bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–11–30
53 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Loss of cell-autonomously secreted laminin-α2 drives muscle stem cell dysfunction in LAMA2-related muscular dystrophy.
  2. Displaced myonuclei are attributable to both resident myonuclear migration and stem cell fusion during mechanical loading in adult skeletal muscle.
  3. Effects of two longevity interventions, calorie restriction and rapamycin treatment, on the kynurenine-aryl hydrocarbon receptor pathway in aging skeletal muscle.
  4. Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging.
  5. Exercise enhances antioxidant protein levels in oxidative skeletal muscle via IL-1β.
  6. Dystrophic Skeletal Muscle Phenotypes Can Be Horizontally Transferred via Fecal Microbiome Transplantations.
  7. SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signalling.
  8. Physical Training Counteracts Mitochondrial Alterations in Myoblasts and Myotubes Derived From Muscle Satellite Cells of Old Mice: An In Vitro Ultrastructural Study.
  9. Load-induced human skeletal muscle hypertrophy: Mechanisms, myths, and misconceptions.
  10. Profiling muscle mass, function and molecular signalling in females aged 18-80 years and their associations with sex hormones.
  11. Lactate as a metabolic-epigenetic signal linking high-intensity interval training (HIIT) to miRNA-Centered remodeling of the skeletal muscle methylome and transcriptome.
  12. Inhibition of potassium chloride cotransporters impairs muscle contraction and induces atrophy in C2C12 myotubes.
  13. MitoQ supplementation does not impact redox responses to acute exercise in skeletal muscle of older individuals.
  14. Proteomics-based evaluation of AAV dystrophin gene therapy outcomes in mdx skeletal muscle.
  15. The Age-Dependent Resident Myonuclear Multi-Omic Response to a Skeletal Muscle Hypertrophic Stimulus.
  16. Multiple Defects in Muscle Regeneration in the HSALR Mouse Model of RNA Toxicity.
  17. Iron Deficiency Impairs Muscle Stem Cell Proliferation and Skeletal Muscle Regeneration via HIF-2α Stabilization.
  18. Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.
  19. Fiber Type and Stimulus Determine Progression of Skeletal Muscle Atrophy.
  20. C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.
  21. Comprehensive transcriptomic analysis identifies Lrg1 as a potential therapeutic target for preventing muscle atrophy in cancer cachexia.
  22. Calcitonin receptor downregulation and exercise-conditioned blood enable systemic muscle stem cell proliferation.
  23. Regulatory role of vitamin D3 on myogenesis and fibrogenesis under Vdr gene silencing and TGF-β1 stimulation in skeletal muscle cells.
  24. Cisplatin-Induced Skeletal Muscle Atrophy: Biomolecular Mechanisms and the Protective Role of Exercise-Induced Myokines.
  25. Neural Cues and Genomic Clues: NGS Insights into Neurogenic Sarcopenia and Muscle Atrophy.
  26. Deficient Cardiolipin Remodeling Alters Muscle Fiber Composition and Neuromuscular Connectivity in Barth Syndrome.
  27. NAMPT modulates muscle fiber type transition in PAD myopathy via the cGMP-PKG signaling pathway.
  28. Epigenetic aging signatures and age prediction in human skeletal muscle.
  29. Non-canonical roles of Keap1/Nrf2 in regulating quiescence and early activation in adult muscle stem cells.
  30. Transcription factor MITF regulates masseter muscle growth and development.
  31. RYR1-Related Myopathies Involve More than Calcium Dysregulation: Insights from Transcriptomic Profiling.
  32. Ubiquitin Specific Peptidase 51 Exacerbates Skeletal Muscle Injury by Enhancing APAF1-Mediated Apoptosis and Pyroptosis.
  33. Opposite directions of association of higher physical activity and higher insulin resistance with human skeletal muscle cell type abundance and fiber type-level gene expression.
  34. Androgen deprivation induces distinct muscle-specific transcriptional changes to genes regulating glucose, lipid, and amino acid metabolism.
  35. Disulfiram inhibits Gasdermin D pores formation and improves insulin-dependent glucose uptake and glucose homeostasis in skeletal muscle of obesity-induced insulin-resistant mice.
  36. Oxytocin treatment reduces cancer cachexia in a pre-clinical model.
  37. Non-coding RNA molecules mediating skeletal muscle mitochondrial function and their potential applications in exercise molecular physiology: A systematic review.
  38. Pretreatment of Mice with 830 nm Light Enhances Endurance During Acute Exercise.
  39. Codon-optimized human Smad7 gene therapy enhances skeletal muscle mass and function in a murine model of Duchenne muscular dystrophy.
  40. Interactive Role of the DHPR β1a SH3 Domain in Skeletal Muscle Excitation-Contraction Coupling.
  41. Synaptic-like coupling of macrophages to myofibers regulates muscle repair.
  42. Thyroxine does not improve skeletal muscle regeneration after injury in aged mice.
  43. Molecular communication from bone to skeletal muscle: an overview.
  44. Association of YY1 with STING activation and the inflammatory response during early muscle injury repair.
  45. Myostatin Exhibits an Evolutionarily Conserved Circadian Pattern in Skeletal Muscles.
  46. Enhancer regulator MLL4 controls skeletal muscle metabolic efficiency by limiting AMPK-mediated fuel catabolism.
  47. Crosstalk between skeletal muscle and the brain during physical activity - in search of epigenetic mechanisms.
  48. Meteorin-Like Protein (Metrnl): An Exercise-Induced Myokine With Therapeutic Potential in Metabolic and Inflammatory Disorders.
  49. Exercise Modulation of the Myostatin-FOXO Pathway in Murine Models of Cancer Cachexia: A Systematic Review.
  50. Emerging Roles of Skeletal Muscle-Derived Exosomal miRNAs in Metabolic Regulation: A Perspective.
  51. Modulating MyoD1 dosage activates alternate cell fate beyond myogenic differentiation.
  52. Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes.
  53. Canonical and non-canonical functions of proteins regulating mitochondrial dynamics in mammalian physiology.
  1. Nat Commun. 2025 Nov 27. 16(1): 10674
    Loss of cell-autonomously secreted laminin-α2 drives muscle stem cell dysfunction in LAMA2-related muscular dystrophy.
    Timothy J McGowan, Judith R Reinhard, Nicolas Lewerenz, Marta Białobrzeska, Shuo Lin, Jacek Stępniewski, Krzysztof Szade, Józef Dulak, Markus A Rüegg.
      The extracellular matrix protein laminin-α2 is essential for preserving the integrity of skeletal muscle fibers during contraction. Its importance is reflected by the severe, congenital LAMA2-related muscular dystrophy (LAMA2 MD) caused by loss-of-function mutations in the LAMA2 gene. While laminin-α2 has an established role in structurally supporting muscle fibers, it remains unclear whether it exerts additional functions that contribute to the maintenance of skeletal muscle integrity. Here, we report that in healthy muscle, activated muscle stem cells (MuSCs) express Lama2 and remodel their microenvironment with laminin-α2. By characterizing LAMA2 MD-afflicted MuSCs and generating MuSC-specific Lama2 knockouts, we show that MuSC-derived laminin-α2 is essential for rapid MuSC expansion and regeneration. In humans, we identify LAMA2 expression in MuSCs and demonstrate that loss-of-function mutations impair cell-cycle progression of myogenic precursors. In summary, we show that self-secreted laminin-α2 supports MuSC proliferation post-injury, thus implicating MuSC dysfunction in LAMA2 MD pathology.
    DOI:  https://doi.org/10.1038/s41467-025-65703-1
  2. bioRxiv. 2025 Oct 11. pii: 2025.10.10.681647. [Epub ahead of print]
    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 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 muscle mechanical overload (MOV, 3 days and 7 days), and fluorescent histology. Our findings show that: 1) displaced myonuclei emerge early during MOV, 2) resident myonuclear movement occurs rapidly during MOV, and 3) the contribution of resident versus exogenous displaced myonuclei depends on MOV duration, fibre type, and fibre size. 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 mechanical loading.
    Summary: Recombination-independent muscle fibre-specific doxycycline-inducible fluorescent myonuclear labelling in adult mice unambiguously reveals how resident myonuclei relocate rapidly during stress and contribute to the appearance of displaced myonuclei.
    DOI:  https://doi.org/10.1101/2025.10.10.681647
  3. Biochimie. 2025 Nov 20. pii: S0300-9084(25)00283-4. [Epub ahead of print]
    Effects of two longevity interventions, calorie restriction and rapamycin treatment, on the kynurenine-aryl hydrocarbon receptor pathway in aging skeletal muscle.
    Mark W Hamrick, Sadanand Fulzele, Carlos M Isales, Meghan McGee-Lawrence.
      The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is thought to play important roles in aging, oxidative stress, and cellular senescence. We have previously shown that the AhR agonist kynurenine (Kyn), a tryptophan metabolite that increases with age, can induce muscle atrophy in young mice. AhR overexpression can also lead to muscle atrophy and neuromuscular junction degradation. Here we utilized existing GEO data sets from skeletal muscles of aged mice to examine the impact of two longevity-related interventions, calorie restriction (CR) or treatment with the drug rapamycin (RM), on the expression of genes in the Kyn-AhR pathway. Data were examined in four skeletal muscles: soleus, gastrocnemius, tibialis anterior and triceps brachii. Results show that AhR expression increased with age in the triceps but was decreased with CR in the soleus and gastrocnemius. RM treatment did not significantly alter AhR expression in any of the four muscles of aged mice. Three enzymes that convert kynurenine to kynurenic acid in skeletal muscle, Kyat1, Kyat3 and Got2/Kyat4, are known to increase with endurance exercise and all three increased significantly with CR in aged skeletal muscle. In contrast, RM treatment did not increase Kyat1 expression in aged muscle and RM significantly decreased Kyat3 expression levels in muscles from aged mice. Together these data point to kynurenine aminotransferases as mediating some of the positive effects of CR on skeletal muscle with aging, and support prior research suggesting that CR and RM modulate different patterns of muscle-specific gene expression.
    Keywords:  Got2; Kyat1; Kyat3; Sarcopenia; Tryptophan
    DOI:  https://doi.org/10.1016/j.biochi.2025.11.010
  4. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2508893122
    Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging.
    Sze Mun Choy, Kah Yong Goh, Wen Xing Lee, Weiyi Jiang, Qian Gou, Priya D Gopal Krishnan, Shi Chee Ong, Kenon Chua, Nathan Harmston, Hong-Wen Tang.
      Skeletal muscle is essential for movement, respiration, and metabolism, with mTORC1 acting as a key regulator of protein synthesis and degradation. In aging muscle, mTORC1 becomes overactivated, contributing to sarcopenia, though the mechanisms remain unclear. Here, we identify DEAF1, a FOXO-regulated transcription factor, as a key upstream driver of mTORC1 in aged muscle. Elevated Deaf1 expression increases mTOR transcription, leading to heightened mTORC1 activity, impaired proteostasis, and muscle senescence. Remarkably, exercise suppresses Deaf1 expression via FOXO activation, restoring mTORC1 balance and alleviating muscle aging. Conversely, FOXO inhibition or Deaf1 overexpression blocks exercise benefits on muscle health. These findings highlight DEAF1 as a critical link between FOXO and mTORC1 and suggest that targeting the FOXO-DEAF1-mTORC1 axis may offer therapeutic potential to preserve muscle function during aging.
    Keywords:  autophagy; mTORC1; muscle; proteostasis; sarcopenia
    DOI:  https://doi.org/10.1073/pnas.2508893122
  5. Am J Physiol Regul Integr Comp Physiol. 2025 Nov 27.
    Exercise enhances antioxidant protein levels in oxidative skeletal muscle via IL-1β.
    Mami Yamada, Masahiro Iwata, Hinata Ito, Eiji Warabi, Hisashi Oishi, Vitor A Lira, Mitsuharu Okutsu.
      Nrf2 activation by sequestosome1/p62 (p62) (Ser351) phosphorylation is a pivotal signal for the exercise-mediated augmentation of antioxidant protein expression in muscle. However, the molecular mechanisms regulating this signal in response to exercise remain unclear. In this study, we demonstrate that exercise-training leads to higher levels of antioxidant proteins (e.g., CuZnSOD and EcSOD) in the mouse predominantly oxidative soleus, but not in the predominantly glycolytic white vastus lateralis muscle. We also observed that muscle-specific p62 overexpression, which leads to higher levels of phosphorylated (Ser351) p62, increases expression of these antioxidant proteins. Evidence for a cell-autonomous signal came from the observations that exercise training increased the expression of the Neighbor of BRCA1 gene 1 (NBR1) protein, which is known to stimulate p62 (Ser351) phosphorylation, in the soleus muscle, while cyclic stretch of C2C12 myotubes led to the same outcomes. Of note, both exercise training in mice and cyclic stretch in myotubes enhanced the expression of cleaved interleukin-1β (IL-1β), which is known to stimulate NBR1 expression. A key upstream role for IL-1β in this signaling was then established by daily injections of IL-1β-neutralizing antibody, which prevented exercise training-mediated increases in NBR1, phosphorylated p62 (Ser351), and EcSOD in the soleus muscle. Collectively, these findings point to IL-1β as an important upstream modulator of NBR1, p62 phosphorylation, and increased antioxidant protein expression in the exercise-trained predominantly oxidative muscle.
