responses in the whole gastrocnemius muscle and isolated myofibers, obtained by incubation in 0.2 % collagenase/medium, immediately after exercise. Our results revealed that exercise activated mitochondrial biogenesis- and protein anabolism-related signaling, including 5'-adenosine monophosphate-activated kinase and Akt/p70 S6 kinases, respectively, as well as increased glucose metabolism-related proteins in whole-muscle samples immediately after exercise. However, these signaling responses were not present in the muscle fiber lysate and mitochondrial oxidative phosphorylation-related protein abundance significantly decreased postexercise. Our data suggest that signaling protein activation and quantitative alterations in myofibers digested in collagenase-dissolved medium post acute exercise do not necessarily reflect the expression responses in whole skeletal muscle tissue.
    Keywords:  Endurance exercise; Myofiber; Signaling protein; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.crphys.2025.100173
  7. Front Cell Dev Biol. 2025 ;13 1741683
    Editorial: Stem cell therapy for hereditary neuromuscular diseases.
    Katsumasa Goto, Atsushi Asakura.
      
    Keywords:  cell therapy; duchenne muscular dystrophy (DMD); live imaging; multiple sclerosis (MS); muscle regeneration; muscle stem cell; skeletal muscle; spatial transcriptomics
    DOI:  https://doi.org/10.3389/fcell.2025.1741683
  8. Commun Biol. 2025 Dec 05. 8(1): 1709
    Tenascin-C from the tissue microenvironment promotes muscle stem cell maintenance and function through Annexin A2.
    Alessandra Cecchini, Mafalda Loreti, Collin D Kaufman, Cedomir Stamenkovic, Gabriele Guarnaccia, Alma Renero, Chiara Nicoletti, Anais Kervadec, Daphne Mayer, Shawn Delaware, Luca Caputo, Xiuqing Wei, Alexandre Colas, Pier Lorenzo Puri, Alessandra Sacco.
      Skeletal muscle regeneration occurs through the finely timed activation of resident muscle stem cells (MuSC). Following injury, MuSC exit quiescence, undergo myogenic commitment, and regenerate the muscle. This process is coordinated by tissue microenvironment cues, however the underlying mechanisms regulating MuSC function are still poorly understood. Here, we demonstrate that the extracellular matrix protein Tenascin-C (TnC) promotes MuSC self-renewal and function. Mice lacking TnC exhibit reduced number of MuSC, and defects in MuSC self-renewal, myogenic commitment, and repair. We show that fibro-adipogenic progenitors are the primary cellular source of TnC during regeneration, and that MuSC respond through the surface receptor Annexin A2. We further demonstrate that TnC declines during aging, leading to impaired MuSC function. Aged MuSC exposed to soluble TnC show a rescued ability to both migrate and self-renew in vitro. Overall, our results highlight the pivotal role of TnC during muscle repair in healthy and aging muscle.
    DOI:  https://doi.org/10.1038/s42003-025-09189-z
  9. bioRxiv. 2025 Nov 19. pii: 2025.11.19.688750. [Epub ahead of print]
    Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.
    Young-Seung Lee, Hee Soo Kim, Phuc L Nguyen, Junhyeong Lee, Dong-Il Kim, Jeongmin Lee, Changjong Moon, Kyoung-Oh Cho, Byung-Eun Kim, Jiyun Ahn, Timothy F Osborne, Taner Duysak, Jeong-Sun Kim, Chang Hwa Jung, Tae-Il Jeon.
      Copper is an essential trace element required for mitochondrial respiration and cellular metabolism, yet its role in skeletal muscle remains incompletely understood. Here, we show that skeletal muscle-specific deletion of the high-affinity copper importer Ctr1 (SMKO) in mice leads to copper deficiency, resulting in exercise intolerance, metabolic dysfunction, and hallmarks of mitochondrial myopathy, including ragged-red fibers, lactic acidosis, and aberrant mitochondrial morphology. Copper deficiency disrupted electron transport chain proteome and induced mitochondrial hyperfusion. We identified mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, as a copper-binding regulator of mitochondrial copper distribution and morphology. Restoring copper levels via the copper ionophore or AAV-mediated Ctr1 re-expression rescued mitochondrial function and alleviated myopathic features in SMKO. These findings highlight MTCH2 as a key mediator of a critical link between copper homeostasis and mitochondrial remodeling required for skeletal muscle function.
    DOI:  https://doi.org/10.1101/2025.11.19.688750
  10. Mol Metab. 2025 Nov 29. pii: S2212-8778(25)00201-7. [Epub ahead of print] 102294
    Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle.
    Dipsikha Biswas, Ever Espino-Gonzalez, Danial Ahwazi, Jordana B Freemantle, Amy M Ehrlich, Charline Jomard, Jonas Brorson, Agnete N Schou, Jean Farup, Julien Gondin, Jesper Just, Marc Foretz, Jonas T Treebak, Marianne Agerholm, Kei Sakamoto.
       OBJECTIVE: Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.
    METHODS: Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1-/-/γ3-/-) and single knockout (imγ1-/- and imγ3-/-) mice were generated. Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed.
    RESULTS: snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1-/-/γ3-/- muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3-/-, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1-/- mice.
    CONCLUSIONS: While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.
    Keywords:  AICAR; AMP-activated protein kinase; MK-8722; Single nucleus RNA sequencing; glucose uptake
    DOI:  https://doi.org/10.1016/j.molmet.2025.102294
  11. FASEB J. 2025 Dec 15. 39(23): e71297
    Cold-Induced Suppression of Myogenesis in Skeletal Muscle Stem Cells Contributes to Delayed Muscle Regeneration During Hibernation.
    Tatsuya Miyaji, Ryuichi Kasuya, Mayuko Monden, Yutaka Tamura, Michito Shimozuru, Toshio Tsubota, Daisuke Tsukamoto, Guangyuan Li, Shota Kawano, Yuri Watanabe, Yoshifumi Yamaguchi, Masatomo Watanabe, Mitsunori Miyazaki.
      Mammalian hibernators experience profound cold stress and prolonged physical inactivity during torpor periods; however, it is unclear how skeletal muscle stem cells (satellite cells; SCs) respond to these challenges. In this study, we demonstrated that SCs from a mammalian hibernator, the Syrian hamster, exhibit remarkable resistance to cold-induced cell death, which is associated with intrinsically higher expression of the antioxidant enzyme GPX4, likely contributing to ferroptosis suppression. RNA-seq analysis revealed widespread downregulation of myogenesis-related genes following cold exposure, suggesting suppression of the myogenic program. Consistently, SCs exposed to cold stress exhibited reduced activation and differentiation capacity upon subsequent rewarming, with an increased number of quiescent Pax7-positive/MyoD-negative cells. Muscle regeneration was markedly delayed during hibernation, accompanied by decreased SC activation and macrophage infiltration, suggesting that cold-induced suppression of SC function underlies the limited regenerative capacity in hibernating hamsters. Our results provide insights into the unique physiology of mammalian hibernators: SC viability is preserved, whereas regenerative activity is selectively suppressed during hibernation.
    Keywords:  cold stress; ferroptosis; hibernation; muscle regeneration; myogenesis; satellite cells; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202502651R
  12. Front Immunol. 2025 ;16 1675567
    Circular RNAs and their emerging roles in muscular immune-related diseases.
    Felicita Urzi, Anja Srpčič, Katja Lakota.
      Circular RNAs (circRNAs) have recently emerged as a highly stable and versatile class of non-coding RNAs that play critical roles in gene regulation, yet their involvement in immune-mediated muscle disorders remains largely underexplored. This review synthesizes how circRNAs influence key processes in both skeletal muscle and immune cells, from myogenesis, regeneration, and muscle stem cell function to inflammatory signaling and muscle wasting. Our aim was to identify circRNA insights across muscle immune-mediated diseases. However, we found no idiopathic inflammatory myopathy-focused circRNA studies, only a limited body of work in Duchenne muscular dystrophy, and predominantly peripheral blood mononuclear cell-based evidence in myasthenia gravis. These gaps highlight clear priorities: subtype-resolved circRNA atlases for idiopathic inflammatory myopathy; paired muscle-biofluid and cell-type-resolved profiling (including infiltrating immune populations); rigorous in vivo functional validation beyond correlative expression; fuller mechanistic delineation beyond miRNA competition (e.g., RNA binding protein interactions, translation, epigenetic regulation); and longitudinal cohorts linking circRNA dynamics to disease activity and treatment response. We particularly noted lack of in-depth studies addressing the interplay between muscle and immune cells in these conditions. Furthermore, we examine pioneering efforts to engineer circRNAs as therapeutic agents, capable of either neutralizing pathogenic pathways that drive muscle atrophy or restoring dystrophin expression in genetic disease models. Finally, we outline future directions for circRNA profiling in patient tissues and biofluids, rigorous functional validation in vivo, and the development of circRNA-based diagnostics. This positions circRNAs at the forefront of next-generation strategies for understanding and combating immune-related muscular disorders.