    Keywords:  Exercise; IL-1β; Mouse; Skeletal muscle; p62
    DOI:  https://doi.org/10.1152/ajpregu.00052.2025
  6. FASEB J. 2025 Dec 15. 39(23): e71281
    Dystrophic Skeletal Muscle Phenotypes Can Be Horizontally Transferred via Fecal Microbiome Transplantations.
    James Butcher, Jessica T Gosse, Jonathan Gobin, Aymeric Ravel-Chapuis, Bernard J Jasmin, Alain Stintzi.
      Duchenne muscular dystrophy (DMD) has no cure and accounts for > 80% of muscular dystrophy cases around the world. DMD patients experience severe muscle degeneration that continues until death and also suffer from gastrointestinal complications that undoubtedly impact their microbiotas. It is unclear whether dystrophic microbiotas simply reflect the disease or whether microbes are directly involved in muscle phenotypes. Here, we sought to determine the microbiota's causal role in promoting dystrophic muscles by performing intra/inter-genotype fecal microbiota transplantations (FMT) between wildtype and mdx mice; assessing FMT's impact on muscles and microbiotas over 9 weeks. Transplanting mdx microbiotas into wildtype mice induced an mdx-like muscle phenotype while the inverse improved muscle features. We identified several taxa differentially abundant between wildtype mice receiving either wildtype or mdx FMT, highlighting their potential role in muscle health. Our results highlight the active role microbes have in impacting muscle health through both beneficial and detrimental mechanisms. Accordingly, microbes represent unexploited therapeutic targets for improving health outcomes in muscular dystrophies.
    DOI:  https://doi.org/10.1096/fj.202502999R
  7. bioRxiv. 2025 Oct 23. pii: 2025.10.22.683887. [Epub ahead of print]
    SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signalling.
    Ankit Kumar Tamta, Bhoomika Shivanaiah, Arathi Bangalore Prabhashankar, Sunayana Ningaraju, Seemadri Subhadarshini, Anurag Nagaraja Sharma, Harsha Mambully Jayaprakasan, Meera Krishnan E R, Apeksha Bhuyar, Devika Sunil, Amarjeet Shrama, Dimple Nagesh, Aastha Munjal, Sukanya Raghu, Manepalli Bhavya Madhuri, Dhevi Rajesh, Venketsubbu Ramasubbu, Mohsen Sarikhani, Himani Tandon, Perumal Arumugam Desingu, Latha Diwakar, Utpal Nath, Deepak Nair, Amit Singh, Ramanathan Sowdhamini, Narayanaswamy Srinivasan, Raul Mostoslavsky, Ninitha Asirvatham-Jeyaraj, Nagalingam Ravi Sundaresan.
      Skeletal muscle atrophy occurs in several diseases and is associated with chronic stress. Studies indicate that glucocorticoid receptor signalling is the major signalling pathway that mediates stress-induced muscle degeneration. Although the glucocorticoid signalling pathway is relatively well characterized, there is a need to identify modulators of this pathway that may be useful for drug targeting to ameliorate muscle atrophy. SIRT2 is a mammalian Sirtuin isoform known to mediate the longevity benefits of calorie restriction and exercise. Currently, the role of SIRT2 in regulating stress-induced skeletal muscle atrophy is unclear. Our study found that SIRT2 is a critical regulator of muscle homeostasis and is required to protect against stress-induced muscle atrophy. Interestingly, SIRT2 levels are reduced during glucocorticoid-induced muscle atrophy in mice. SIRT2 depletion exacerbates glucocorticoid-induced reduction in myotube diameter and atrophy gene expression. In contrast, SIRT2 overexpression ameliorates myotube atrophy in primary myotubes. Our findings indicate that SIRT2 knockout mice are susceptible to glucocorticoid-induced muscle atrophy, while muscle-specific SIRT2-transgenic mice exhibit improved muscle function and are protected from glucocorticoid-induced atrophy. Mechanistically, SIRT2 binds to the glucocorticoid receptor to negatively regulate its activity, possibly via deacetylation of critical residues in its DNA-binding domain. Our findings suggest that SIRT2 activation may protect against glucocorticoid-induced skeletal muscle atrophy and serve as a potential therapeutic target for treating muscle atrophy.
    DOI:  https://doi.org/10.1101/2025.10.22.683887
  8. Microsc Res Tech. 2025 Nov 26.
    Physical Training Counteracts Mitochondrial Alterations in Myoblasts and Myotubes Derived From Muscle Satellite Cells of Old Mice: An In Vitro Ultrastructural Study.
    Barbara Cisterna, Anna Dal Pero, Carlo Zancanaro, Manuela Malatesta.
      Skeletal muscle is a complex organ that undergoes aging through a multifactorial process leading to muscle atrophy and strength reduction. Mitochondrial dysfunctions prove to be a critical contributor to skeletal muscle aging, affecting the regenerative functions and differentiation of muscle satellite cells (MuSCs). Physical exercise is a nonpharmacological approach that positively affects mitochondrial functions, promoting increased mitochondrial biogenesis, enzyme activities, and respiration in the aging skeletal muscle. By means of morphological and morphometrical analyses at transmission electron microscopy, this in vitro study identified the fine structural modifications induced in mitochondria of MuSC-derived myoblasts by a long-term adapted physical exercise applied to old mice, and verified the persistence of the exercise-driven changes in the myoblast-derived myotubes. In myoblasts, physical exercise decreased mitochondrial volume while increasing mitochondrial elongation and cristae extension in comparison to the sedentary condition, a mitochondrial remodeling suggestive of higher functionality. In myotubes, physical exercise increased mitochondrial volume and decreased cristae extension, partially reverting the age-associated alterations. These findings demonstrate that physical exercise administered in elderly exerts positive effects on mitochondria of the progeny of resident MuSCs.
    Keywords:  aging; mitochondria; morphometry; physical exercise; primary cell culture; transmission electron microscopy
    DOI:  https://doi.org/10.1002/jemt.70097
  9. J Sport Health Sci. 2025 Nov 21. pii: S2095-2546(25)00086-9. [Epub ahead of print] 101104
    Load-induced human skeletal muscle hypertrophy: Mechanisms, myths, and misconceptions.
    Derrick W Van Every, Matthew J Lees, Brandan Wilson, Jeff Nippard, Stuart M Phillips.
      Mechanical tension is widely recognized as the primary stimulus underlying the molecular mechanisms that influence muscle hypertrophy induced by resistance training. Despite this, several outdated or overstated concepts continue to persist, both in the scientific literature and in the practical application of resistance training coaching and program design. Claims that acute hormonal responses, metabolic stress, cell swelling or "the pump" meaningfully contribute to hypertrophy are not supported by scientific evidence. Additionally, the concept of sarcoplasmic hypertrophy as a distinct and functionally meaningful contributor to hypertrophy lacks strong evidence. In this review, we critically evaluate several persistent misconceptions and contrast them with evidence-based mechanistic insights into load-induced hypertrophy. Specifically, we discuss the role (or lack thereof) of systemic hormones, metabolites, and cell swelling in promoting muscle hypertrophy. We also critically review the concept of sarcoplasmic hypertrophy and propose that it is not a meaningful contributor to muscle hypertrophy. Lastly, to translate knowledge for trainees and coaches, we discuss the upper limit of muscle hypertrophy and provide readers with evidence-based, reasonable expectations for muscle hypertrophy. We aimed, through this review, to use scientific evidence to enhance our understanding of what drives muscle hypertrophy and provide an evidence-based framework for resistance exercise training.
    Keywords:  Mechanical tension; Muscle mass; Resistance training; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.jshs.2025.101104
  10. J Physiol. 2025 Nov 23.
    Profiling muscle mass, function and molecular signalling in females aged 18-80 years and their associations with sex hormones.
    Annabel J Critchlow, Danielle Hiam, Steven J O'Bryan, Ross M Williams, Megan Soria, Viktor Engman, Karel Van Belleghem, Ross P Wohlgemuth, Andrew Garnham, Christopher S Fry, David Scott, Séverine Lamon.
      Whether and how ovarian hormone fluctuations mediate the skeletal muscle response to ageing in females remains to be elucidated. We examined a tightly controlled, cross-sectional cohort of 96 females 18-80 years of age to map the functional and molecular trajectory of muscle ageing and determine its relationship with female sex hormones. Across every decade, we quantified body composition (using dual-energy X-ray absorptiometry), muscle morphology (using peripheral quantitative computed tomography), and voluntary and evoked muscle function. Circulating sex hormone concentrations were measured with GC-MS and immunoassays. Morphology and gene expression of vastus lateralis muscle samples were assessed with immunohistochemical staining and RNA sequencing, respectively. Age was negatively associated with muscle mass, strength and muscle fibre size, and positively associated with hybrid type I/IIa fibre prevalence and fibrosis. We found 37 unique patterns of gene expression across individual decades of age. Immune signalling, cellular adhesion and extracellular matrix organization pathways were the most upregulated with age, whilst mitochondrial function pathways were the most downregulated. Independently of age, circulating oestradiol and progesterone, but not testosterone, concentrations were positively associated with lean mass and negatively associated with hybrid muscle fibres across the lifespan. Oestrogen receptor binding sites were significantly enriched in upregulated genes in pre- versus post-menopausal muscle, suggesting a reduction in the translation of oestrogen target genes after menopause. Altogether, sex hormone fluctuations across the female lifespan may contribute to age-related muscle wasting, although longitudinal and interventional studies are needed to determine the causal nature of the relationship. KEY POINTS: Females live longer than males but experience worse disability in the later decades of life, highlighting the need to study female-specific patterns of ageing. This study mapped female body composition, muscle morphology, function and gene expression across every decade from 18 to 80 years of age in tightly controlled conditions and examined the relationships with circulating sex hormones. Unique patterns of muscle gene expression across ageing showed an overall increase in immune signalling and a decrease in mitochondrial respiration pathways, but limited associations with circulating sex hormones. Independently of age, circulating oestradiol and progesterone, but not testosterone, were associated with muscle mass and morphology across the lifespan, after adjusting for influential lifestyle factors (protein intake and physical activity). Fluctuations in female sex hormones across the lifespan should be considered when developing therapies to mitigate age-related muscle wasting and improve the female health span.
    Keywords:  ageing; female; gene expression; sex hormones; skeletal muscle
    DOI:  https://doi.org/10.1113/JP289765
  11. Redox Biol. 2025 Nov 25. pii: S2213-2317(25)00456-2. [Epub ahead of print]88 103943
    Lactate as a metabolic-epigenetic signal linking high-intensity interval training (HIIT) to miRNA-Centered remodeling of the skeletal muscle methylome and transcriptome.
    Lei Zhou, Soroosh Mozaffaritabar, Kumpei Tanisawa, Takuji Kawamura, Mitsuru Higuchi, Istvan Boldogh, Xueqing Ba, Sataro Goto, George Brooks, Yaodong Gu, Zsolt Radák.
       BACKGROUND: Lactate, a key exercise-derived metabolite and exerkine, is increasingly recognized as a metabolic-epigenetic signal, yet whether lactate and its transport directly shape skeletal-muscle epigenetic and transcriptional adaptations to exercise remains unclear.
    METHODS: Young male mice underwent six-week interventions: Control, lactate administration, high intensity interval training (HIIT), monocarboxylate transporter isoforms 1 and 2 (MCT1/2) inhibition, or HIIT plus inhibition. Gastrocnemius muscle was profiled by DNA methylation arrays, mRNA and miRNA-seq, together with analyses of signaling proteins, metabolites, and running performance.
    RESULTS: Exogenous lactate and HIIT each elicited broad, site-specific remodeling of the skeletal muscle methylome and transcriptome with substantial overlap at promoter CpGs and differentially expressed genes. Promoter methylation changes showed weak coupling to steady-state mRNA, whereas integrative analyses revealed robust anti-directional miRNA-mRNA networks and included numerous chromatin and epigenetic regulators, identifying a lactate-driven, miRNA-centered axis. At the protein level, lactate increased TET2/DNMT3A and activated signaling involved in satellite-cell activation, angiogenesis, and AKT-S6 axis, accompanied by reciprocal miRNA-mRNA pairs. HIIT increased TET1/2 and DNMT3A, reduced DNMT3B, and uniquely enhanced mitochondrial/antioxidant signaling. Pharmacologic MCT1/2 blockade abrogated HIIT-induced methylome and miRNA remodeling and blunted transcriptomic and protein adaptations, demonstrating that intact lactate flux is required for exercise-induced epigenetic reprogramming. Despite molecular convergence, chronic lactate did not improve running performance, suggesting that lactate is necessary, but not sufficient for the full physiological benefits of HIIT.
    CONCLUSIONS: These data support a lactate-miRNA-transcriptome/epigenome interplay that links metabolic perturbation to gene regulation in skeletal muscle. Using an integrated multi-omics approach, we propose a mechanistic framework for future studies targeting metabolic-epigenetic signaling in both physiology and pathology.
    Keywords:  DNA methylation; Epigenetic regulation; High-intensity interval training (HIIT); Lactate; MCT1; MCT2; Skeletal muscle adaptation; Transcriptome; microRNA
    DOI:  https://doi.org/10.1016/j.redox.2025.103943
  12. Biosci Biotechnol Biochem. 2025 Nov 26. pii: zbaf175. [Epub ahead of print]
    Inhibition of potassium chloride cotransporters impairs muscle contraction and induces atrophy in C2C12 myotubes.
    Haruka Kimura, Makoto Shimizu, Yu Takahashi, Yoshio Yamauchi, Ryuichiro Sato, Takashi Sasaki.
      In skeletal muscle cells, the resting membrane potential is primarily determined by Cl-, necessitating precise regulation of intracellular and extracellular Cl- balance. Potassium chloride cotransporters (KCCs), members of the cation-chloride cotransporter superfamily, facilitate the efflux of K+ and Cl- at a 1:1 ratio. However, the specific roles of KCCs in skeletal muscle remain poorly understood. In this study, we investigated the function of KCCs in skeletal muscle cells using [(dihydroindenyl)oxy]acetic acid (DIOA), a KCCs inhibitor. DIOA treatment of cultured C2C12 myotubes impaired contractility in response to electrical pulse stimulation. Additionally, DIOA-treated myotubes exhibited muscle atrophy, accompanied by increased expression of atrogenes such as Atrogin-1 and MuRF1. These findings reveal a novel role for KCCs in skeletal muscle and provide insights that may contribute to the development of preventive or therapeutic strategies for muscle disorders and atrophy.
    Keywords:  DIOA; KCC; Skeletal muscle; electrical pulse stimulation; muscle atrophy
    DOI:  https://doi.org/10.1093/bbb/zbaf175
  13. Redox Biol. 2025 Nov 14. pii: S2213-2317(25)00440-9. [Epub ahead of print]88 103927
    MitoQ supplementation does not impact redox responses to acute exercise in skeletal muscle of older individuals.
    Sophie C Broome, Jamie Whitfield, Kristel Janssens, John A Hawley.
      Ageing is associated with attenuated exercise responses in skeletal muscle, which may be related to a failure of muscle redox signalling. The attenuation of redox responses to exercise in aged muscle has been linked to perturbations in redox homeostasis induced by age-related increases in mitochondrial oxidative stress. Accordingly, we investigated the effects of supplementation with the mitochondria-targeted antioxidant MitoQ on mitochondrial bioenergetics and H2O2 emission as well as acute exercise-induced redox responses in skeletal muscle of older individuals. In a randomised, double-blind, placebo-controlled, parallel design, 10 males and 12 females aged 65-80 years were randomised to receive either MitoQ (20 mg/day) or a placebo for 12 weeks before completing a single bout of exercise. Vastus lateralis muscle biopsies were collected before supplementation and before, immediately post- and 4 h post-exercise. MitoQ supplementation reduced mitochondrial H2O2 emission capacity in skeletal muscle but did not impact mitochondrial respiration, H2O2 emission in the presence of ADP, or the sensitivity for ADP to stimulate respiration (apparent Km) and attenuate H2O2 emission (apparent IC50). Acute exercise-induced peroxiredoxin oxidation in skeletal muscle was not altered by MitoQ supplementation. Similarly, MitoQ had no effect on the phosphorylation of several redox-sensitive protein kinases (AMPK, p38 MAPK, and ERK1/2) or the upregulation of mitochondrial and antioxidant genes following exercise. Collectively, these findings indicate that MitoQ supplementation did not influence the basal myocellular redox state or redox responses to exercise in skeletal muscle of older individuals.
    Keywords:  Ageing; Antioxidant; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.redox.2025.103927
  14. JCI Insight. 2025 Nov 27. pii: e197759. [Epub ahead of print]
    Proteomics-based evaluation of AAV dystrophin gene therapy outcomes in mdx skeletal muscle.
    Erynn E Johnson, Theodore R Reyes, Jeffrey S Chamberlain, James M Ervasti, Hichem Tasfaout.
      Duchenne muscular dystrophy (DMD) is a fatal genetic muscle-wasting disease characterized by loss of dystrophin protein. Therapeutic attempts to restore a functional copy of dystrophin to striated muscle are under active development, and many utilize adeno-associated viral (AAV) vectors. However, the limited cargo capacity of AAVs precludes delivery of full-length dystrophin, a 427 kDa protein, to target tissues. Recently, we developed a novel method to express large dystrophin constructs using the protein trans-splicing (PTS) mechanism mediated by split inteins and myotropic AAV vectors. The efficacy of this approach to restore muscle function in mdx4cv mice was previously assessed using histology, dystrophin immunolabeling, and western blotting. Here, we expand our molecular characterization of dystrophin constructs with variable lengths using a mass spectrometry-based proteomics approach, providing insight into unique protein expression profiles in skeletal muscles of wild-type, dystrophic mdx4cv, and AAV-treated mdx4cv. Our data reveal several affected cellular processes in mdx4cv skeletal muscles with changes in the expression profiles of key proteins to muscle homeostasis, whereas successful expression of dystrophin constructs results in an intermediate to complete restoration. This study highlights several biomarkers that could be used in future preclinical or clinical studies to evaluate the effectiveness of therapeutic strategies.
    Keywords:  Biomarkers; Gene therapy; Genetics; Muscle biology; Proteomics
    DOI:  https://doi.org/10.1172/jci.insight.197759
  15. bioRxiv. 2025 Oct 30. pii: 2025.10.29.685384. [Epub ahead of print]
    The Age-Dependent Resident Myonuclear Multi-Omic Response to a Skeletal Muscle Hypertrophic Stimulus.
    Pieter J Koopmans, Ronald G Jones, Ana Regina Cabrera, Francielly Morena, Nicholas P Greene, John J McCarthy, Ahmed Ismaeel, Yuan Wen, Kevin A Murach.
      A detailed analysis of how muscle fiber nuclei (myonuclei) respond to a hypertrophic stimulus would provide a critical step toward understanding compromised skeletal muscle plasticity with age. We used recombination-independent doxycycline-inducible myonucleus-specific fluorescent labelling, tissue RNA-sequencing, myonuclear DNA methylation analysis, multi-omic integration, and single myonucleus RNA-sequencing to define the molecular characteristics of adult (6-8 month) and aged (24 month) murine skeletal muscle after acute mechanical overload (MOV). In adult and aged MOV muscles, we found that: 1) similarities in the transcriptional response to loading - specifically in metabolism genes - were partly explained by a post-transcriptional microRNA-mediated mechanism, which we corroborated using an inducible muscle fiber-specific miR-1 knockout model, 2) differences in age-dependent transcriptional responses were linked to the magnitude and location of differential DNA methylation in resident myonuclei, specifically around hypertrophy-associated genes such as Myc , Runx1 , Mybph , Ankrd1, collagen genes, and minichromosome maintenance genes, 3) adult and aged resident myonuclear transcriptomes had differing enrichment for innervation-related transcripts as well as unique transcriptional profiles in an Atf3+ "sarcomere assembly" population after MOV, and 4) cellular deconvolution analysis supports a role for neuromuscular junction regulation in age-specific hypertrophic adaptation. These data are a roadmap for uncovering molecular targets to enhance aged muscle adaptability.
    DOI:  https://doi.org/10.1101/2025.10.29.685384
  16. Int J Mol Sci. 2025 Nov 13. pii: 10985. [Epub ahead of print]26(22):
    Multiple Defects in Muscle Regeneration in the HSALR Mouse Model of RNA Toxicity.
    Ramesh S Yadava, Mira A Zineddin, Mani S Mahadevan.
      Myotonic dystrophy type 1 (DM1) results from the toxicity of RNA produced from the mutant allele of the DMPK gene. The mechanism by which the toxic RNA causes muscular dystrophy in DM1 is unknown. Dystrophy in DM1 is associated with defective muscle regeneration and repair. Here, we used the BaCl2-induced damage model of muscle injury to study muscle regeneration in the HSALR mouse model of DM1. We have previously shown delayed muscle regeneration and deleterious effects on satellite cell numbers in another mouse model of RNA toxicity using similar experimental approaches. We found that HSALR mice show no apparent deleterious effects on satellite cell number or early markers of muscle regeneration. Further analysis at later time points after damage showed increased numbers of internal nuclei as compared to control mice undergoing the same protocol. Muscle fiber type analysis using immunostaining for type IIA and IIB fibers identified a switch to slower fibers (increased fraction of IIA and reduced fraction of IIB fibers) after regeneration in HSALR mice as compared to regenerated muscle from wildtype mice.
    Keywords:  RNA toxicity; fiber type; muscle regeneration; muscular dystrophy; myotonic dystrophy; satellite cells
    DOI:  https://doi.org/10.3390/ijms262210985
  17. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70124
    Iron Deficiency Impairs Muscle Stem Cell Proliferation and Skeletal Muscle Regeneration via HIF-2α Stabilization.
    Wenyan Fu, Yang Liu, Amelia Yin, Liwei Xie, Hang Yin.
       BACKGROUND: Functional iron deficiency affects a large proportion of patients with chronic diseases and is increasingly observed in older adults. Clinical evidence links iron deficiency to sarcopenia, yet the mechanistic relationship between iron status and muscle regeneration remains poorly defined. This study investigates how iron depletion alters muscle stem cell (MuSC) proliferation and skeletal muscle regeneration, focusing on HIF-2α signalling.
    METHODS: Male and female C57BL/6 J mice (4 week old, n > 20 per group in total) were fed iron-sufficient (IS) or iron-deficient (ID) chow for 4 weeks before cardiotoxin-induced tibialis anterior (TA) muscle injury. Muscle mass, MuSC proliferation and histological changes in regenerating TA muscles were evaluated at 10 and 30 days after injury (dpi). Pharmacological HIF-2α inhibition (PT2385) was used to determine causal mechanisms. Data were analyzed by t tests and one-way ANOVA.
    RESULTS: Iron deficiency significantly reduced MuSC proliferation (-10.2% Ki67+ MuSC at 10 dpi, p < 0.01, n = 5) and myoblast EdU incorporation (-18.1%, p < 0.001), leading to smaller regenerating myofibres (-22.7% median cross-sectional area at 30 dpi, p < 0.01, n = 3) and impaired muscle mass recovery (males: -13.9% p < 0.001, females: -9.4% p < 0.05, n = 6). HIF-2α inhibition with PT2385 in ID mice increased MuSC proliferation (+7.1% Ki67+ MuSC at 10 dpi, p < 0.01, n = 5) and restored muscle mass (males: +10.3% p < 0.001, females: +5.5% p < 0.05, n = 6). Mechanistically, iron deficiency stabilized HIF-2α in proliferating MuSC, which upregulated retinoblastoma protein (Rb1), repressed E2F target RNA levels and induced G0/G1 cell cycle arrest. This impaired myoblast expansion and delayed muscle regeneration in vitro and in vivo. In ID mice, PT2385 restored MuSC proliferation, accelerated myofibre maturation and enhanced muscle mass recovery without compromising MuSC self-renewal. Chromatin immunoprecipitation demonstrated HIF-2α binding at the Rb1 promoter, increasing Rb transcription and reducing H3K27 acetylation at E2F target loci.
    CONCLUSIONS: Iron deficiency impairs skeletal muscle regeneration by stabilizing HIF-2α in MuSC, inducing Rb1 RNA expression, and repressing E2F-dependent proliferation. Transient HIF-2α inhibition rescues MuSC proliferation and muscle repair under iron-deficient conditions, highlighting HIF-2α as a potential therapeutic target to counteract sarcopenia in aging and chronic diseases.
    Keywords:  HIF‐2α; cell cycle regulation; iron deficiency; muscle regeneration; muscle stem cells; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.70124
  18. Exp Gerontol. 2025 Nov 20. pii: S0531-5565(25)00299-2. [Epub ahead of print] 112970
    Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.
    Shota Uebo, Yoshiyuki Ikeda, Yoshihiro Uchikado, Yuichi Sasaki, Yuichi Akasaki, Takuro Kubozono, Mitsuru Ohishi.
      Aim Sarcopenia, a major cause of frailty in postmenopausal women, is linked to mitochondrial dysfunction, but the underlying mechanisms remain unclear. This study aimed to clarify whether mitophagy, a mitochondrial quality control mechanism, contributes to postmenopausal sarcopenia, to elucidate its underlying mechanism, and to assess whether it can be rescued.
    METHODS: C57BL/6 mice (12-week-old females) underwent ovariectomy to establish a menopause mouse model, or sham surgery, and the therapeutic effects of nicotinamide mononucleotide (NMN) were assessed. Human skeletal muscle myoblasts (HSMMs) differentiated under postmenopausal conditions with or without 17β-estradiol (E2), and Rab9 expression was modulated using CRISPR activation.
    RESULTS: Ovariectomized mice exhibited decreased muscle mass and strength. E2 deficiency in HSMMs inhibited skeletal muscle cell differentiation, promoted senescence, impaired mitochondrial function, and reduced mitophagy. However, E2 deficiency did not modulate light chain 3 and autophagy-related 7 but reduced Rab9 expression and the colocalization of Rab9 with lysosomal-associated membrane protein 2, suggesting that E2 mediates mitophagy through Rab9-dependent alternative autophagy. Furthermore, overexpression of Rab9 in E2-deficient HSMMs enhanced mitophagy, improved mitochondrial function, suppressed cellular senescence, and promoted skeletal muscle cell differentiation. The administration of NMN to ovariectomized mice increased Rab9 expression and improved sarcopenia through increased mitophagy.