    Keywords:  Duchenne muscular dystrophy; circular RNA; idiopathic inflammatory myopathies; immune cells; myasthenia gravis; skeletal muscle
    DOI:  https://doi.org/10.3389/fimmu.2025.1675567
  13. Commun Biol. 2025 Dec 02. 8(1): 1736
    Conditional Dmd ablation in muscle and brain causes profound effects on muscle function and neurobehavior.
    Muthukumar Karuppasamy, Katherine G English, James R Conner, Shelby N Rorrer, Michael A Lopez, David K Crossman, Jodi R Paul, Miguel A Gutierrez-Monreal, Karen L Gamble, Karyn A Esser, Jeffrey J Widrick, Louis M Kunkel, Matthew S Alexander.
      Duchenne muscular dystrophy (DMD) patients suffer from skeletal and cardiopulmonary weakness, and up to one third are diagnosed on the autism spectrum. Dystrophin is an essential protein for regulating intracellular force transmission to the extracellular matrix (ECM) within the skeletal muscle, but also plays key roles in neurobehavior and cognitive function. The mouse Dmd gene is X-linked and has several isoforms with enriched tissue expression in the skeletal muscle, heart, and the brain. Constitutive and inducible deletion of muscle dystrophin resulted in a skeletal muscle myopathy, dystrophic histopathology, and functional deficits compared to the mdx mouse. Transcriptomic analysis of Dmd mKO muscles revealed dysregulation of ECM and cytokine pathways. Purkinje dystrophin knockout (Dmd:Pcp2 KO) mice displayed neurobehavioral deficits in social approach, social memory, and spatial memory. These studies reveal the essential requirement for dystrophin expression in both the skeletal muscle and brain for normal physiological and neurobehavioral function.
    DOI:  https://doi.org/10.1038/s42003-025-09128-y
  14. Res Sq. 2025 Nov 18. pii: rs.3.rs-8079717. [Epub ahead of print]
    Divergent alterations in the skeletal muscle and serum proteome in a rodent model of anorexia nervosa and weight recovery.
    Megan Rosa-Caldwell, Pieter Koopmans, L Breithaupt, Towia Libermann, Simon Dillon, Gu Xuesong, Kevin Murach, Ursula Kaiser, Seward Rutkove, Christos Mantzoros.
      Anorexia nervosa (AN) is a severe psychiatric disorder characterized by prolonged caloric restriction and significant weight loss, including loss of skeletal muscle. However, physiological changes during AN and following weight restoration are poorly understood, especially skeletal muscle physiology and how it relates to systemic physiology. In this study, we utilized a rodent model of AN and weight gain to investigate proteomic changes across the skeletal muscle and serum and how these proteomic alterations relate to muscle functional outcomes. Using SOMAscan proteomics, we identified extensive alterations in the skeletal muscle proteome during 30 days of simulated AN, with the majority of these changes persisting after weight restoration. Muscle mass and strength were not fully recovered after weight restoration, aligning with sustained dysregulation of proteins related to apoptosis, calcium handling, and satellite cell proliferation in skeletal muscle. By contrast, serum proteomic changes were modest during AN but markedly altered and largely distinct from muscle during recovery. TRAIL (TNF-related apoptosis-inducing ligand) emerged as a potential non-invasive biomarker of muscle health as TRAIL content correlated between muscle and serum as well as muscle functional assessments. Proteomic biomarkers of muscle versus systemic AN are largely unique, underlining the complexity of this illness and the need for novel analytical approaches; however, TRAIL dysregulation may be a conserved feature across tissues and should be further investigated as potential non-invasive biomarker of muscle health and a possible mechanistic target for AN-induced muscle loss.
    DOI:  https://doi.org/10.21203/rs.3.rs-8079717/v1
  15. Stem Cell Res Ther. 2025 Dec 03.
    Juvenile vs. adult skeletal muscle transplants in the treatment of volumetric muscle loss injury.
    John J Payne, Samuel R Frandsen, Zachary H Rasmussen, Matthew J Mangus, Anna C Taylor, Mason K Kephart, Sandy S Huang, Thomas K Schiefer, Kyndal M Jones, Erastus W Evans, Jacob R Sorensen.
       BACKGROUND: Volumetric muscle loss (VML) causes irreversible structural and functional deficits by removing myofibers, nerves, vasculature, extracellular matrix, and satellite cells, the resident muscle stem cells essential for regeneration. Skeletal muscle transplantation can restore tissue volume and reintroduce regenerative cells, yet functional outcomes remain incomplete. Age of the donor muscle has not been evaluated, despite evidence that juvenile muscle contains higher satellite cell density and greater myogenic plasticity than adult muscle. We hypothesized that these features would yield superior regenerative outcomes when juvenile muscle is used as a transplant source.
    METHODS: Tibialis anterior (TA) muscles from juvenile (21 d), adolescent (34 d), and adult (~ 120 d) male Lewis rats were compared for myofiber morphology, satellite cell density, and in-vitro myogenic behavior. GFP⁺ juvenile or adult muscle was then transplanted into standardized VML defects (~ 15-20% TA volume) in adult rats. Seven weeks post-surgery, in-vivo isometric strength, donor fiber integration, satellite cell distribution, and centralized nuclei were assessed.
    RESULTS: Juvenile muscle exhibited ~ 15× greater satellite cell density than adult (122.8 ± 28.4 vs. 8.4 ± 3.3 cells/mm², p < 0.0001) with enhanced in-vitro differentiation (fusion index + 73% vs. adult, p = 0.0067). In-vivo, both juvenile and adult transplants restored myofiber number to control levels (juvenile: 11,369 ± 1,511; adult: 9,115 ± 1,274; controls: 10,316 ± 685) and improved strength versus untreated VML (juvenile: +50%, p = 0.0016; adult: +36%, p = 0.0299). No significant functional differences were observed between donor ages. Donor fibers integrated but remained small, with localized satellite cell enrichment and increased centralized nuclei in transplant regions, consistent with ongoing regeneration.
    CONCLUSIONS: Juvenile skeletal muscle displays cellular and structural attributes favorable for regeneration and superior in-vitro myogenic behavior compared to adult muscle. However, these advantages did not translate into greater short-term in-vivo recovery following VML transplantation. Enhancing donor fiber hypertrophy, neuromuscular integration, and satellite cell expansion beyond the transplant region, potentially through rehabilitation or pharmaceutical interventions, may be necessary to realize the full therapeutic potential of juvenile donor muscle for regenerative medicine applications.
    Keywords:  Donor age; Juvenile muscle; Muscle regeneration; Regenerative medicine; Satellite cells; Skeletal muscle transplantation; Stem cell therapy; Tissue engineering; Volumetric muscle loss
    DOI:  https://doi.org/10.1186/s13287-025-04844-y
  16. Mol Cell Biochem. 2025 Dec 01.
    Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
    Chuanlong Zhang, Xiaoxia Zheng, Lijuan Xiang, Zhanguo Su.
      The deterioration of mitochondrial function is a hallmark of aging muscle and markedly accelerates the onset and progression of a range of mitochondrial diseases. Symptoms including limited mobility, persistent fatigue, and muscle weakness are often attributed to impaired mitochondrial dynamics, involving key mechanisms such as mitophagy, fusion, and fission. Exercise has been shown to positively influence mitochondrial health by regulating mitochondrial biogenesis, dynamics, and turnover. This review examines the exercise-induced modulation of mitochondrial processes in aging muscle and delineates its prospects as an intervention for managing mitochondrial diseases. We highlight the molecular mechanisms by which exercise orchestrates mitochondrial dynamics, augments organelle function, and triggers mitophagy-all of which are crucial for the preservation of muscle cell homeostasis. Furthermore, we explore how pivotal molecular pathways such as AMPK, PGC-1α, and SIRT1 regulate mitochondrial adaptations to exercise. This review also underscores the therapeutic promise of exercise in attenuating mitochondrial disease progression via enhanced mitochondrial quality control and improved muscle function. By integrating findings from mitochondrial science, gerontology, and exercise physiology, this review positions exercise as a crucial regulator of mitochondrial dynamics and a viable non-pharmacological strategy for maintaining muscle integrity in the contexts of aging and mitochondrial disease.
    Keywords:  Aging muscle; Exercise; Mitochondrial diseases; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s11010-025-05441-6
  17. Gene Ther. 2025 Dec 04.
    Precision rewriting of muscle genetics: therapeutic horizons of base and prime editing in skeletal muscle disorders.
    Selin Saydam, Pervin Dinçer.