    CONCLUSION: This study demonstrates that estrogen deficiency impairs mitophagy originated from Rab9-dependent alternative autophagy, leading to mitochondrial dysfunction and sarcopenia, while enhancement of Rab9 restores mitochondrial quality control and muscle function. These results identify Rab9-dependent mitophagy as a potential therapeutic target for postmenopausal sarcopenia.
    Keywords:  Alternative autophagy; Estrogen; Menopause-induced sarcopenia; Mitochondria; Mitophagy; Nicotinamide mononucleotide; Rab9
    DOI:  https://doi.org/10.1016/j.exger.2025.112970
  19. bioRxiv. 2025 Nov 14. pii: 2025.11.13.687882. [Epub ahead of print]
    Fiber Type and Stimulus Determine Progression of Skeletal Muscle Atrophy.
    Gregory L Maas, Marcus P Mullen, Brooke D Shepard, Jack F Gugel, Dakota R Hunt, Virginia Ferguson, Sarah Calve, Thomas G Martin, Leslie A Leinwand.
       Background: Skeletal muscle atrophy is prevalent worldwide and is a major detractor from length and quality of life. It is often diagnosed and treated as a single disorder, but the causal stimuli and progression of atrophy vary widely. Malnutrition and disuse are two common causes of muscle atrophy, and despite their prevalence and extensive characterization, there have been no direct comparisons of how these two types of atrophy progress and whether they differentially affect skeletal muscle fiber types. The purpose of this study is to directly compare atrophy from fasting and disuse and provide a transcriptomic resource for future research on both conditions.
    Methods: We fasted or hindlimb suspended (HS) two cohorts of 12-week-old female C57/bl6 mice. Mice were fasted for up to 72 hours to induce malnutrition atrophy or were hindlimb suspended for 0, 3, 7, 14, or 28 days to induce disuse atrophy. At each timepoint, mice were euthanized and three muscles (tibialis anterior (TA), extensor digitorum longus (EDL), and soleus) were weighed and collected for RNA sequencing. Atrophy progression and gene expression changes were compared across muscle fiber types and atrophy stimuli.
    Results: We found differences in atrophy progression between muscle fiber types based on fiber twitch speed and atrophy stimulus. Fasted mice lost 25% of their body weight and 23% of fast-twitch TA mass with little change in soleus. In contrast, HS mice lost 40% of the slower-twitch soleus but the effect on the TA was negligible. Gene expression varied in response to both atrophy stimuli, but a greater number of genes changed with fasting compared to HS in the EDL and soleus. By muscle type, a greater transcriptional shift occurred in the EDL with fasting while the soleus showed more gene changes during HS. Enrichment analysis of transcriptional changes showed similarities (downregulation in muscle growth pathways) and differences (increased fatty acid metabolism in fasting and increased neuronal activity in HS) between atrophy stimuli.
    Conclusions: Atrophy progression varies based on stimuli and muscle fiber type. This study provides a large, matched data set where the effects of different atrophic stimuli can be easily and directly compared in multiple fiber types. To our knowledge, this is the first study to closely compare these two atrophy stimuli in a muscle type-specific context. This work demonstrates that atrophy is not a single disorder and that the development of therapies may need to be tailored to the atrophic stimulus.
    DOI:  https://doi.org/10.1101/2025.11.13.687882
  20. Cells. 2025 Nov 11. pii: 1765. [Epub ahead of print]14(22):
    C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.
    Francesca Sironi, Paola Parlanti, Cassandra Margotta, Jessica Cassarà, Valentina Bonetto, Caterina Bendotti, Massimo Tortarolo, Valentina Cappello.
      The C9ORF72 gene mutation is a major cause of amyotrophic lateral sclerosis (ALS). Disease mechanisms involve both loss of C9ORF72 protein function and toxic effects from hexanucleotide repeat expansions. Although its role in neurons and the immune system is well studied, the impact of C9ORF72 deficiency on skeletal muscle is not yet well understood, despite muscle involvement being a key feature in ALS pathology linked to this mutation. This study examined skeletal muscle from C9ORF72 knockout mice and found a 19.5% reduction in large muscle fibers and altered fiber composition. Ultrastructural analysis revealed mitochondrial abnormalities, including smaller size, pale matrix, and disorganized cristae. Molecular assessments showed increased expression of Atrogin-1, indicating elevated proteasomal degradation, and markers of enhanced autophagy, such as elevated LC3BII/LC3BI ratio, Beclin-1, and reduced p62. Mitochondrial quality control was impaired, with a 3.6-fold increase in PINK1, upregulation of TOM20, reduced Parkin, and decreased PGC-1α, suggesting disrupted mitophagy and mitochondrial biogenesis. These changes led to the accumulation of damaged mitochondria. Overall, the study demonstrates that C9ORF72 is critical for maintaining muscle protein and mitochondrial homeostasis. While C9orf72-haploinsufficiency does not directly compromise muscle strength in mice, it may increase the vulnerability of skeletal muscle in C9ORF72-associated ALS.
    Keywords:  amyotrophic lateral sclerosis; atrogenes; autophagy; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.3390/cells14221765
  21. Am J Physiol Cell Physiol. 2025 Nov 25.
    Comprehensive transcriptomic analysis identifies Lrg1 as a potential therapeutic target for preventing muscle atrophy in cancer cachexia.
    Hanbi Lee, Aeyung Kim, Kyuwon Son, Ahyoung Choi, Seongwon Cha, Hyunjin Shin, No Soo Kim, Haeseung Lee.
      Cancer cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting and systemic inflammation, primarily observed in patients with advanced-stage cancer. Cachexia severely impacts patients' quality of life and even increases mortality rates; however, effective therapeutic interventions remain elusive. To identify key mediators of muscle atrophy, we integrated more than one hundred bulk and single-cell transcriptomic datasets from diverse murine cachexia models, including colorectal, lung, and pancreatic cancer. This analysis identified leucine-rich alpha-2-glycoprotein 1 (Lrg1), as consistently upregulated in skeletal muscle endothelial cells across cachexia models and progressively increased during disease progression. Functional studies demonstrated that recombinant Lrg1 induced myotube atrophy in vitro, accompanied by reduced fusion index, shortened myotube length, and increased expression of the atrogenes MAFbx and MuRF1. Neutralization of Lrg1 or pharmacological inhibition of Stat3 prevented these effects. Our findings nominate Lrg1 as a candidate biomarker and potential therapeutic target for preventing skeletal muscle wasting in cancer cachexia.
    Keywords:  Lrg1; RNA sequencing; cancer cachexia; muscle atrophy; stat3
    DOI:  https://doi.org/10.1152/ajpcell.00319.2025
  22. Nat Commun. 2025 Nov 26. 16(1): 10576
    Calcitonin receptor downregulation and exercise-conditioned blood enable systemic muscle stem cell proliferation.
    Lidan Zhang, Takayuki Kaji, Ayasa Nakamura, Nagomu Maesawa, Kanako Iwamori, Jiayao Xu, Yilin Liu, Akiyoshi Uezumi, Daisuke Kamimura, Masaaki Murakami, Atsushi Kubo, Takashi Yamada, Takayuki Akimoto, So-Ichiro Fukada.
      Quiescent muscle stem cells (MuSCs) respond to exercise; however, the coordinated regulation of increased loading, exerkines, and quiescence signaling remains unclear. We found that increased loading reduces calcitonin receptor (CalcR) expression, and forced activation of protein kinase A (PKA), a downstream of CalcR signaling, suppresses MuSC proliferation. Although MuSC-specific Calcr knockout (C-cKO) alone is insufficient, exercised C-cKO mice exhibit significant MuSC proliferation independent of increased loading. Reinforcement of CalcR signaling, either through PKA induction or Yap1 depletion, suppresses MuSC proliferation. Load-independent MuSC proliferation is also suppressed by the deletion of gp130 in C-cKO mice. Serum from exercised mice recapitulates MuSC proliferation in all analyzed muscles of sedentary C-cKO mice, which is abrogated by anti-IL-6 antibodies, and we find cross-talk between CalcR and gp130 signaling via Yap1 phosphorylation. Together, our findings reveal an integrated mechanism by which increased loading, exerkine-gp130, and CalcR signaling converge to fine-tune MuSC activity during exercise.
    DOI:  https://doi.org/10.1038/s41467-025-65684-1
  23. Sci Rep. 2025 Nov 24. 15(1): 41599
    Regulatory role of vitamin D3 on myogenesis and fibrogenesis under Vdr gene silencing and TGF-β1 stimulation in skeletal muscle cells.
    Wasina Watcharanapapan, Muthita Hirunsai, Ratchakrit Srikuea.
      Vitamin D deficiency is associated with a decline in muscle function and an increasing risk of muscle injury in athletes and the elderly. Nevertheless, how vitamin D3 and vitamin D receptor (VDR) regulate skeletal muscle cells under profibrotic factor stimulation that could be pronounced during repetitive muscle damage have not been elucidated. Therefore, this study aimed to investigate the regulatory role of cholecalciferol (D3), calcidiol (25D3), calcitriol (1,25D3), and the effect of Vdr gene suppression under TGF-β1 stimulation in C2C12 mouse skeletal muscle cells. All forms of vitamin D3 exerted antifibrotic effects under TGF-β1 stimulation by suppression of COL1A1; however, D3 preserves this effect without negative impact on myogenesis. Moreover, LC-MS/MS-based proteomics analysis revealed that myoblast fusion protein and mitochondrial regulation were altered following Vdr knockdown. These changes were associated with exacerbation of α-SMA expression in TGF-β1-treated cells and suggested VDR modulates fibrogenesis in skeletal muscle cells regardless of ligand binding. Under TGF-β1 stimulation, antifibrotic effects of 1,25D3 but not D3 were diminished after Vdr knockdown, supporting that D3 action is largely mediated independently of VDR. Collectively, understanding antifibrotic effects of vitamin D3 is beneficial for providing a strategy of vitamin D supplementation to counteract fibrosis development after muscle injury.
    DOI:  https://doi.org/10.1038/s41598-025-25496-1
  24. Biomolecules. 2025 Oct 23. pii: 1495. [Epub ahead of print]15(11):
    Cisplatin-Induced Skeletal Muscle Atrophy: Biomolecular Mechanisms and the Protective Role of Exercise-Induced Myokines.
    Miaomiao Xu, Xiaoguang Liu.
      Cisplatin is a widely used chemotherapy drug for the treatment of various cancers; however, its clinical use is often accompanied by skeletal muscle atrophy, which not only impacts patients' physical health but also significantly diminishes their quality of life. The mechanisms underlying cisplatin-induced muscle atrophy are complex and involve a series of molecular biological processes, including oxidative stress, inflammation, protein degradation, and muscle cell apoptosis. Recent studies have suggested that exercise intervention can significantly alleviate cisplatin-induced muscle damage by modulating exercise-induced myokines. Myokines, such as muscle-derived cytokines (e.g., IL-6, irisin) and other related factors, can mitigate muscle atrophy through anti-inflammatory, antioxidative, and muscle-synthesis-promoting mechanisms. This review explores the molecular mechanisms of cisplatin-induced skeletal muscle atrophy, examines the potential protective effects of exercise intervention, and highlights the role of exercise-induced myokines in this process. The findings suggest that exercise not only alleviates chemotherapy-induced muscle atrophy by improving metabolic and immune status but also activates myokines to promote muscle regeneration and repair, offering a promising adjunctive therapy for cisplatin-treated patients.
    Keywords:  chemotherapy; cisplatin; exercise intervention; myokines; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/biom15111495
  25. Int J Mol Sci. 2025 Nov 19. pii: 11185. [Epub ahead of print]26(22):
    Neural Cues and Genomic Clues: NGS Insights into Neurogenic Sarcopenia and Muscle Atrophy.
    Darya Kupriyanova, Airat Bilyalov, Nikita Filatov, Sergei Brovkin, Dmitrii Shestakov, Natalia Bodunova, Oleg Gusev.
      Sarcopenia is a progressive loss of skeletal muscle mass and strength with major clinical and economic consequences. While traditional models emphasize mitochondrial dysfunction, inflammation, and proteostasis imbalance, emerging data highlight a neurogenic component involving motor neuron loss, fiber denervation, neuromuscular junction remodeling, and disrupted trophic signaling. To synthesize current evidence on neurogenic mechanisms of sarcopenia revealed by next-generation sequencing and related multi-omics, to map molecular networks across cell types, and to outline translational opportunities for diagnostics and targeted therapy. A narrative review of human and animal studies indexed in PubMed, Web of Science, and Scopus through November 2025. Search terms combined sarcopenia, denervation, neuromuscular junction, neurotrophic signaling, genomics, transcriptomics, epigenomics, single-cell, and spatial transcriptomics. Eligible studies reported omics or physiological endpoints related to neuromuscular function. Convergent omics data support a central role of the nervous system in the onset and progression of sarcopenia. Genetic and regulatory factors linked to denervation, transcriptomic signatures of junctional disassembly, and cell-specific dysfunctions in motor neurons, Schwann cells, satellite cells, and fibro-adipogenic progenitors have been identified. Epigenetic and transcriptional networks underlying neuromuscular homeostasis, along with candidate circulating biomarkers, provide targets for clinical translation. Neurogenic sarcopenia represents a tractable target for precision prevention and therapy. Integration of multi-omics, artificial intelligence, and advanced models such as innervated organoids and NMJ-on-chip systems can accelerate target validation and enable personalized strategies to preserve neuromuscular function.