      Base Editing (BE) and Prime Editing (PE), novel precision tools of the CRISPR/Cas toolbox, have emerged as transformative technologies that enable highly specific genetic modifications. Their compatibility with post-mitotic cell types makes them invaluable for treating genetic skeletal muscle disorders. Despite their severity and progressive nature, monogenic muscle diseases remain without definitive treatments. They are caused by diverse mutations in critical muscle proteins, for which gene editing offers a promising therapeutic avenue. However, traditional CRISPR/Cas9 applications face challenges such as genotoxicity and inefficiency in post-mitotic tissues. BE and PE technologies overcome these limitations by enabling safe and efficient modifications without causing double-strand breaks or requiring homology-directed repair. Their therapeutic potential comes from two key features: their ability to work in non-dividing cells such as myotubes and cardiomyocytes, and their capacity to target a broad range of mutations found in genetic muscle diseases. In this review, we explore mechanisms of BE and PE and summarize their current applications in monogenic skeletal muscle disorders. We discuss the challenges of in vivo application in skeletal muscle and highlight innovations to bypass them. Collectively, both systems offer flexible precision solutions with immense potential for mutation-specific and personalized gene therapy approaches for monogenic skeletal muscle disorders.
    DOI:  https://doi.org/10.1038/s41434-025-00574-1
  18. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70159
    C2C12-Derived ApoVs Promote Skeletal Muscle Development and Ameliorate Age-Related Muscle Loss Through Igf1r/PI3K/AKT/mTOR Pathway.
    Aiwen Jiang, Yi Liu, Luyao Wang, Haifei Wang, Shenglong Wu, Wenbin Bao.
       BACKGROUND: Apoptosis coincides with the differentiation of skeletal myoblasts, and numerous studies have shown that the apoptotic activity is required for myogenic differentiation. Although the role of apoptosis in skeletal muscle differentiation has been well documented, its mechanism is largely unknown.
    METHODS: Apoptotic extracellular vesicles (apoVs) were extracted from differentiated C2C12 cells or STS-treated undifferentiated C2C12 myoblasts. C2C12 myoblasts, 8-week-old male mice or 15-month-old male mice were used as in vitro and in vivo models, respectively. These models were treated with C2C12-derived apoVs to explore the biological function and mechanism of apoVs in myogenic differentiation, skeletal muscle development and aging.
    RESULTS: Proteomic analysis revealed that inhibition of apoptotic activity by Z-VAD-FMK (ZVAD) affected extracellular components. Using immunofluorescence staining, western blotting and transmission electron microscopy analysis, our results demonstrated the generation of apoVs during myogenic differentiation. C2C12-derived apoVs exhibited a typical double-membrane spherical structure, phosphatidylserine exposure and were highly positive for the general apoV markers cleaved caspase 3 (CASP3), Alix and TSG101. Inhibition of apoptotic activity significantly reduced (p = 0.0029) the protein level of myosin heavy chain (1.05 in the Con group vs. 0.38 in the ZVAD group) accompanied by a marked decrease (p < 0.0001) in apoV production (5.91e+10 ± 8.93e+09 in the Con group vs. 1.77e+10 ± 1.36e+09 in the ZVAD group). Proteomic analysis of apoVs suggested that C2C12-derived apoVs contain multiple pro-differentiation proteins, including insulin-like growth factor 1 receptor (Igf1r). ApoVs could be taken up by recipient cells and subsequently rescued the impaired C2C12 differentiation induced by ZVAD (p < 0.0001) and promoted the normal myogenic differentiation process (p = 0.0081) by carrying Igf1r and promoting PI3K/AKT/mTOR activation. Knockdown of Igf1r or inhibition of PI3K activation diminished the positive role of apoVs. In addition, apoV treatment promoted skeletal muscle development in 8-week-old male mice (n = 6, Cohen's d = 1.993, power = 0.874) and relieved age-related muscle loss (n = 6, Cohen's d = 3.97, power = 0.999).
    CONCLUSIONS: In summary, this study demonstrates the generation of apoVs during myogenic differentiation. The apoVs derived from skeletal muscle cells promote skeletal muscle cell differentiation and delay age-related muscle loss. These results provide a theoretical basis for elucidating the mechanism of skeletal muscle development and treating skeletal muscle-related diseases.
    Keywords:  Igf1r; apoVs; apoptosis; myogenic differentiation
    DOI:  https://doi.org/10.1002/jcsm.70159
  19. Clin Epigenetics. 2025 Dec 04.
    Histone deacetylases in Duchenne muscular dystrophy: a role in the mechanism of disease and a target for inhibition.
    Mariarita Bertoldi, Emilio Albamonte, Luca Bello, Adele D'amico, Riccardo Masson, Vincenzo Nigro, Marika Pane, Chiara Panicucci, Maria Sframeli, Federica Ricci.
      Aberrant activity of histone deacetylases (HDACs) is a pathological phenomenon in several diseases, including Duchenne muscular dystrophy (DMD). In DMD, the upregulation of HDACs is driven by the disassembly of the dystrophin-associated protein complex (DAPC), which, under normal physiological conditions, provides mechanical stability to muscle fibres and acts as a signalling hub anchoring signalling proteins and molecules to their functional sites. In dystrophic muscle, DAPC disassembly causes delocalisation of signalling proteins and, therefore, disrupts signalling pathways. Displacement of epigenetic signalling molecules leads to the uncontrolled activity of HDACs and excessive removal of acetyl groups from histone proteins. Consequently, chromatin becomes tightly bound, preventing the expression of genes involved in muscle homeostasis. The pathological consequences of increased HDAC activity extend beyond muscle fibres, affecting several cell types, translating into a chronically activated immune system, promoting fibrotic and adipose tissue formation and impairing muscle regeneration. Here, we review the current evidence implicating HDACs as a key driver in DMD disease development and progression. We describe the mechanism of HDAC overactivity and the downstream consequences that contribute to the pathogenesis of the disease by disrupting muscle repair and regeneration. Finally, we highlight HDACs as targets for inhibition, offering a novel therapeutic strategy to counteract the multiple pathological events in DMD.
    DOI:  https://doi.org/10.1186/s13148-025-02031-7
  20. Biochem Pharmacol. 2025 Dec 02. pii: S0006-2952(25)00854-8. [Epub ahead of print] 117589
    Dual role of Macrophages in skeletal muscle Atrophy: Mechanisms and therapeutic strategies.
    Tongxin Shang, Hongyi Xu, Xinlei Yao, Zihao Zhao, Xinxin Niu, Yuntian Shen, Bingqian Chen, Hualin Sun.
      Skeletal muscle atrophy represents a pathological condition characterized by impaired protein homeostasis that commonly occurs with aging, chronic inflammatory diseases, physical inactivity, and neuromuscular disorders. This condition significantly reduces patients' quality of life and increases mortality risk. Emerging research highlights the immune system, especially macrophages, as key regulators of this process. As core components of innate immunity, macrophages exhibit high plasticity and orchestrate muscle repair and the regulation of chronic inflammation through polarized pro-inflammatory (M1) and anti-inflammatory/reparative (M2) phenotypes. This review systematically examines the dual role of macrophages in muscle pathology. On one hand, they facilitate muscle regeneration by removing necrotic tissue and secreting growth factors like Insulin-like Growth Factor 1 (IGF-1) and Interleukin-10 (IL-10) to promote satellite cell activation. On the other hand, improper macrophage activation or polarization shifts toward sustained M1 dominance can release harmful cytokines such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6), activating Nuclear Factor-kappa B (NF-κB) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways that increase protein breakdown, inhibit muscle formation, and accelerate atrophy. Additionally, we evaluate macrophage-focused treatments including drug inhibitors, stem cell therapies, plant compounds that modify polarization, and genetic approaches to rebalance immune function and reduce muscle wasting. Collectively, these advances provide novel mechanistic insights into immune-mediated skeletal muscle pathology and lay the groundwork for a translational framework for targeted interventions.
    Keywords:  Inflammatory Response; Macrophages; Muscle Regeneration; Skeletal Muscle Atrophy; Therapeutic Strategies
    DOI:  https://doi.org/10.1016/j.bcp.2025.117589
  21. J Vet Med Sci. 2025 Dec 02.
    Beta-nicotinamide mononucleotide attenuates creatine kinase release in Duchenne muscular dystrophy model rats.
    Katsuyuki Nakamura, Masanobu Kanou, Sara Ito, Toshie Jimbo, Karina Kouzaki, Koichi Nakazato, Ryota Nakamjima, Keitaro Yamanouchi, Hiroshi Ueda, Kei Yamana.
      Beta-nicotinamide mononucleotide (beta-NMN) is a direct precursor of nicotinamide adenine dinucleotide (NAD+), a coenzyme essential for maintaining homeostasis in living organisms. NMN administration has attracted attention as a potential treatment for aging and age-related conditions, including diabetes, Alzheimer's disease, and chronic kidney disease. Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscle disease caused by X-linked frameshift mutations in the Dmd gene. NAD+ levels in skeletal muscle decline in DMD pathology. In this study, we explored the therapeutic potential of NMN as an NAD+ booster for muscular dystrophy by administering NMN to DMD rats, which exhibit severe phenotypes comparable to those of human DMD patients, for 2 months. Although NMN administration did not improve muscle function in DMD rats, it did reduce the release of creatine kinase in their blood. RNA-seq analysis revealed that NMN administration could reverse DMD-related gene expression changes associated with skeletal muscle homeostasis. These results suggest that NMN can protect skeletal muscle against degeneration in DMD and may hold therapeutic potential for DMD patients.
    Keywords:  Duchenne muscular dystrophy; nicotinamide adenine dinucleotide (NAD+); nicotinamide mononucleotide (NMN); rat model; skeletal muscle
    DOI:  https://doi.org/10.1292/jvms.25-0258
  22. PLoS One. 2025 ;20(12): e0327701
    Control of quiescence and activation of human muscle stem cells by cytokines.
    Katharine Striedinger, Emilie Barruet, Elena Atamaniauc, Karla Linquist, Chris Knott, Andrew Brack, Jason H Pomerantz.
      Skeletal muscle homeostasis and repair depend on the activation of tissue resident stem cells called satellite cells. To understand the early molecular basis of human satellite cell activation, epigenomics, transcriptomics and protein analysis were performed in quiescent and experimentally activated human satellite cells. Cytokine signaling pathways were enriched in activated human satellite cells revealing high cytokine enrichment, including CCL2, CCL20, CXCL8, IL-6, TNFRSF12A, ILR1, CSF-1 and FGF2. Functional roles of these observed changes are supported by in vivo experiments showing that chemokine inhibitors increase engraftment and regeneration capacity of human satellite cells xenotransplants. Cytokines, chemokines and associated signaling pathways in the early stages of human satellite cell activation may underlie disparate muscle responses in neuromuscular inflammatory and degenerative disorders and consequently are potential entry points for clinical applications towards muscle repair.
    DOI:  https://doi.org/10.1371/journal.pone.0327701
  23. Nat Metab. 2025 Dec 03.
    Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
    Ignacio Ramírez-Pardo, Silvia Campanario, Bhakti Chavda, Olaya Santiago-Fernández, Marta Flández, Mercedes Grima-Terrén, Andrés Cisneros, Aina Calls-Cobos, Daniel N Itzhak, Bryan Ngo, Sudha Janaki-Raman, Edward D Kantz, Laura Ortet, Antonio Diaz, Kristen Lindenau, Julio Doménech-Fernández, Mari Carmen Gómez-Cabrera, Emilio Camafeita, Jesús Vázquez, Marta Martinez-Vicente, Antonio L Serrano, Eusebio Perdiguero, Joan Isern, Ana Maria Cuervo, Pura Muñoz-Cánoves.
      Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.
    DOI:  https://doi.org/10.1038/s42255-025-01411-w
  24. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70144
    Decorin Deficiency Promotes D-Galactose-Induced Skeletal Muscle Atrophy and Fibrosis by Regulating ITGB1/Akt/mTOR Signalling Pathway.
    Xiaoqin Luo, Mengxue Zhang, Lili Chen, Ruichang Wang, Jiabing Lian, Zhe Yang, Renato V Lozzo, Jin Wang, Yan Zhang, Xiuli Bi.
       BACKGROUND: Primary sarcopenia is an age-associated disorder with progressive and generalised loss of skeletal muscle strength and mass. Skeletal muscle fibrosis is one of the significant pathological manifestations of age-associated sarcopenia. Decorin, a small dermatan-sulfate proteoglycan, participates in extracellular matrix assembly. In numerous studies, the involvement of decorin is not restricted to matrix structural proteins, and it also affects a diverse variety of biological functions like cell growth, adhesion, migration, proliferation and differentiation. Additionally, it modulates the process of inflammation and fibrillogenesis. Based on these preclinical evidences, we hypothesised that decorin may potentially play an important role in skeletal muscles during ageing.
    METHODS: Natural ageing mice (Dcn+/+), D-galactose (D-gal)-induced Dcn+/+, Dcn-/- mice and NOR-10 cell models were established. Grip strength and exercise capacity were evaluated, after the mice were sacrificed to collect their gastrocnemius muscles for assessment of atrophy and fibrosis by haematoxylin and eosin staining, qRT-PCR and Western blotting. Co-immunoprecipitation was used to identify the interaction between decorin and integrin β1 (ITGB1).
    RESULTS: The expression levels of decorin were reduced at both mRNA and protein levels in muscle during natural ageing in mice (-75.3% of mRNA level; -29.5% of protein level) and NOR-10 cells (-78% of protein level). si-Dcn promoted the expression of α-SMA (+37.2%) and fibronectin (+53.1%), which are related to muscle fibrosis in D-gal-induced NOR-10 cells. In addition, in Dcn-/--D-gal mice, which exhibited more aggravated muscle atrophy including smaller grip strength (-21.7%, p < 0.001), downregulation of the ratio of gastrocnemius weight (-7.3%), fibre size (Gast: -15.3%) and increased levels of α-SMA (+70.2%), MuRF-1 (+30.2%), NLRP3(+19.4%) and p21(+27.2%) proteins compared with Dcn+/+-D-gal mice. In terms of the underlying mechanisms, the Akt/mTOR signalling pathway was downregulated in Dcn-/--D-gal mice compared with aged Dcn+/+-D-gal mice (p-S473-Akt/Akt: -38.1%; p-Ser2448-mTOR/mTOR: -28.8%; p-p70S6K/p70: -40.3%; p-4E-BP1: -42.3%, p < 0.05). Decorin activation enhanced ITGB1 expression (+46.7% vs. NC, p < 0.01). si-ITGB1 suppressed the expression of p-S473-Akt and p-Ser2448-mTOR in NOR-10 cells with Dcn overexpression. The interaction between decorin and ITGB1 was found in skeletal muscle, suggesting that the regulation of decorin on Akt/mTOR might depend on ITGB1. Notably, decorin deficiency increased the accumulation of p62 (+47.2%, p < 0.05) and LC3b (+50.9%, p < 0.01).
    CONCLUSIONS: The comprehensive results show that decorin plays a sarcoprotective role by activating the ITGB1/Akt/mTOR pathway and may serve as a potential therapeutic reagent in age-associated sarcopenia.
    Keywords:  Akt/mTOR; decorin; fibrosis; sarcopenia; skeletal muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.70144
  25. Front Physiol. 2025 ;16 1717233
    The role of cell death in the physiological and pathological processes of skeletal muscle.
    Hongyi Xu, Zihui Gao, Xinlei Yao, Jiacheng Sun, Bingqian Chen.
      Skeletal muscle is the largest metabolic and motor organ in the human body. It facilitates daily movement and maintains posture through contraction. It also acts as a core tissue for energy metabolism by participating in glucose uptake, lipid oxidation, and thermogenesis. Thus, it plays a vital role in regulating systemic metabolic homeostasis. Under physiological conditions, skeletal muscle maintains a dynamic regulatory network to coordinate multiple cellular processes for tissue homeostasis. Apoptosis selectively removes damaged myonuclei and maintains myofiber structural integrity. Necroptosis prevents excessive inflammatory responses. Autophagy degrades abnormal proteins and organelles to ensure cytoplasmic quality control. Additionally, pyroptosis supports immune surveillance. In pathological states, abnormal activation of cell death programs occurs. These include apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis. Such dysregulation can lead to myonuclear loss, myofiber atrophy, and fibrosis. While previous reviews have often focused on individual cell death pathways, this review provides a novel, integrated perspective by systematically outlining the roles and regulatory mechanisms of multiple death modalities in skeletal muscle. The interactions and balances among these pathways collectively determine muscle fate. We further discuss the implications of this network across various pathological contexts, such as muscular dystrophy, sarcopenia, and sepsis-induced atrophy. Finally, we identify promising therapeutic targets arising from this integrated view and discuss the challenges and future directions for translating these findings into clinical strategies. This review provides a comprehensive theoretical foundation for understanding the pathogenesis and treatment of skeletal muscle-related diseases.
    Keywords:  apoptosis; autophagy; cuproptosis; ferroptosis; necrosis; pyroptosis; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2025.1717233
  26. Am J Physiol Cell Physiol. 2025 Dec 05.
    Effects of acidosis and inorganic phosphate on Ca2+ sensitivity of young and older adult skeletal muscle fibers.
    Laura E Teigen, Carlos S Zepeda, Isabell Dobrzycki, Sandra K Hunter, Robert H Fitts, Christopher W Sundberg.