    Keywords:  NGS; aging; artificial intelligence; model; motor neuron; neuromuscular disease; neuromuscular junction (NMJ); omics data; sarcopenia; skeletal muscle; synapse
    DOI:  https://doi.org/10.3390/ijms262211185
  26. bioRxiv. 2025 Nov 03. pii: 2025.10.31.685856. [Epub ahead of print]
    Deficient Cardiolipin Remodeling Alters Muscle Fiber Composition and Neuromuscular Connectivity in Barth Syndrome.
    Catalina Matias, Paige L Snider, Elizabeth A Sierra Potchanant, Joshua R Huot, Rahul Raghav, Michael T Chin, Simon J Conway, Jeffrey J Brault.
       Background: Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by mutations in the TAFAZZIN gene, which disrupts cardiolipin (CL) remodeling and mitochondrial function. While cardiac manifestations of BTHS are well characterized, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood.
    Methods: We investigated neuromuscular and mitochondrial alterations in a novel murine model (Taz PM ) carrying a patient-derived D75H point mutation in Tafazzin . This mutation preserves protein abundance but abolishes enzymatic activity. Skeletal muscle function was assessed via weightlifting and hanging tests. Muscle fiber composition and neuromuscular junction (NMJ) integrity were evaluated using immunofluorescence, western blotting, and in vivo electrophysiology. Mitochondrial morphology was examined by transmission electron microscopy, and bioenergetics were quantified using ultra-performance liquid chromatography. Stress signaling was assessed by western blotting.
    Results: Male Taz PM mice exhibited elevated monolysocardiolipin and reduced mature CL levels, confirming deficient transacylase activity. These mice exhibited lower muscle strength and endurance, smaller muscle fibers of all types, and a shift toward fast-twitch type 2B fibers, which are more susceptible to fatigue. Electrophysiological analysis revealed a 60% reduction in motor unit number and an increase in average single motor unit potential, indicating motor neuron remodeling. NMJ protein analysis showed decreased MUSK and DOK7 and increased CHRNA1, suggesting impaired NMJ integrity. Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins (NDUFB8, MCU, TMEM65), resting ATP, phosphocreatine, and adenine nucleotide ratios were unchanged in both glycolytic and oxidative muscles. However, stress signaling pathways were markedly activated, including phosphorylation of eIF2α, increased CHOP, DELE1, p53 expression, and altered Wnt/β-catenin signaling components.
    Conclusions: Deficiency of Tafazzin enzymatic activity in skeletal muscle is sufficient to result in widespread neuromuscular remodeling, including fiber size/type shifts, motor unit loss, NMJ dysregulation, and stress pathway activation, without overt energetic failure at rest. These findings suggest that myopathy in BTHS arises not solely from mitochondrial ATP insufficiency but rather from cumulative structural and signaling disruptions.
    DOI:  https://doi.org/10.1101/2025.10.31.685856
  27. Biol Direct. 2025 Nov 27. 20(1): 113
    NAMPT modulates muscle fiber type transition in PAD myopathy via the cGMP-PKG signaling pathway.
    Qiaoyun Yang, Yani Shi, Wei Li, Xiaojing Xiong, Qingwei Chen, Minming Zheng.
       BACKGROUND: Peripheral artery disease (PAD), caused by atherosclerosis resulting in reduced blood flow in the lower extremities, impairs both skeletal muscle mass and function in humans, and its molecular mechanism is not clear. Recent studies have demonstrated that Nicotinamide phosphoribosyl transferase (NAMPT) influences skeletal muscle mass and function by modulating NAD+ levels and cellular Ca²⁺ homeostasis. However, its role in muscle fiber type transition remains to be elucidated.
    RESULTS: NAMPT is downregulated in ischemic skeletal muscle and CoCl2-treated C2C12 myotubes. NAMPT enhances the functional performance of ischemic limbs, reduces apoptosis, increases the formation of oxidative muscle fibers, and improves mitochondrial function. The cGMP‒PKG pathway is activated by NAMPT in ischemic limbs. Exogenous inhibition of cGMP-PKG signaling inhibits the formation of oxidative muscle fibers induced by NAMPT.
    CONCLUSIONS: NAMPT protects against ischemic limb injury via the cGMP‒PKG signaling pathway, suggesting that it is a promising therapeutic and predictive target for myopathy associated with PAD.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Mitochondria; NAMPT; Oxidative muscle fiber formation; Peripheral artery disease; cGMP-PKG
    DOI:  https://doi.org/10.1186/s13062-025-00705-z
  28. Aging (Albany NY). 2025 Nov 26. 17
    Epigenetic aging signatures and age prediction in human skeletal muscle.
    Soo-Bin Yang, Jeong Min Lee, Moon-Young Kim, Soong Deok Lee, Hwan Young Lee.
      Aging causes progressive molecular and cellular changes that impair skeletal muscle function. DNA methylation is a key epigenetic regulator of this process, but its role in skeletal muscle, especially in Asian populations and postmortem samples, remains underexplored. We analyzed DNA methylation profiles from 103 pectoralis major muscle samples from autopsies of South Korean individuals (18-85 years) using the Infinium EPIC array. Targeted validation and age prediction modeling were performed with Next-Generation Sequencing (NGS) and Single Base Extension (SBE). We identified 20 age-associated CpG markers linked to genes involved in muscle structure, metabolism, and stress response. Machine learning models built on these CpG sites showed high prediction accuracy, with mean absolute errors of 5.537 years in sequencing and 3.797 years in extension platforms, and strong correlation with chronological age. This study introduces the skeletal muscle epigenetic clocks in an Asian population using postmortem skeletal muscle tissue. These novel prediction models, based on 20 common CpG markers using SBE and NGS platforms, provide a robust framework for forensic applications and enable population-tailored epigenetic profiling. Beyond predictive utility, the identified age-associated methylation signatures offer valuable insights into the molecular pathways of muscle aging and hold promise as biomarkers for translational research and age-related clinical interventions.
    Keywords:  DNA methylation; age; next generation sequencing; single base extension; skeletal muscle
    DOI:  https://doi.org/10.18632/aging.206341
  29. Nat Commun. 2025 Nov 25. 16(1): 10505
    Non-canonical roles of Keap1/Nrf2 in regulating quiescence and early activation in adult muscle stem cells.
    Lifang Han, Yudan Qiu, Liangqiang He, Chuan Gao, Nan Zhou, Xinrong Fu, Jingyan Xu, Lirong Lin, Huating Wang, Shyam Biswal, Zhenguo Wu.
      Adult muscle satellite cells (MuSCs) are mostly quiescent in uninjured muscles under normal homeostasis. Although several mechanisms underlying quiescence maintenance are known, our understanding of the process remains incomplete. Here, we show that Keap1 regulates MuSC quiescence maintenance by promoting Nrf2 protein degradation. Inducible deletion of Keap1 activates MuSCs to different extent in a sex-specific manner via differential Nrf2 protein levels: in Keap1-null MuSCs from male mice, Nrf2 protein is at an intermediate level due to the action of a GSK3β-dependent Nrf2 degradation system, which promotes mutant MuSCs to enter a GAlert-like state; in Keap1-null MuSCs from female mice, the loss of Keap1 together with estrogen-mediated GSK3β inactivation renders Nrf2 at its highest level, which induces the expression of multiple metabolic genes resulting in metabolic reprogramming, spontaneous activation and gradual depletion of MuSCs. Consistently, interference of selected Nrf2-regulated metabolic genes impairs early activation of MuSCs. Thus, Keap1/Nrf2 regulates quiescence maintenance and early activation of MuSCs independently of its canonical roles in the antioxidant response.
    DOI:  https://doi.org/10.1038/s41467-025-65506-4
  30. Physiol Rep. 2025 Nov;13(22): e70677
    Transcription factor MITF regulates masseter muscle growth and development.
    Megumi Nariyama, Yoshiki Ohnuki, Kenji Suita, Misao Ishikawa, Ren Matsubara, Ichiro Matsuo, Takao Mitsubayashi, Yasumasa Mototani, Aiko Ito, Mariko Abe, Yoshio Hayakawa, Takako Nomura, Satoshi Wada, Yoshinobu Asada, Satoshi Okumura.
      The microphthalmic mouse with a mutation at the locus of the microphthalmia-associated transcriptional factor (MITF) gene exhibits masticatory dysfunction due to impaired masseter muscle development and needs to be fed with powdered diet. However, the effects of MITF mutation on masseter muscle remain poorly understood. Here, we show that masseter muscle mass is markedly decreased in MITF-mutant mice (mi/mi), in contrast to the corresponding tibialis anterior and soleus muscles. The area of fibrosis and degree of myocyte apoptosis were strikingly increased in the masseter muscle of mi/mi. The expression of muscle-specific microRNAs (miR-1, miR-206, and miR-133a), which are necessary for proper skeletal muscle development and function, was strongly suppressed in the masseter muscle of mi/mi during development. In addition, the regulation of reactive oxygen species production, calcium homeostasis via sarcoendoplasmic reticulum calcium transport and autophagic activity, which are important for maintaining skeletal muscle mass and function, were all altered in the masseter muscle of mi/mi. These results indicate that MITF is required for masseter muscle growth and development.
    Keywords:  cell signaling; microRNA; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.70677
  31. Biomolecules. 2025 Nov 14. pii: 1599. [Epub ahead of print]15(11):
    RYR1-Related Myopathies Involve More than Calcium Dysregulation: Insights from Transcriptomic Profiling.
    Daniele Sabbatini, Domenico Gorgoglione, Giovanni Minervini, Aurora Fusto, Matteo Suman, Chiara Romualdi, Sara Vianello, Giuliana Capece, Gianni Sorarù, Caterina Marchioretti, Maria Pennuto, Luca Vedovelli, Gyorgy Szabadkai, Luca Bello, Elena Pegoraro.
      Ryanodine receptor 1-related myopathies (RYR1-RM) are caused by RYR1 gene variants and comprise a wide spectrum of histopathological manifestations. Here, we focus on patients carrying RYR1 variants and muscle histopathology consistent with central core disease (CCD) or multi-minicore disease (MmD). RNA-sequencing analyses of skeletal muscle biopsies obtained from both CCD and MmD patients and from healthy controls were performed to better understand the molecular pathways activated by RYR1 variants. Our analyses revealed that, beyond the well-established role of RYR1 in calcium homeostasis, broader cellular pathways are implicated. In CCD, differentially expressed genes were enriched for pathways related to oxidative stress response, SMAD signalling, and apoptosis, consistent with the role of intracellular calcium dysregulation in promoting mitochondrial dysfunction and cell death. In contrast, MmD patients exhibited enrichment of pathways related to immune activation. This was corroborated by the upregulation of GTPase-regulating genes and the down-regulation of transcriptional repressors such as ZFP36 and ATN1. When considering all RYR1-RM patients collectively, Wnt signalling, immune-related pathways, and oxidative phosphorylation emerged as shared enriched pathways, indicating possible convergent mechanisms across histopathological phenotypes. Our study suggests that complex gene regulation driven by RYR1 variants may be a unifying feature in CCD and MmD, offering new insight into potential therapeutic targets.
    Keywords:  CCD; MmD; RNASeq; RYR1; RYR1-RM; skeletal muscle diseases
    DOI:  https://doi.org/10.3390/biom15111599
  32. FASEB J. 2025 Nov 30. 39(22): e71242
    Ubiquitin Specific Peptidase 51 Exacerbates Skeletal Muscle Injury by Enhancing APAF1-Mediated Apoptosis and Pyroptosis.
    Yu Chen, Jie Xu, Yue Ma, Rudong Zhan, Shangjun Gao, Shiguo Zhou, E Chen.
      Skeletal muscle injury (SMI) involves complex cellular events, including oxidative stress, inflammation, and programmed cell death. However, the molecular mechanisms governing the cell death pathways in SMI remain incompletely understood. In this study, we identified the deubiquitinating enzyme USP51 as a novel modulator of SMI. Ubiquitin Specific Peptidase 51 (USP51) expression is significantly upregulated in the tBHP-induced oxidative stress C2C12 myotubes model. Functional assays demonstrated that USP51 knockdown enhances cell viability and suppresses both apoptosis and pyroptosis. Bioinformatic screening and protein-protein interaction analysis identified APAF1, a key regulator of intrinsic apoptosis, as a potential USP51-interacting partner. Co-immunoprecipitation and ubiquitination assays confirmed that USP51 interacts with and deubiquitinates APAF1, thereby increasing its protein stability in C2C12 cells. Notably, APAF1 overexpression in USP51-deficient C2C12 myotubes mitigated the protective effects of USP51 knockdown, restoring apoptosis and pyroptosis. AAV-mediated knockdown of USP51 alleviated muscle damage, preserved myofiber integrity, reduced inflammation, and decreased apoptotic and pyroptotic cell death in the SMI mouse model. However, concurrent APAF1 overexpression abolished these beneficial effects, underscoring the critical role of the USP51-APAF1 axis in amplifying SMI. Collectively, our study suggests that targeting the USP51-APAF1 axis may represent a promising therapeutic strategy for mitigating muscle damage.
    Keywords:  USP51; apoptosis; pyroptosis; skeletal muscle injury
    DOI:  https://doi.org/10.1096/fj.202503043R
  33. bioRxiv. 2025 Oct 28. pii: 2025.10.27.683567. [Epub ahead of print]
    Opposite directions of association of higher physical activity and higher insulin resistance with human skeletal muscle cell type abundance and fiber type-level gene expression.
    Dan L Ciotlos, Sarah C Hanks, Arushi Varshney, Michael R Erdos, Nandini Manickam, Heather M Stringham, Peter Orchard, Erin M Hill-Burns, Narisu Narisu, Lori L Bonnycastle, Michael D Sweeney, Jouko Saramies, Markku Laakso, Jaakko Tuomilehto, Timo A Lakka, Karen L Mohlke, Michael Boehnke, Francis S Collins, Heikki A Koistinen, Stephen C J Parker, Laura J Scott.
      To investigate the interplay between physical activity and cardiometabolic traits in human skeletal muscle, we characterized gene expression and chromatin accessibility across skeletal muscle cell types in 263 Finnish individuals from the FUSION Tissue Biopsy Study. We analyzed skeletal muscle single nucleus RNA-sequencing data (168,309 nuclei, 23,841 genes), single nucleus ATAC-sequencing data (242,069 nuclei, 924,519 peaks), and bulk RNA-sequencing data (22,309 genes). Lower insulin resistance (HOMA-IR) and higher total physical activity were both associated with higher proportions of Type 1 nuclei and lower proportions of Type 2x nuclei. We identified cell type-level and tissue-level gene expression-trait and gene set-trait associations for cardiometabolic and physical activity traits, and a smaller proportion of cell type-level chromatin accessibility-trait associations. Traits typically associated with better health - lower trait values of cardiometabolic traits (BMI, HOMA-IR, normal glucose tolerance vs. type 2 diabetes, fasting plasma glucose) and higher physical activity levels (total and vigorous) - were associated with higher expression of energy metabolism genes, and lower expression of signaling pathway genes across muscle fiber types, total pseudobulk, and to some extent in bulk tissue. For HOMA-IR and physical activity these directions of association remained when adjusting for both traits in the same model, indicating apparently independent associations on the same pathways.
    DOI:  https://doi.org/10.1101/2025.10.27.683567
  34. Mol Cell Endocrinol. 2025 Nov 20. pii: S0303-7207(25)00255-2. [Epub ahead of print]612 112704
    Androgen deprivation induces distinct muscle-specific transcriptional changes to genes regulating glucose, lipid, and amino acid metabolism.
    Wayne A Ayers-Creech, Jennifer L Steiner, Grant R Laskin, Bradley S Gordon.
       BACKGROUND: Androgens such as testosterone regulate whole-body metabolic homeostasis. Low androgen levels lead to undesirable shifts in metabolism including lower glucose oxidation, greater lipid reliance, and altered amino acid metabolism. Skeletal muscle is a primary site regulating fuel substrate metabolism, but whether all muscles contribute to the undesirable metabolic shifts in response to low androgen levels is unclear.
    METHODS AND RESULTS: Male mice underwent sham or castration surgery and muscles were harvested 7, 14-, 21-, 28-, or 49-days post-surgery. The content of genes related to glucose, lipid, and amino acid metabolism were assessed in the tibialis anterior (TA) and gastrocnemius muscles. The content of genes related to glucose metabolism were altered in a manner consistent with lower rates of oxidation in both the TA and gastrocnemius following castration although the magnitudes of change were generally more pronounced in the TA. Genes related to lipid oxidation were altered in a manner consistent with higher oxidation rates only in the TA following castration. Genes related to amino acid catabolism were paradoxically unaltered or even lower in both muscles in response to castration.
    CONCLUSION: These findings indicate that the TA undergoes more pronounced transcriptional changes related to glucose and lipid metabolism compared to the gastrocnemius, likely contributing more to whole-body metabolic shifts during androgen deprivation.
    Keywords:  Hypogonadism; Muscle atrophy; Testosterone
    DOI:  https://doi.org/10.1016/j.mce.2025.112704
  35. Sci Rep. 2025 Nov 26.
    Disulfiram inhibits Gasdermin D pores formation and improves insulin-dependent glucose uptake and glucose homeostasis in skeletal muscle of obesity-induced insulin-resistant mice.
    Cynthia Cadagan, Javier Russell-Guzmán, Luan Américo-Da-Silva, Paula Montaña, Genaro Barrientos, Sonja Buvinic, Gladys Tapia, Manuel Estrada, Paola Llanos.
      Insulin resistance (IR), which involves impaired insulin signaling diminished insulin sensitivity in skeletal muscle, is closely associated with chronic low-grade inflammation. A key mediator of this process is the NLRP3 inflammasome, which activates Gasdermin D (GSDMD). Upon cleavage, the N-terminal fragment of GSDMD (GSDMD-NT) forms membrane pores that facilitate interleukin-1β (IL-1β) release. Disulfiram (DSF), an FDA-approved drug that also inhibits GSDMD-NT pore formation, has emerged as a potential therapeutic for inflammasome-mediated inflammation. However, the role of GSDMD in skeletal muscle during IR remains poorly understood. This study evaluated whether GSDMD-NT-mediated IL-1β release contributes to skeletal muscle inflammation and IR, and whether DSF can restore insulin sensitivity. Male C57BL/6 mice were fed a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks; a subgroup of HFD-fed mice received intraperitoneal DSF (50 mg/kg) for 3 weeks. The flexor digitorum brevis (FDB) and gastrocnemius muscles were collected for single-fiber isolation, quantitative PCR, immunoblotting, and immunofluorescence. IL-1β levels were measured by ELISA. Insulin sensitivity was assessed via 2-NBDG uptake, Akt phosphorylation, and glucose tolerance tests (IPGTT). HFD-fed mice exhibited increased GSDMD-NT and oligomer levels, localized to the sarcolemma and T-tubules, along with elevated IL-1β in skeletal muscle. DSF administration reduced weight gain, fasting glycemia, IPGTT, and systemic IL-1β, while enhancing insulin-stimulated 2-NBDG uptake and Akt phosphorylation in FDB. Moreover, DSF reduced GSDMD-NT oligomerization and IL-1β release in the gastrocnemius muscle. These findings suggest a novel pathogenic role for GSDMD in skeletal muscle IR and support DSF as a potential candidate for metabolic disease intervention.
    Keywords:  GSDMD-NT; Glucose uptake; IL-1β release; Insulin signaling; NALP3 inflammasome
    DOI:  https://doi.org/10.1038/s41598-025-30058-6
  36. Biomed Pharmacother. 2025 Nov 25. pii: S0753-3322(25)01019-4. [Epub ahead of print]193 118825
    Oxytocin treatment reduces cancer cachexia in a pre-clinical model.
    Alexandra Sviercovich, Etsuko Watanabe, Estefania S Fernandez, Alessandra Renzini, Chao Liu, Grace Xie, Jasmine Cao, Zhenlin Li, Onnik Agbulut, Marilia Seelaender, Jose Pinhata Otoch, Daniele De Meo, Gianluca Cera, Viviana Moresi, Francesca Palermo, Sergio Adamo, Michael J Conboy, Irina M Conboy, Dario Coletti.
      Oxytocin (OT) is a neurohypophyseal peptide with decreased expression during aging, essential for skeletal muscle homeostasis, and counteracts sarcopenia in aged mice. Yet, its function in cancer cachexia remains unexplored. We investigated OT serum levels in cancer patients, comparing these with cachectic patients and non-cancer controls, as well as OT/OT-receptor (OTR) mRNA in sarcopenic muscle. Potential benefits of OT were assessed in vitro using L6C5 myoblasts and murine isolated myofibers exposed to C26-conditioned medium and in vivo using the C26/Balb/c cancer cachexia model. Finally, the molecular effects of OT on de novo protein synthesis via bio-orthogonal non-canonical amino acid tagging (BONCAT) were investigated using MetRSL274G C57BL/6 mice. Circulating OT was significantly lower in cancer patients than in non-cancer disease (-60 %, p < 0.01). Sarcopenic muscle showed over threefold downregulation of the OTR (p < 0.032). In vitro, OT reversed the myogenic inhibition induced by tumor cell-conditioned medium, boosting fusion index (>6-fold, p < 0.001), nuclei per myotube (>8-fold, p < 0.001), and myotube diameter (>6-fold, p < 0.001). In C26 tumor-bearing mice, OT restored skeletal muscle mass (>1.5-fold, p < 0.001), fiber cross-sectional area (>1.5-fold, p < 0.001), and overall body weight, while reducing the muscle degradation determinants: MuRF1 (>8-fold, p < 0.001) and Atrogin1 (>6-fold, p < 0.001). Metabolic proteomics showed that cancer perturbed and OT restored the synthesis of key proteins (+23 %, p < 0.05) that play essential roles in muscle regeneration and inter-organ communication. Given that OT is approved for clinical use, our findings suggest that it could quickly be translated into effective therapies for preventing or treating cachexia in cancer patients.
    Keywords:  BONCAT; Cancer cachexia; Oxytocin; Protein metabolism
    DOI:  https://doi.org/10.1016/j.biopha.2025.118825
  37. Am J Physiol Cell Physiol. 2025 Nov 25.
    Non-coding RNA molecules mediating skeletal muscle mitochondrial function and their potential applications in exercise molecular physiology: A systematic review.
    Isaac A Chavez-Guevara, Héctor Vázquez-Lorente, Lourdes Herrera-Quintana, Mariazel Rubio-Valles, Luis C López, Julio Plaza-Díaz, Francisco J Amaro-Gahete.
      This systematic review investigates the role of non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, circRNAs, and tRNAs, in regulating mitochondrial biogenesis, dynamics, oxidative phosphorylation, and mitophagy in skeletal muscle and the potential applications of these ncRNAs in exercise molecular physiology. We conducted a comprehensive search in PubMed, Scopus, and Web of Science databases, identifying 45 relevant studies out of 2,378 records. The main findings indicate that miRNAs such as miR-128, miR-133a, miR-696, and miR-499 are critical regulators of mitochondrial function. Moreover, lncRNAs (lncEDCH1 and lncRNA-H19) and circRNA (circ-PTPN4) significantly influence mitochondrial biogenesis and function. Exercise interventions were shown to modulate the expression of these ncRNAs, particularly miR-133a and miR-696, leading to enhanced mitochondrial biogenesis and function. The review highlights the potential of these ncRNAs as biomarkers and therapeutic targets for improving mitochondrial function and treating metabolic and mitochondrial disorders. Further research is needed to explore the muscle-specific and exercise-modality-specific effects of ncRNAs to develop personalized interventions. Understanding the complex regulatory mechanisms of ncRNAs in mitochondrial adaptations can pave the way for innovative therapeutic strategies in exercise molecular physiology and metabolic health.
    Keywords:  cell biology; energy metabolism; epigenetics; physical activity
    DOI:  https://doi.org/10.1152/ajpcell.00313.2025
  38. Muscles. 2025 Oct 23. pii: 48. [Epub ahead of print]4(4):
    Pretreatment of Mice with 830 nm Light Enhances Endurance During Acute Exercise.
    Nashwa Cheema, Namrata Ghag, Linh Pham, Emma Wise, Christiane Fuchs, Rox Anderson, Joshua Tam.
      Light therapy has been shown to produce several beneficial physiological effects in a wide range of tissues. The musculoskeletal system can be irradiated with deeply penetrating wavelengths in near infrared (NIR) regions. Photobiomodulation therapy (PBMT) reduces pain and inflammation and enhances physical performance. However, the mechanism(s) of cellular responses to PBMT in muscle is not clearly understood. Therefore, the goal of this study is to improve our understanding of the mechanism(s) of action of PBMT effects in exercised and sedentary muscle. In sedentary mice, PBMT using a wavelength of 830 nm increased the gene expression for muscle tissue development, including cFos, which is critical for activating interstitial and satellite cells that repair muscle. Immunostaining for cFOS expression confirmed an increase in the number of activated cells in PBMT-treated muscle. We observed that PBMT-treated mice showed increased performance on the treadmill, reduced muscle fiber damage, and altered mitochondrial structure. RNA sequencing from fatigued TA tissue suggested that PBMT treatment increased the gene expression of tissue regeneration and remodeling, suggesting tissue adaptation and muscle repair after exercise with PBMT. In conclusion, our study suggests that the 830 nm wavelength may have altered the muscle by activating regenerative genes that protect the tissue from exercise-induced cellular stress.
    Keywords:  exercise; fatigue; low-level light therapy; mitochondria; mouse; near-infrared light; photobiomodulation; skeletal muscle
    DOI:  https://doi.org/10.3390/muscles4040048
  39. Gene Ther. 2025 Nov 25.
    Codon-optimized human Smad7 gene therapy enhances skeletal muscle mass and function in a murine model of Duchenne muscular dystrophy.
    Buel D Rodgers, Christopher W Ward.