      The cellular mechanisms for the age-related loss in skeletal muscle contractile function and increased fatigability are unresolved. We previously observed that the depressive effects of fatiguing levels of hydrogen (H+)(pH6.8-6.6-6.2) and inorganic phosphate (Pi)(12-20-30mM) did not differ in myofibers from young compared with older adults. However, these studies used saturating Ca2+, when fatigue during high-intensity contractions in vivo also likely involves a decrease in myoplasmic free Ca2+. Thus, we compared the Ca2+ sensitivity of myofibers from 10 young (22.1±3.6; 5women) and 13 older (71.7±5.5; 7women) adults in conditions mimicking quiescent (pH7+4mM Pi) and fatigued (pH6.2+30mM Pi) muscle. Fast fiber cross-sectional area was ~35% smaller in older (4,859±2,116μm2) compared with young (7,446±2,399μm2, P=0.002), which corresponded with lower maximal absolute force (Po) in both quiescent (old=0.75±0.30mN; young=1.13±0.32 mN, P=0.002) and fatigue conditions (old=0.35±0.14mN; young=0.52±0.16mN, P=0.002). There were no differences in fast fiber size-specific Po, indicating the age-related decline in force was due to differences in fiber size. Elevated H+ and Pi shifted the force-pCa relationship to the right, confirming non-human studies that these metabolites contribute to fatigue by depressing the sensitivity of the myofilaments to Ca2+. However, Ca2+ sensitivity was not different with age or sex in either condition, and the metabolite-induced shift in the force-pCa relationship did not differ with age in either the slow (P=0.507) or fast (P=0.115) fibers. These data suggest the age-related increase in fatigability of limb muscles cannot be explained by an increased sensitivity of the myofibers to elevated H+ and Pi in maximal or submaximal Ca2+.
    Keywords:  aging; calcium; fatigue; metabolites; skeletal muscle fibers
    DOI:  https://doi.org/10.1152/ajpcell.00445.2025
  27. bioRxiv. 2025 Nov 22. pii: 2025.09.10.674099. [Epub ahead of print]
    TAS1R3 regulates GTPase signaling in human skeletal muscle cells for glucose uptake.
    Joseph M Hoolachan, Rekha Balakrishnan, Karla E Merz, Debbie C Thurmond, Rajakrishnan Veluthakal.
       Background: Taste receptor type 1 member 3 (TAS1R3) is a class C G protein-coupled receptor (GPCR) traditionally associated with taste perception. While its role in insulin secretion is established, its contribution to skeletal muscle glucose uptake a process responsible for 70-80% of postprandial glucose disposal remains unclear.
    Methods: TAS1R3 expression was assessed in skeletal muscle biopsies from non-diabetic and type 2 diabetes (T2D) donors using qPCR and immunoblotting. Functional studies in human LHCN-M2 myotubes involved TAS1R3 inhibition with lactisole or siRNA-mediated knockdown, followed by measurement of insulin-stimulated glucose uptake using radiolabeled glucose assays. Rac1 activation and phospho-cofilin were analyzed by G-LISA and Western blotting, and Galphaq/11 involvement was tested using YM-254890.
    Results: TAS1R3 mRNA and protein levels were significantly reduced in T2D skeletal muscle. Pharmacological inhibition or knockdown of TAS1R3 impaired insulin-stimulated glucose uptake in myotubes.
    Conclusion: TAS1R3 regulates skeletal muscle glucose uptake through a non-canonical insulin signaling pathway involving Rac1 and phospho-cofilin, independent of IRS1-AKT and Galphaq/11 signaling. These findings identify TAS1R3 as a key determinant of Rac1-mediated glucose uptake and a potential therapeutic target for improving insulin sensitivity in T2D.
    DOI:  https://doi.org/10.1101/2025.09.10.674099
  28. MedComm (2020). 2025 Dec;6(12): e70508
    Negative Impact of p21-Activated Kinase 4-Mediated AMP-Activated Protein Kinase Inhibition on Sarcopenia in Mice and Humans.
    Jiacheng Du, Hwang Chan Yu, Young Jae Moon, Sun-Jung Yoon, Seung-Yong Seo, Byung-Hyun Park, Eun Ju Bae.
      We recently identified that AMP-activated protein kinase (AMPK) α2 phosphorylation at S491 is mediated by p21-activated kinase 4 (PAK4), leading to muscular and systemic insulin resistance. This study examined how muscle PAK4 deletion affects atrophy in male mice and its link to human sarcopenia. Dexamethasone treatment increased the mRNA and protein levels of PAK4, which was partially the result of glucocorticoid response elements activation in the promoter of the Pak4 gene. Muscle-specific Pak4 knockout mice were protected from both dexamethasone- and denervation-induced muscle atrophy. Likewise, treatment with a proteolysis-targeting chimera (PROTAC) targeting PAK4 also mitigated muscle atrophy. PAK4 inhibition alleviated mitochondrial dysfunction and enhanced the expression of biogenesis-related genes via AMPK activation with reduced AMPKα2-S491 phosphorylation. Notably, muscle overexpression of phospho-deficient AMPKα2S491A mutant preserved mass in dexamethasone-treated mice, whereas constitutively phosphorylated AMPKα2S491D mutant abolished PAK4 PROTAC's antiatrophy effect. In humans, sarcopenic muscle exhibited higher levels of PAK4 protein and AMPKα2-S491 phosphorylation compared with non-sarcopenia controls, with an inverse correlation to sarcopenic index and grip strength. These findings reveal a novel AMPK phosphorylation-dependent mechanism by which PAK4 regulates mitochondrial function and muscle mass, offering new therapeutic avenues for combating muscle atrophy in chronic disease and aging. Clinical trial registration: Not applicable.
    Keywords:  AMPK; mitochondria; muscle atrophy; p21‐activated kinase 4; proteolysis‐targeting chimera
    DOI:  https://doi.org/10.1002/mco2.70508
  29. J Appl Physiol (1985). 2025 Dec 01.
    Dystrophin-deficiency stiffens skeletal muscle and impairs elasticity: an in vivo rheological examination.
    Pavithran Devananthan, Rebecca Craven, Kellie Joe, Gretel S Major, Jiayi Chen, Natalia Kabaliuk, Angus Lindsay.
      Loss of dystrophin alters the biomechanical properties of skeletal muscle, including stiffness. Stiffness is typically assessed passively in excised muscle, but here we present the development of an in vivo rheological method to assess the mechanical properties of the tibialis anterior muscle in anaesthetised wild-type (WT; dystrophin-positive) and mdx (dystrophin-deficient) mice using a custom-designed apparatus compatible with an MCR 702 rheometer. To characterise stiffness, compressibility, and elasticity, rheological testing included compressive and shear strain protocols, along with recovery and assessments following contraction-induced strength loss. Relative to WT mice, the tibialis anterior of mdx mice were thicker, stiffer, and less compressible. These genotype differences aligned with hydroxyproline content, a marker of fibrosis. Post-deformation recovery was impaired in mdx mice under shear strain, and eccentric contraction-induced injury further increased stiffness and energy dissipation in the tibialis anterior of mdx mice. This rheological platform maintained the in vivo integrity of the tibialis anterior muscle of mice and consistently showed that storage and loss moduli can sensitively detect the detrimental impact of dystrophin-deficiency on the in vivo viscoelastic properties of skeletal muscle. This rheological platform, termed myomechanical profiling could be a viable and sensitive tool for assessing muscle quality and mechanical behaviour of skeletal muscle where viscoelastic properties are affected by disease.
    Keywords:  Duchenne muscular dystrophy; fibrosis; muscle mechanics; rheology; viscoelasticity
    DOI:  https://doi.org/10.1152/japplphysiol.00492.2025
  30. Front Nutr. 2025 ;12 1701520
    Skeletal muscle memory: implications for sports, aging and nutrition.
    Íñigo M Pérez-Castillo, Sergio R Ruiz-Caride, Ricardo Rueda, José López-Chicharro, Felipe Segura-Ortiz, Hakim Bouzamondo.
      Observations of an enhanced hypertrophic response in previously trained muscles following periods of detraining have led researchers to propose that muscle tissue retains a form of "cellular memory", even after returning to baseline muscle mass. Recent advances in research methodologies have enabled deeper investigation into the underlying mechanisms, with myonuclear permanence emerging as a potential candidate. While intracellular signaling pathways that mediate anabolic stimuli and promote translational efficiency have been extensively studied, the role of transcriptional output, governed by the number of myonuclei, remains comparatively underexplored. A solid body of evidence in humans supports the need for satellite cell-mediated myonuclear accretion to achieve muscle growth that exceeds the transcriptional limits of existing myonuclei. However, it remains unclear whether accrued myonuclei persist indefinitely or are eventually removed, and the mechanisms governing their potential removal remain speculative. Notably, aging populations may not only exhibit diminished capacity to recruit satellite cells but also potentially reduced ability to retain myonuclei, which may be linked to age-related muscle wasting. Training exercise combined with nutritional strategies leveraged by athletes, including protein/amino acid intake, polyphenol-rich ingredients, and different ergogenic compounds such as creatine, might be beneficial to promote satellite cell responses and myonuclear accretion in situations where muscle mass regain and maintenance are purposed, such as injury recovery and aging.