      Commercial development of gene therapeutics often requires transitioning to human payload genes as initial proof-of-concept studies in animal models often use taxa-specific orthologs. Such transitions also provide opportunities to address potential secondary structure and immune-related subsequences as with human Smad7 cDNA, which was optimized by removing several repeats, potential hairpins and negative cis elements. Thermodynamic modeling at or above minimal free energy states revealed substantial improvements in secondary structure with fewer hairpins and improved diversity scores. Serotype 6 adeno-associated viral vectors with optimized human Smad7 (AVGN7.2) expression constructs were equally or more effective than those with wild-type mouse Smad7 in stimulating skeletal muscle hypertrophy and enhancing isometric torque of hind-limb dorsiflexor muscles in vivo. In murine models of Duchenne Muscular dystrophy, where deficits in muscle mass and disproportionate declines in force are pathognomonic, AVGN7.2 proportionally increased muscle mass and isometric torque while normalizing contractile kinetics. Such improvements occurred without deleterious impacts on serum creatine kinase, fibrosis or myofiber central nucleation. These data suggest that AVGN7.2 is capable of enhancing dystrophic muscle function without exacerbating muscle degeneration. Although these functional effects were partial, they resembled those of several dystrophin-targeting drugs and suggest that combinatorial approaches may safely yield further benefit.
    DOI:  https://doi.org/10.1038/s41434-025-00583-0
  40. Biomolecules. 2025 Nov 17. pii: 1610. [Epub ahead of print]15(11):
    Interactive Role of the DHPR β1a SH3 Domain in Skeletal Muscle Excitation-Contraction Coupling.
    Yamuna Karunasekara, Shouvik Aditya, Nicole C Norris, Jean Cappello, Angela F Dulhunty, Philip G Board, Jose M Eltit, Claudio F Perez, Marco G Casarotto.
      Excitation-contraction (EC) coupling in skeletal muscle requires a physical interaction between the voltage-gated calcium channel, dihydropyridine receptor (DHPR), and the ryanodine receptor (RyR1) Ca2+ release channel. Although the exact mode of communication that links these two membrane proteins remains to be fully resolved, both the α1s and β1a subunits of DHPR are two of a select number of critical proteins involved in this process. A detailed in vitro interaction study of these two proteins reveals that their association occurs between the β1a SH3 domain and the polyproline motifs located in a critical region of the α1s II-III loop. We demonstrate that subtle changes in the composition of the β1a SH3 domain influences the ability of β proteins to bind to II-III loop proteins and investigate the effect of these changes on EC skeletal coupling. Furthermore, investigation into the composition of the II-III loop shows that previously identified amino acids demonstrated to be important in EC coupling are implicated in in vitro binding. In summary, we ascribe a role for the DHPR β1a which involves the engagement of its SH3 domain with the α1s II-III loop and propose a scenario whereby this interaction may facilitate skeletal muscle EC coupling.
    Keywords:  SH3 domain; dihydropyridine receptor; excitation contraction coupling; ryanodine receptor; skeletal muscle
    DOI:  https://doi.org/10.3390/biom15111610
  41. Curr Biol. 2025 Nov 21. pii: S0960-9822(25)01458-7. [Epub ahead of print]
    Synaptic-like coupling of macrophages to myofibers regulates muscle repair.
    Gyanesh M Tripathi, Adam J Dourson, Fabian Montecino-Morales, Jennifer L Wayland, Sahana Khanna, Megan C Hofmann, Hima Bindu Durumutla, Thirupugal Govindarajan, Luis F Queme, Douglas P Millay, Michael P Jankowski.
      Peripheral injury responses essential for muscle repair and nociception require complex interactions of target tissues, immune cells, and primary sensory neurons. Nociceptors and myofibers both react robustly to signals generated from circulating immune cells, which promote repair, growth, and regeneration of muscle while simultaneously modulating peripheral sensitization. Here, we found that macrophages form a synaptic-like contact with myofibers to hasten repair after acute incision injury and to facilitate regeneration after major muscle damage. Transient chemogenetic activation of macrophages enhanced calcium-dependent membrane repair, induced muscle calcium transients in vivo, elicited low-level electrical activity in the muscles, and enhanced myonuclear accretion. Under severe injury, macrophage activation could also modulate pain-like behaviors. This study identifies a novel mechanism by which synaptic-like functions of macrophages impact muscle repair after tissue damage.
    Keywords:  behavior; calcium imaging; electromyography; muscle injury; muscle regeneration; pain
    DOI:  https://doi.org/10.1016/j.cub.2025.10.077
  42. J Endocrinol. 2025 Nov 25. pii: JOE-25-0203. [Epub ahead of print]
    Thyroxine does not improve skeletal muscle regeneration after injury in aged mice.
    Thamires Siqueira Oliveira, Alexander Pereira da Rosa, Matheus da Silva Ferreira, Victoria Regina de Siqueira Monteiro, Juliana de Brito, Hanailly Ribeiro Gomes, Kayo Moreira Bagri, Lívia Maria Marvulo Pires, Júlia Taconi da Silva, Claudia Mermelstein, Flávia Alessandra Guarnier, Tania Maria Ortiga-Carvalho, Flavia Fonseca Bloise.
      Thyroid hormone levels decrease with aging, and low thyroxine levels are correlated to sarcopenia development. While thyroid hormone stimulates myogenesis in young subjects, its effect on aged muscle regeneration is unclear. We aimed to investigate the impact of a low dose of thyroxine (T4) replacement therapy (7.5 ng/g body weight) on tibial anterior regeneration seven days after injury by 1.2% BaCl2 injection in 24-27-month-old male mice. Our primary data suggest that regenerating aged skeletal muscle exhibits local resistance to thyroid hormone action without altering myogenic regulatory factors expression. However, T4 treatment decreases the number of central nuclei, indicative of newformed fibers. Also, we observed decrease in cross-sectional area and increases myonuclei domain, cell death and laminin expression in T4 treatment injured muscles. Rather than improving regeneration, T4 replacement therapy appears to induce atrophy and tissue remodelling. Our data highlight the need to understand aging physiology since thyroid hormones are crucial for muscle regeneration in young animals, although T4 replacement therapy does not improve muscle regeneration post-injury in elderly mice. This research may support clinical recommendations against treating sarcopenic patients with subclinical hypothyroidism, especially following fall-related injuries.
    Keywords:  injury; regeneration; skeletal muscle; thyroid hormone
    DOI:  https://doi.org/10.1530/JOE-25-0203
  43. Front Cell Dev Biol. 2025 ;13 1715009
    Molecular communication from bone to skeletal muscle: an overview.
    Guobin Li, Mingyan Qi, Yuzhen Wang, Shibin Liang, Huiyun Xu.
      The intricate interactions between bone and muscle are central to musculoskeletal health. It was historically assumed that bone and muscle interact through mechanical coupling, that is, skeletal muscles attach to bone and facilitate movement of the bone via muscular contraction. However, recent studies have recognized bone and muscle as endocrine organs, capable of producing and releasing osteokines and extracellular vesicles (EVs) that influence each other's functions, thereby introducing a novel concept known as "bone-muscle crosstalk". The influence of muscle on bone has been extensively studied, little has reported regarding the muscle regulation by bone. Emerging studies indicate that the transmission of signaling molecules from bone to muscle is partially mediated by hemichannels and gap junctions formed by connexin 43 (Cx43) in osteoblasts and osteocytes. This review aims to summarize the latest findings on bone-muscle crosstalk, with a particular emphasis on the roles of osteokines and EVs derived from bone. Furthermore, it highlights the channel functions of Cx43 in the release of secretory factors through this crosstalk mechanism. The continued research into bone-muscle crosstalk is expected to identify new therapeutic targets for the twin diseases of osteoporosis and sarcopenia.
    Keywords:  bone; connexin43; crosstalk; extracellular vesicles; muscle; osteokines
    DOI:  https://doi.org/10.3389/fcell.2025.1715009
  44. Mol Immunol. 2025 Nov 21. pii: S0161-5890(25)00264-0. [Epub ahead of print]188 142-153
    Association of YY1 with STING activation and the inflammatory response during early muscle injury repair.
    Xili Yan, Zhongxing Hou, Wenxin Li, Shuang Miao, Zejia Zhang, Jie Luo, Yinan Tao, Qiang Li, Jian Zhao, Zhiliang Xu.
       BACKGROUND: Skeletal muscle injury is a common sports injury. Although the cGAS-STING signaling pathway is implicated in myoblast differentiation and muscle regeneration, its precise mechanisms remain unclear. Yin Yang 1 (YY1), a multifunctional transcriptional and chromatin regulator involved in various pathologies, also requires investigation for its specific role in regeneration.
    OBJECTIVES: This study aimed to investigate the association between YY1 and cGAS-STING pathway activation during early muscle regeneration, and explore its potential role in the inflammatory phase of myoblast differentiation.
    METHODS: A skeletal muscle injury model was established in C57BL/6 mice using 1.2 % barium chloride. H&E staining evaluated muscle regeneration. Immunohistochemistry (IHC) quantified MyoG, YY1, H2Bub, and RNF20 expression. Immunofluorescence (IF) determined STING and YY1 expression. Western blotting measured cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20 protein levels. qPCR analyzed mRNA of inflammatory factors (IL-6, IL-17, IL-1β, TNF-α), myogenic regulators (MyoD, MyoG, Myf5), and signaling molecules (cGAS, STING, YY1, IRF3, caspase-3). Co-immunoprecipitation (Co-IP) assessed STING-YY1 interaction.
    RESULTS: Post-injury histology revealed significant pathology and inflammation. qPCR indicated upregulated mRNA levels of inflammatory factors and myogenic/signaling molecules at day 3, with partial recovery by day 7. Consistently, IHC (YY1, H2Bub, RNF20), IF (STING, YY1), and WB (cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20) all demonstrated elevated expression at day 3, declining by day 7. Co-IP confirmed a direct STING-YY1 interaction.
    CONCLUSION: Our findings reveal a significant association between YY1 and cGAS-STING signaling activation, suggesting that this interplay contributes to the modulation of the inflammatory response during the early phase of skeletal muscle repair.
    Keywords:  Inflammatory response; STING; Skeletal muscle injury; YY1; cGAS
    DOI:  https://doi.org/10.1016/j.molimm.2025.11.011
  45. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70130
    Myostatin Exhibits an Evolutionarily Conserved Circadian Pattern in Skeletal Muscles.
    Xiangpeng Liu, Changyou Song, Yan Xiong, Jinxin Gu, Lianxin Wu, Taole Liu, Xiyue Chen, Hui Shu, Yingying Dong, Tizhong Shan, Sheng Wang, Yucheng Zhu, Tongxing Song, Lei Fu, Yaqiu Lin, Can Liu, Ruiqi Zheng, Xiao Zhao, Hongxia Li, Yong Xu, Shihuan Kuang, Han Wang, Bin Guo, Pao Xu, Zhihao Jia.
       INTRODUCTION: Myostatin (MSTN), a transforming growth factor-beta (TGF-β) superfamily member, is an evolutionarily conserved negative regulator of skeletal muscle mass. Loss of MSTN commonly promotes augmentation in skeletal muscle mass in all animal species examined. Recent studies have demonstrated that circadian clock proteins play a critical role in the regulation of muscle mass and function, in part by modulating the expression of key muscle-related genes. While myostatin has an important role in sustaining skeletal muscle protein turnover, it is unknown if circadian clock proteins regulate myostatin in a circadian pattern.
    METHODS: We analysed time-course muscle samples from 16 animal species ranging from Caenorhabditis elegans to humans and examined the rhythmic expression pattern of Mstn. We also used various circadian clock deficient models such as muscle-specific Bmal1 knockout, Per1/Per2 double knockout, genetic knockout of per0 and tim0 genes in fruit flies, clocka gene in zebrafish and environmental perturbation.
    RESULTS: Both mRNA and protein of MSTN exhibit rhythmic expression patterns in a variety of animal species ranging from Caenorhabditis elegans (C. elegans) to humans. The rhythmicity of Mstn orthologs in muscle is evolutionarily conserved along with their sequence evolution in C. elegans, Drosophila melanogaster, Crustacea, fish and mammals including mice (mRNA: amplitude = 0.188, p < 0.0001; protein: amplitude = 0.255, p < 0.05), goats, pigs and humans. In murine skeletal muscle, rhythmic expression of Mstn is synchronized with the core circadian genes, Per2. We then constructed a muscle-specific Bmal1 knockout mouse model (Bmal1MKO). Notably, Bmal1MKO mice had increased body weight (29.30 ± 0.85 vs. 32.16 ± 0.79, p < 0.05) and lean mass (WT 23.33 ± 0.35 vs. 25.35 ± 0.45, p < 0.01), while the difference in lean mass at 12 weeks of age (~1.996 g) closely matches the difference in total body weight (~ 2.000 g). Muscle-specific Bmal1 knockout reduced the mRNA and protein levels of mstn/MSTN by ~ 50%. In addition, disruption of the circadian clock by constant light or Per1/Per2 double knockout also abolishes the rhythmicity of Mstn. Similarly, genetic knockout of per0 and tim0 genes in fruit flies, clocka gene in zebrafish (mstna: p < 0.01 vs. p = 0.6397) and environmental perturbation (Aplodinotus grunniens, mstn1: p < 0.0001 vs. p = 0.04; mstn2: p < 0.05 vs. p = 0.06) all alter Mstn oscillation profoundly.
    CONCLUSIONS: These findings reveal an evolutionarily conserved rhythmic expression pattern of Mstn in skeletal muscles.
    Keywords:  circadian clock; myostatin; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.70130
  46. Nat Commun. 2025 Nov 26.
    Enhancer regulator MLL4 controls skeletal muscle metabolic efficiency by limiting AMPK-mediated fuel catabolism.
    Likun Yang, Lin Liu, Wen Wang, Chenyun Ding, Aneesh K Asokan, Tingze Feng, Danxia Zhou, Zhisheng Xu, Tingting Fu, Qiqi Guo, Zheng Zhou, Shaojun Pei, Gonghao Shen, Liwei Xiao, Yujing Yin, Zongchao Sun, Yan Mao, Wanping Sun, Jinjie Li, Jiacheng Xue, Min-Sheng Zhu, Kai Ge, K Sreekumaran Nair, Hai-Long Piao, Zhenji Gan.
      Skeletal muscle is a major organ for maintaining whole-body energy balance, yet how it adapts its transcriptional and metabolic programs to environmental cues remains unclear. Here, we report that histone mono-methyltransferase mixed lineage leukemia 4 (MLL4), a key enhancer regulator, directs muscle metabolic adaptation and systemic metabolism through AMPK signaling. Nutrient availability modulates MLL4 expression, and skeletal muscle-specific ablation of MLL4 in male mice protects against diet-induced obesity and improves glucose homeostasis despite reduced exercise endurance. These effects arise from enhanced fuel catabolism caused by marked activation of AMPK in MLL4-depleted muscles. Mechanistically, MLL4 cooperates with myocyte enhancer factor 2 to induce AMP-metabolizing enzymes cytosolic 5'-nucleotidase 1A and AMP-deaminase 3, which suppress AMPK activity. Pharmacologic inhibition of AMP-metabolizing pathway by Pentostatin activates muscle AMPK, confers resistance to obesity and improves metabolic health. These findings identify an enhancer regulator limiting AMPK-mediated muscle fuel catabolism, offering a potential strategy for treating obesity-related disorders.
    DOI:  https://doi.org/10.1038/s41467-025-66684-x
  47. Epigenetics. 2025 Dec;20(1): 2590237
    Crosstalk between skeletal muscle and the brain during physical activity - in search of epigenetic mechanisms.
    Cayla Boycott, Ewa Kilanczyk, Huiying A Zhang, Jiaxi Zhang, Arian Abolhassani, Malgorzata Kubiak, Jan Celichowski, Katarzyna Kryściak, Dominika Gruszka, Joanna H Sliwowska, Barbara Stefanska.
      Recent research highlights the crucial role of muscle-brain crosstalk in metabolic regulation, particularly in individuals with type 2 diabetes and obesity. Myokines, protein hormones secreted by skeletal muscle, play a crucial role in this communication, influencing brain functions such as neuroplasticity, memory, and mood. Specific myokines like cathepsin B, FNDC5/irisin and interleukin-6 have been identified as key players in this muscle-brain axis. Physical activity modulates the production of these molecular factors, enhancing muscle-brain crosstalk and influencing cellular interactions. Moreover, exercise training may lead to adaptive long-term changes in gene expression, mediated by epigenetic regulators. Metabolic pathways activated during exercise can directly impact epigenetic marks by modulating the availability of metabolic intermediates required for these modifications. In the present review, we summarize the latest findings on the association between obesity/diabetes and cognitive impairment due to hippocampal dysfunction, and elaborate on how exercise influences cognitive functions via the communication between skeletal muscle and the brain. We focus on the underlying mechanisms responsible for the muscle-brain crosstalk, emphasizing dynamic changes in the epigenome and epitranscriptome, which sheds light on novel preventive and therapeutic approaches to combat obesity and cognitive decline.
    Keywords:  Muscle-brain crosstalk; epigenetics; epitranscriptomics; myokines; physical activity
    DOI:  https://doi.org/10.1080/15592294.2025.2590237
  48. Obes Rev. 2025 Nov 28. e70046
    Meteorin-Like Protein (Metrnl): An Exercise-Induced Myokine With Therapeutic Potential in Metabolic and Inflammatory Disorders.
    Lijun Zhou, Huanyu Long, Hamid Alizadeh.
      The global prevalence of obesity and metabolic disorders presents a substantial public health issue, with projections indicating that, by 2035, approximately 54% of the worldwide adult population will be classified as having overweight or obesity. Exercise immunometabolism has developed as a field investigating the mechanistic interplay between physical activity and the reciprocal regulation of immune and metabolic processes. Central to this paradigm are myokines, cytokines secreted by skeletal muscle during contraction, mediating the systemic benefits of exercise. Myokine meteorin-like protein (Metrnl) has attracted scientific attention due to its multiple roles in health and disease, including both protective metabolic effects and potential involvement in cancer progression. This review synthesizes current knowledge on Metrnl as an exercise-responsive myokine, examining its molecular regulation and its modulation by various exercise modalities, with high-intensity and resistance training showing the most pronounced effects. We present evidence from both preclinical models and clinical studies of Metrnl's anti-inflammatory and metabolic actions across multiple organ systems, including its role in mediating muscle-adipose, muscle-pancreas, muscle-cardiovascular, muscle-liver, muscle-immune, and muscle-brain crosstalk. Preclinical research has demonstrated Metrnl's effects on glucose homeostasis, insulin sensitivity, adipose tissue browning, and cardiovascular function while attenuating inflammation, with clinical studies beginning to validate these findings in humans. Despite promising results, challenges remain in translating these insights into clinical practice, including variability in human responses and knowledge gaps regarding demographic influences. This review addresses these translational challenges and proposes future research directions to utilize the therapeutic potential of Metrnl in metabolic and inflammatory disorders.
    Keywords:  anti‐inflammatory effects; exercise immunometabolism; metabolic health; meteorin‐like protein (Metrnl); myokine; therapeutic target
    DOI:  https://doi.org/10.1111/obr.70046
  49. Medicina (Kaunas). 2025 Nov 12. pii: 2022. [Epub ahead of print]61(11):
    Exercise Modulation of the Myostatin-FOXO Pathway in Murine Models of Cancer Cachexia: A Systematic Review.
    Zahra Zare, Mahfoodha Al Kitani, Shahnaz Shahrbanian.
      Background and Objectives: Cancer cachexia is a debilitating metabolic syndrome highly prevalent in colorectal cancer (CRC), characterized by progressive skeletal muscle wasting. The myostatin-FOXO signaling pathway contributes to this process by activating the E3 ubiquitin ligases MuRF-1 and Atrogin-1. Exercise is a promising non-pharmacological strategy, but its effects on this pathway in CRC cachexia remain unclear. This review aimed to synthesize preclinical evidence on the impact of exercise on the myostatin-FOXO axis. Materials and Methods: A comprehensive search was performed in PubMed/MEDLINE, Scopus, Web of Science, and Science Direct from inception through August 2025. Eligible studies included murine CRC models (C26 or ApcMin/+) exposed to aerobic, resistance, or combined exercise interventions, with outcomes assessing myostatin, FOXO, MuRF-1, or Atrogin-1. Study quality was appraised using the CAMARADES 10-item checklist. Results: eleven studies met the criteria, with quality scores ranging from 6 to 8. Aerobic exercise, particularly voluntary wheel running, most consistently reduced MuRF-1 expression and systemic inflammation, whereas resistance and eccentric training exerted stronger inhibitory effects on FOXO and Atrogin-1. Myostatin was directly measured in two studies, yielding inconsistent results. Resistance and eccentric training promoted anabolic signaling (e.g., mTORC1), whereas aerobic protocols improved oxidative capacity. Variability in exercise type, intensity, and duration contributed to heterogeneity across findings. Conclusions: Exercise attenuates skeletal muscle catabolism in CRC-induced cachexia, mainly through modulation of the myostatin-FOXO pathway and downstream ligases. However, limited direct data on myostatin and methodological heterogeneity underscore the need for standardized protocols and translational studies. This review provides the first focused synthesis of exercise-mediated regulation of this pathway in CRC cachexia.
    Keywords:  colorectal neoplasms; muscular atrophy; resistance training; ubiquitin–proteasome
    DOI:  https://doi.org/10.3390/medicina61112022
  50. Aging Dis. 2025 Nov 23.
    Emerging Roles of Skeletal Muscle-Derived Exosomal miRNAs in Metabolic Regulation: A Perspective.
    Fei Zhang, Ziwen Wang, Zhong Wang.
      Skeletal muscle (SKM) is now recognized not only for its classical functions but also as a secretory organ. It communicates with other tissues through myokines and extracellular vesicles, such as exosomes. Among these components, microRNAs (miRNAs) are particularly notable due to their stability, evolutionary conservation, and ability to potently regulate gene expression. Growing evidence suggests that these exosomal miRNAs act as important mediators of inter-organ communication in both glucose and lipid metabolism. Exosomal miRNAs derived from senescent SKMs drive systemic metabolic dysregulation by targeting critical signaling pathways in insulin sensitivity and lipid metabolism. Consequently, SKM-derived exosomal miRNAs have emerged as a promising new class of biomarkers and therapeutic targets for metabolic diseases.
    DOI:  https://doi.org/10.14336/AD.2025.1331
  51. bioRxiv. 2025 Nov 14. pii: 2025.11.13.688391. [Epub ahead of print]
    Modulating MyoD1 dosage activates alternate cell fate beyond myogenic differentiation.
    Oscar N Whitney, Gina M Dailey, Joseph K McKenna, Xavier Darzacq, Robert Tjian.
      Transcription factor (TF) expression and dosage regulate developmental cell fate decisions. Increased TF dosage has been predicted to enhance expression of high-affinity target genes but also increase the binding of lower-affinity loci. The relative importance of high- versus lower-affinity TF binding in guiding cell fate decisions remains unclear. To test the roles of TF dosage, we examined the effects of increasing the dosage of MyoD1, the "master regulator of myogenesis", on skeletal muscle differentiation. Unexpectedly, increased MyoD1 dosage inhibited canonical myogenesis and redirected myoblast differentiation towards forming spontaneously contracting myotubes. This novel phenotype was driven by the MyoD1-dose-dependent upregulation of non-myogenic genes, including cell adhesion genes whose ectopic expression also inhibited classical myogenic differentiation and enabled myotube contraction. Live-cell single-molecule imaging showed that elevated MyoD1 dosage increased total chromatin binding and CUT&RUN profiling demonstrated that this increase occurred via preferential binding to lower-affinity loci. Integration of CUT&RUN, ATAC-seq and RNA-seq experiments revealed that increased MyoD1 binding correlated to the upregulation of otherwise lowly expressed genes. These findings suggest that increased MyoD1 dosage induced a selective gene regulatory expansion from high- to lower-affinity cis-regulatory elements, activating a broader ensemble of target genes, revealing a TF dose-dependent mechanism that can trigger distinct developmental programs.
    DOI:  https://doi.org/10.1101/2025.11.13.688391
  52. Int J Mol Sci. 2025 Nov 13. pii: 10977. [Epub ahead of print]26(22):
    Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes.
    Neil V Yang, Sean Rogers, Rachel Guerra, Justin Y Chao, David J Pagliarini, Elizabeth Theusch, Ronald M Krauss.
      Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of TOMM40 and TOMM22, genes that encode major subunits of the translocase of the outer mitochondrial membrane (TOM) complex. Mitochondrial effects of knockdown of TOMM40 and TOMM22 in mouse C2C12 and primary human skeletal cell myotubes include impaired oxidative function, increased superoxide production, reduced cholesterol and CoQ levels, and disrupted markers of mitochondrial dynamics and morphology as well as increased mitophagy, with similar effects resulting from simvastatin exposure. Overexpression of TOMM40 and TOMM22 in simvastatin-treated mouse and human skeletal muscle cells rescued effects on markers of mitochondrial dynamics and morphology, but not oxidative function or cholesterol and CoQ levels. These results show that TOMM40 and TOMM22 have key roles in maintaining both mitochondrial dynamics and function and indicate that their downregulation by statin treatment results in mitochondrial effects that may contribute to statin-induced myopathy.
    Keywords:  mitochondrial dynamics; skeletal muscle; statin; translocase of outer mitochondrial membrane; transmission electron microscopy
    DOI:  https://doi.org/10.3390/ijms262210977
  53. J Physiol. 2025 Nov 22.
    Canonical and non-canonical functions of proteins regulating mitochondrial dynamics in mammalian physiology.
    Rémi Chaney, Vincent Marcangeli, Krystel Desjardins, Shima Taherkhani, Gilles Gouspillou.
      Mitochondria are dynamic and multifunctional organelles central to cellular bioenergetics and metabolism and acting as vital signalling hubs. Their morphology is finely regulated by the opposing processes of fusion and fission, predominantly controlled by four key GTPases: mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (DRP1). In humans, mutations in their genes are linked to a broad range of pathological disorders. In animal models, both loss- and gain-of-function manipulations of these proteins lead to diverse physiological outcomes. Recent research has uncovered that, beyond their canonical roles in shaping mitochondrial morphology, these GTPases also participate in a variety of non-canonical cellular functions, impacting broader aspects of cell physiology. In this review, we examine the established functions of these GTPases in mitochondrial dynamics alongside their emerging roles beyond shaping mitochondrial morphology. We also provide an in-depth overview of how alterations in their expression or activity influence mammalian health and physiology. By highlighting the multifaceted roles and broad physiological impact of mitochondrial fusion and fission proteins, we aim to underscore their complex biology and promote further investigation into their broader physiological significance.
    Keywords:  GTPases; Mitofusins; dynamin‐related protein 1; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial quality control; optic atrophy 1
    DOI:  https://doi.org/10.1113/JP287149
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