    Keywords:  aging; athlete; detraining; hypertrophy; myonuclei; nutrition; retraining; satellite cells
    DOI:  https://doi.org/10.3389/fnut.2025.1701520
  31. J Inflamm Res. 2025 ;18 16729-16746
    Aging-Associated CD55⁺ Fibroblasts Promote Chronic Inflammation and ECM Dysregulation in Sarcopenia.
    Xianfei Xie, Jiawen Zhao, Tong Wu, Yi Yang, Yuan Zong, Lei Li, Yiming Gao, Liting Jiang, Yuelong Cao, Linhui Shen.
       Background: Sarcopenia, defined as the progressive loss of muscle mass and function with aging, is a major contributor to frailty and disability in the elderly. Fibroblasts, traditionally considered passive extracellular matrix (ECM) producers, are increasingly recognized for their active roles in inflammation, fibrosis, and immune modulation. However, the heterogeneity and specific functions of fibroblast subtypes in sarcopenic muscle remain poorly understood.
    Methods: We employed an integrative multi-omics and multi-modal approach combining single-nucleus RNA sequencing (snRNA-seq), untargeted metabolomics, and histological analyses to systematically characterize fibroblast populations in human skeletal muscle.
    Results: Several distinct fibroblast subtypes were identified, among which a CD55⁺ fibroblast subpopulation (FB_4) emerged as a major contributor to the pro-inflammatory and fibrotic microenvironment of aged and sarcopenic muscle. FB_4 demonstrated activation of NF-κB signaling, glycolytic metabolism, and oxidative stress pathways. Histological validation confirmed increased expression of inflammatory and fibrotic markers such as TGF-β1 and TLR4. Moreover, FB_4 activity correlated with senescence-associated secretory phenotype (SASP) expression and enhanced immune cell infiltration.
    Conclusion: Our findings reveal CD55⁺ FB_4 as a critical driver of chronic inflammation and ECM remodeling in aging muscle. Targeting fibroblast-mediated inflammation and fibrosis may represent a promising therapeutic strategy for sarcopenia. The integration of transcriptomic, metabolic, and histological data provides new insights into fibroblast heterogeneity and offers a framework for future interventions in age-related muscle degeneration.
    Keywords:  extracellular matrix remodeling; fibroblast heterogeneity; senescence-associated secretory phenotype; skeletal muscle aging
    DOI:  https://doi.org/10.2147/JIR.S542613
  32. Commun Biol. 2025 Dec 04. 8(1): 1746
    Irisin regulates the phosphorylation of glucocorticoid receptor Ser212 and Ser234 and mediates glucocorticoid-induced muscle atrophy in mice.
    Jingjing Yang, Pu Zhang, Yina An, Shuyu Tan, Siqi Sun, Yifan Liu, Lin Zhu, Haidong Wang, Ting Gao, Yanjun Dong.
      Glucocorticoid-induced skeletal muscle atrophy severely limits the clinical use of glucocorticoids and occurs in various endocrine and metabolic diseases. However, a detailed understanding of how glucocorticoid receptor (GR) transcriptional responses contribute to muscle atrophy is lacking. Irisin is a myokine induced by exercise and has been shown to exert multiple beneficial effects on muscle mass and metabolism regulation. Here, we show that glucocorticoid genomic effects are the main pathway through which glucocorticoids induce muscle atrophy in mice. Increased GR Ser212 and Ser234 site phosphorylation reduces glucocorticoid-induced muscle atrophy in mice. Irisin ameliorates high-fat diet (HFD) and dexamethasone (Dex)-induced muscle atrophy. Mechanistically, this effect depends on irisin promoting the phosphorylation of ERK and JNK through integrin αVβ5 receptors, which in turn impairs the dephosphorylation of GR Ser212 and Ser234 sites, affecting the GCs genomic effect on the transcription of muscle atrophy-related genes. These findings highlight the genomic effects of GCs as an intervention target to ameliorate GC-induced muscle atrophy and suggest that irisin could be a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s42003-025-09203-4
  33. Front Physiol. 2025 ;16 1686942
    Chronic circadian misalignment accelerates sarcopenia progression in mice.
    Takashi Seya, Nobuya Koike, Naoki Okubo, Yasuhiro Umemura, Yoshiki Tsuchiya, Kazuya Yabumoto, Yasuhiro Endo, Kanako Iinuma, Akiyo Kakibuchi, Akira Sugimoto, Kenji Takahashi, Seung-Hee Yoo, Zheng Chen, Kazuhiro Yagita.
       Introduction: In today's 24/7 society, circadian misalignment caused by environmental and lifestyle factors is associated with various adverse health consequences. Understanding tissue-specific pathology is required to counter this growing public health challenge. A potential association of environmental circadian misalignment with sarcopenia, or accelerated loss of skeletal muscle strength and mass, is poorly documented.
    Methods: 14-week-old wild-type C57BL/6J male mice were exposed to a chronic jet lag (CJL) paradigm consisting of an 8-h phase advance every 4 days (the ADV group) or a fixed light-dark cycle (the LD group) for 64 weeks. Grip strength was measured during the experiment, and hindlimb muscle weight was assessed after the 64-week CJL. In addition, transcriptomic and histological analysis of the hindlimb muscles were performed in all animals.
    Results: ADV mice exhibited significant reductions in grip strength and muscle weight relative to LD mice. Transcriptomic and histological analyses showed activation of TWEAK/Fn14 signaling and reduced myofiber cross-sectional area, hallmark features of sarcopenia, in the ADV group. Somewhat surprisingly, ADV mice showed increased centrally nucleated fibers, myosin heavy chain co-expressing fibers, and myogenic gene expression, suggesting that compensatory muscle regeneration and remodeling processes are activated but remain insufficient to counter muscle atrophy.
    Conclusion: These findings demonstrate that circadian misalignment is a potential risk factor for sarcopenia, underscoring circadian rhythms as a key regulator and actionable target for sarcopenia prevention.
    Keywords:  TWEAK/Fn14 signaling; circadian misalignment; circadian rhythm; frailty; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2025.1686942
  34. Am J Physiol Cell Physiol. 2025 Dec 05.
    Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.
    Angad Yadav, Susan Schmitt, Wenxia Ma, James A Mobley, Anna Elizabeth Thalacker-Mercer.
      Extracellular glutamine (Gln) is essential for muscle progenitor cell (MPC) function and skeletal muscle regeneration / development, especially under physiological stress like aging or catabolic conditions. Gln availability regulates MPC proliferation by modulating intracellular metabolic and epigenetic states. Gln deficiency reduces cell viability, induces G0/G1 cell cycle arrest, and downregulates MyoD expression, collectively inhibiting myogenesis in human primary myoblasts (HSMM) and mouse C2C12 cells. Mechanistically, Gln deficiency enhances nuclear localization of TCA cycle enzyme, KGDHC, components (i.e., DLST and OGDH), elevates histone succinylation, and reduces chromatin accessibility at the myogenic regulatory regions (MyoD1 locus). These changes establish a direct link between Gln availability and an epigenetic-metabolic axis crucial for myogenic gene regulation. Thus, extracellular Gln acts as a key regulator of MPC proliferation through metabolic mediated control of chromatin state.
    Keywords:  Chromatin accessibility; Glutamine metabolism; Succinylation; TCA cycle compartmentalization; myogenesis
    DOI:  https://doi.org/10.1152/ajpcell.00568.2025
  35. Genesis. 2025 Dec;63(6): e70035
    Transcriptomic Analysis of Skeletal Muscle Systems Comparing Bovines, Humans, and Mice Using scRNA-Seq.
    Cuicui Cai, Xueyao Yang, Hui Wang, Xin Cai, Jiabo Wang, Jikun Wang, Haibo Wang, Ming Zhang, Zhijuan Wu, Jiangjiang Zhu, Jincheng Zhong, Fengwei Zhang, Peng Wan, Binglin Yue.
      Skeletal muscle is the most widespread tissue in mammals and mediates several functions, and whose development is controlled by a coordinated transcriptional hierarchy that regulates the activities of a range of muscle genes. Skeletal muscle comprises various cells that create communication strategies for exchanging biological information. Nevertheless, the features and developmental programs of several of these cell lines remain unknown. We constructed a complete single-cell landscape of prenatal to postnatal developing bovine skeletal muscle and compared its single-cell transcriptomic characteristics with those of humans and mice. This landscape involved cellular heterogeneity, dynamic gene expression profiles, critical regulons during cell fate decisions, extensive networks of intercellular communication, and a gene regulation network. Overall, our results identify a developmental coordinate of the pluripotency spectrum among bovines, humans, and mice. This finding suggests evolutionary conservation and species-specific differences in the skeletal muscle systems, extending to cell types, gene expression, and regulatory elements. These results offer insights into evolutionary conserved and divergent processes during mammalian skeletal muscle development.
    Keywords:  bovine; comparative transcriptomic analysis; human; mouse; scRNA‐seq; skeletal muscle
    DOI:  https://doi.org/10.1002/dvg.70035
  36. Skelet Muscle. 2025 Dec 05.
    The metabolic role of corticotropin-releasing hormone receptor 2 and its UCN peptides: emerging therapeutic potential.
    Pablo Vidal, Natalie Janzen, Joseph T Brozinick.
      Skeletal muscle is a highly plastic tissue that plays a crucial role in overall metabolic health, and in diseases such as obesity and type 2 diabetes. Recently, the importance of preserving muscle mass during weight loss has gained appreciation, especially with significant weight loss observed from incretin therapies, which includes loss of both fat and lean mass (Conte et al, JAMA 332:9-10, 2024). This has prompted investigation into pharmacological candidates that can prevent the loss of muscle mass seen during weight loss. Urocortins and their cognate receptors pose an interesting target, as recent evidence shows that they play a role in diseases such as heart failure, diabetes, and obesity. Urocortin treatment results in decreased food intake, muscle hypertrophy and improved skeletal muscle glucose uptake. However, the molecular mechanisms by which urocortins act have yet to be elucidated. The aim of this review is to highlight our current understanding of the effects of urocortins on metabolic adaptations.
    Keywords:  CRHR2; Glucose regulation; Muscle hypertrophy; Skeletal muscle; Urocortin
    DOI:  https://doi.org/10.1186/s13395-025-00405-2
  37. Nat Commun. 2025 Dec 01.
    Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
    J Botella, E Perri, N J Caruana, S López-Calcerrada, M Brischigliaro, N A Jamnick, V Oorschot, N J Saner, J Díaz-Lara, D F Taylor, A Garnham, E Fernández-Vizarra, C Ugalde, G Ramm, D A Stroud, M Lazarou, D J Bishop.
      Exercise is a key lifestyle intervention for mitochondrial health, yet the molecular mechanisms by which different exercise prescriptions regulate mitochondrial remodeling remain unclear. We conducted an open-label counterbalanced randomized controlled trial (ACTRN12617001105336) and observed that sprint-interval exercise (SIE; n = 14), compared to moderate-intensity continuous exercise (MICE; n = 14), induces a mitochondrial stress signature and unfolded protein response (UPRmt). SIE triggers morphological and structural mitochondrial alterations along with activation of the integrated stress response (ISR) and mitochondrial quality control (MQC) pathways. Following eight weeks of training, moderate-intensity continuous training (MICT) increases mitochondrial content, complex I activity, and displays an enrichment of tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) proteins, while sprint-interval training (SIT) improves respiratory function and upregulates pathways involved in 1-carbon metabolism and protein quality control. We identify COX7A2L accumulating in III2 + IV1 supercomplexes only after SIT. These findings elucidate how exercise intensity shapes mitochondrial remodeling, informing tailored exercise prescriptions.
    DOI:  https://doi.org/10.1038/s41467-025-66625-8
  38. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2508707122
    Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle-tumor metabolic competition.
    Brooks P Leitner, Andin E Fosam, Won D Lee, Kaylee Zilinger, Susana C B R Nakandakari, Xinyi Zhang, Rafael C Gaspar, Wanling Zhu, Curtis J Perry, Joshua D Rabinowitz, Rachel J Perry.
      Higher exercise capacity and regular exercise training improve cancer prognosis at all stages of disease. However, the metabolic adaptations to aerobic exercise training that mediate tumor-host interactions are poorly understood. Here, we demonstrate that voluntary wheel running slows tumor growth and repartitions glucose uptake and oxidation to skeletal and cardiac muscle and away from breast and melanoma tumors in mice. Further, prehabilitation induces repartitioning of glucose metabolism in obese mice: Uptake and oxidation of glucose are enhanced in skeletal and cardiac muscle, and reduced in tumors. These increases in muscle glucose metabolism and reductions in tumor glucose metabolism, correlated with slower tumor progression. Using [U-13C6] glucose infusion, we show that exercise increases the fractional contribution of glucose to oxidative metabolism in muscle while reducing it in tumors, suggesting that aerobic exercise shifts systemic glucose metabolism away from the tumor microenvironment and toward metabolically active tissues. Transcriptional analysis revealed downregulation of mTOR signaling in tumors from exercised mice. Collectively, our findings suggest that voluntary exercise may suppress tumor progression by enhancing host tissue glucose oxidation and limiting tumor glucose availability, supporting a model in which exercise-induced metabolic competition constrains tumor energetics.
    Keywords:  breast cancer; exercise; melanoma; tumor metabolism
    DOI:  https://doi.org/10.1073/pnas.2508707122
  39. Nat Protoc. 2025 Dec 01.
    Assaying the myosin super-relaxed state across muscle types, cells and proteins for understanding muscle biology and use in drug discovery.
    Samuel T M Jones, Flair E Paradine Cullup, Sampath K Gollapudi, Elise G Melhedegaard, Violetta Steeples, Manuel Schmid, Yiangos Psaras, Paul Robinson, Alexandra Pena, David Y Barefield, Julien Ochala, Suman Nag, Christopher N Toepfer.
      The myosin super-relaxed (SRX) state is a biochemical and structural conformation of myosin that modulates contractility and energy expenditure and is in equilibrium with the disordered relaxed (DRX) state of myosin, which can hydrolyze ATP to produce force. The proportion of myosin SRX-DRX states is perturbed in various muscle disorders, and myosin SRX-DRX states have become a promising drug target. There are many approaches that can be used to interrogate myosin conformations, including X-ray diffraction, stopped-flow kinetics and electron microscopy. These techniques are highly informative but necessitate highly skilled researchers and specialist equipment, limiting wider uptake and accessibility. For this reason, we provide a set of protocols detailing established assays to measure biochemically defined myosin SRX-DRX states in skeletal muscle, cardiac muscle, induced pluripotent stem cell-derived cardiomyocytes, myofibrils, reconstituted thick filaments and isolated molecular motors by using a simple chase assay incorporating a fluorescent ATP analogue: methylanthraniloyl (Mant)-ATP. The Mant-ATP assay provides a biochemical measure of myosin states that is distinct from assays that are used to visualize myosin structure directly. These Mant-ATP assays have various protocol lengths, ranging from 1-2 d for preparation and 30 min to run an experiment. With this set of protocols, we make the Mant-ATP assay accessible to those working in biochemistry, muscle physiology and cell biology. At the end of this protocol, users should be able to ascertain a clean fluorescent decay trace that can be fit to define the ratio of SRX/DRX myosin in their sample of choice.
    DOI:  https://doi.org/10.1038/s41596-025-01291-0
  40. Neurosci Biobehav Rev. 2025 Nov 29. pii: S0149-7634(25)00502-0. [Epub ahead of print]180 106501
    Postmenopausal sarcopenia and Alzheimer's disease: The interplay of mitochondria, insulin resistance, and myokines.
    Fardous Farhana, Most Arifa Sultana, Raksa Andalib Hia, Vijay Hegde.
      As life expectancy increases, cognitive impairments such as Alzheimer's disease (AD) create serious problems for older adults. Women regardless of ethnicity and age group, are disproportionately affected, accounting for two-thirds of AD cases, with post-menopausal women representing over 60 % of those affected. Sarcopenia, defined by gradual reduction of skeletal muscle mass, strength, and activities, is increasingly correlated with an elevated risk of cognitive decline in post-menopausal women. Menopause-related hormonal decline (particularly estrogen loss) and aging contribute to sarcopenia, characterized by muscle mitochondrial dysfunction, oxidative stress, and insulin resistance. This sarcopenia-driven reduction in muscle mass and functional capacity further reduces the production of myokines (e.g., BDNF, irisin), impairing neuronal proliferation, adult neurogenesis, and spatial learning/memory. These pathophysiological changes show a contributing link between sarcopenia and AD progression in post-menopausal women. This review is unique in that it discusses the triangular interplay between menopause, sarcopenia, and AD, offering an integrated mechanistic framework that links hormonal decline, muscle loss, and neurodegeneration. We aim to clarify the pathophysiological causes behind the muscle-brain axis and suggest viable treatment approaches to slow down sarcopenia and cognitive deterioration in postmenopausal women based on current evidence. The formulation of targeted strategies for enhancing the quality of life and lessening healthcare expenditures in this expanding population depends on the advancement of understanding this complex interconnection between menopause, sarcopenia and cognition.
    Keywords:  Alzheimer’s disease; Insulin resistance; Menopause; Mitochondrial dysfunction; Myokines; Oxidative stress; Sarcopenia
    DOI:  https://doi.org/10.1016/j.neubiorev.2025.106501
  41. Eur J Med Res. 2025 Dec 01. 30(1): 1197
    UQCR10 and TNNT1: novel biomarkers for sarcopenia identified through integrated transcriptomic analysis and machine learning.
    Wenhan Sun, Zhitao Shangguan, Jiandong Li, Xiaoqing Ye, Qiong Lin, Gang Chen.
       BACKGROUND: Sarcopenia, the age-related loss of muscle mass and function, significantly impacts health outcomes in older adults. Despite its prevalence, molecular diagnostics and targeted therapies remain limited due to incomplete understanding of its pathophysiology.
    METHODS: We analyzed the GSE226151 dataset comparing skeletal muscle transcriptomes from sarcopenic (n = 20) and healthy adults (n = 20) using differential expression analysis and weighted gene co-expression network analysis (WGCNA). Key genes were identified through the intersection of differentially expressed genes and hub genes. Machine learning feature selection (LASSO, XGBoost, and Random Forest) was employed to identify optimal biomarkers, followed by validation in an independent cohort (GSE111016, n = 40, 20 sarcopenia vs. 20 healthy controls). Comprehensive functional enrichment analysis was performed using Gene Ontology, KEGG, and Reactome databases. We employed fivefold cross-validation to account for modest sample size, with performance metrics reported with 95% confidence intervals obtained via bootstrapping (1000 iterations).
    RESULTS: Integration of differential expression analysis (97 DEGs) and WGCNA (269 hub genes from the darkolivegreen module) identified five key genes in sarcopenia: COX6C, ETFB, TNFAIP3, TNNT1, and UQCR10. Multi-method machine learning feature selection consistently ranked UQCR10 and TNNT1 as the most important biomarkers. A two-biomarker panel (UQCR10 + TNNT1) achieved superior performance with Random Forest modeling (AUC = 0.738 [95% CI 0.559-0.875], PRAUC = 0.643 [95% CI 0.405-0.832], sensitivity = 0.850, specificity = 0.600) in the validation cohort, substantially outperforming single-biomarker approaches. Three-group analysis (Healthy/Pre-sarcopenia/Sarcopenia) revealed continuous dose-response patterns: all five genes showed significant linear trends across disease progression (p < 0.005), with UQCR10 (mitochondrial) and TNNT1 (contractile) exhibiting strongest relationships (R2 = 0.281 and 0.192 respectively), suggesting continuous pathophysiological progression rather than discrete disease stages. Functional enrichment analysis revealed three major dysregulated biological processes: energy metabolism and mitochondrial function (UQCR10, COX6C, ETFB), muscle structure and contractile function (TNNT1), and inflammatory response regulation (TNFAIP3).
    CONCLUSIONS: Our integrated transcriptomic approach identified a promising two-biomarker panel (UQCR10 + TNNT1) for sarcopenia detection and elucidated key molecular mechanisms underlying the condition. While these findings are hypothesis-generating and require validation in larger, more diverse cohorts, they provide mechanistic insights and candidate biomarkers warranting further development. The identified genes and pathways offer potential targets for novel therapeutic interventions aimed at preserving muscle health during aging.
    Keywords:  Biomarkers; Machine learning; Mitochondrial dysfunction; Sarcopenia; TNNT1; Transcriptomics; UQCR10
    DOI:  https://doi.org/10.1186/s40001-025-03471-w
  42. Am J Physiol Cell Physiol. 2025 Dec 04.
    Eccentric overload training promotes serial sarcomerogenesis to a greater extent than conventional resistance training.
    Amelia Rilling, Avery Hinks, Alexandra Kirkup, Martino V Franchi, Geoffrey A Power.
      Eccentric exercise has been shown to increase serial sarcomere number (SSN) through sarcomerogenesis in both animal and human models. However, eccentric contractions rarely occur in isolation and are often used in conjunction with concentric movements, limiting the ability to evoke a maximal eccentric contraction. Eccentric overload training provides an increased eccentric stimulus, yet its impact on muscle morphology and mechanics is not widely understood. We compared the effects of eccentric overload training (ECCOVERLOAD) and conventional resistance training (CONV) on morphological (serial sarcomere number (SSN), fascicle length (FL), sarcomere length (SL), physiological cross-sectional area (PCSA), wet weight) and mechanical changes (torque, normalized torque, power, passive torque pre- to post-training. Nineteen Sprague-Dawley (n=10; ECCOVERLOAD, n=9; CONV) male and female rats (13-14 weeks, 317g) completed 4 weeks (3× week) of training. SSN increased with training by 17% in the soleus (p<0.001) and 6% in the medial gastrocnemius (p=0.021) in the ECCOVERLOAD group, compared to 2% and 4%, in the CONV group. Peak plantar flexion torque increased ~27% in the ECCOVERLOAD and ~21% in the CONV group (p<0.001) but did not differ between groups (p=0.318). There was a 26% increase in normalized torque for the ECCOVERLOAD, as compared to 2.5% in the CONV group at 90° demonstrating an interaction of training × group (p<0.001). Power increased ~9%, with an interaction of sex×training×group (p=0.021) driven by increases in torque at peak power in the ECCOVERLOAD male group. These findings indicate that overload training provided a more robust stimulus for longitudinal muscle remodelling than conventional resistance training.
    Keywords:  architecture; eccentric overload; fascicle; sarcomerogenesis; sex-differences
    DOI:  https://doi.org/10.1152/ajpcell.00713.2025
  43. Autophagy Rep. 2025 ;4(1): 2593060
    Autophagy cargo profiles in skeletal muscle during starvation and exercise.
    Mohd Farhan, Shangze Lyu, Trezze P Nguyen, Dakai Zhang, Hong Liang, Yong Zhou, Yu A An, Jun Wang, Hongyuan Yang, Guangwei Du, Yang Liu.
      Autophagy is a cellular process to clear unwanted and dysfunctional cellular cargoes, which are sequestered in autophagosomes before their delivery to lysosomes for degradation. Autophagy cargo selection, mediated by cargo receptors, varies across cell types and conditions. Understanding the cargo features is essential for elucidating autophagy's function in specific physiological or pathological contexts. Here, we present a simple and rapid method for isolating LC3B-positive autophagosomes from the tissues of GFP-LC3 transgenic mice, a widely used autophagy reporter model, without relying on the complex ultracentrifugation steps required by traditional methods. When combined with quantitative proteomics, this approach enables efficient in vivo characterization of autophagy cargoes. We applied this method to establish autophagy cargo profiles in skeletal muscle during starvation and exercise, two physiological conditions that activate autophagy, and identified distinct cargo selection patterns, with significantly higher levels of ER-phagy and ribophagy observed during starvation. We further revealed the ER-phagy receptors TEX264 and RETREG1/FAM134B as potential mediators of the elevated ER-phagy under starvation. In summary, we report an efficient workflow for in vivo autophagy cargo characterization and provide detailed analysis and comparison of cargo profiles under starvation and exercise conditions.
    Keywords:  Autophagy cargo; autophagosome isolation; exercise; selective autophagy; starvation
    DOI:  https://doi.org/10.1080/27694127.2025.2593060
  44. Front Public Health. 2025 ;13 1611571
    Trends and frontiers in disuse muscle atrophy research.
    Shenghui Wu, Yu Miao, Jiong Mei, Shengren Xiong.
       Background: To investigate the progress and status of the disuse muscle atrophy (DMA) and to highlight the current hot research areas.
    Materials and methods: A comprehensive literature search was conducted in the PubMed database, covering the period from 2010 to 2024. The R software (version 4.2.0) was used for the bibliometric analysis.
    Results: A total of 689 articles related to DMA have been published, demonstrating a consistent upward trend in research output. The University of Utah was identified as the most productive institution in this field, while the United States led in the number of publications. Notable authors, including Marlou L. Dirks and Benjamin T. Wall, were recognized as the most prolific contributors, significantly advancing the literature. Key journals such as the Journal of Applied Physiology, Journal of Cachexia, Sarcopenia and Muscle, and International Journal of Molecular Sciences were highlighted for their high citation metrics and considerable influence. Hot keywords, such as "oxidative stress," "aging," "exercise," "protein synthesis," "mitochondria," "inflammation," "Murf1," "soleus muscle," "Foxo3," "ROS," and "glucocorticoids," were the most frequently occurring terms. Additionally, most countries were actively engaged in extensive collaborative networks.
    Conclusion: This study highlighted an increasing emphasis on molecular mechanisms of DMA, such as oxidative stress, aging, protein synthesis, mitochondrial function, and inflammation. Murf1 and Foxo3 played crucial roles in the process of DMA. Both exercise and glucocorticoids were primary methods for enhancing muscle recovery. The soleus muscle was the primary focus in DMA studies. This study provided a valuable reference for guiding future research and optimizing potential intervention strategies for DMA.
    Keywords:  PubMed; R software; bibliometric analysis; disuse muscle atrophy; visuliasation
    DOI:  https://doi.org/10.3389/fpubh.2025.1611571
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