bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–05–17
forty-four papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Key hormones for the control of muscle mass: Myokines.
  2. Ryanodine Receptor Ca2+ Leak-Induced Redistribution of Ca2+ in Dystrophic mdx Mouse Muscle.
  3. TAK1 Regulates Skeletal Muscle Mass, Hypertrophic Signaling, and Metabolic Homeostasis in Male and Female Mice.
  4. Chrono overexpression blunts exercise-induced improvement in muscular glucose metabolism by inhibiting the BMAL1 transcriptional activity in high-fat diet-fed mice.
  5. Exercise-induced modulation of the unfolded protein response: a therapeutic avenue for muscle wasting disorders.
  6. Heme Metabolism-Derived Carbon Monoxide Regulates Skeletal Muscle Function.
  7. Recent advances in understanding skeletal muscle ageing: Functional, morphological and omics perspectives.
  8. Dysregulation of the ubiquitin-proteasome system in aging skeletal muscle.
  9. Type 2A fibers exhibit higher mitochondrial content than type 1 fibers in mouse skeletal muscles across physiological conditions.
  10. EMILIN1 emerges as a TGFβ/SETDB1-regulated secreted biomarker in Duchenne muscular dystrophy.
  11. Cell Death in Skeletal Muscle Diseases: Diverse Roles and Pathological Processes.
  12. Brain senescence drives sarcopenia-like transcriptomic remodeling in skeletal muscle.
  13. Tauroursodeoxycholic acid (TUDCA) ameliorates age-related skeletal muscle loss.
  14. Sex differences in mitochondrial function in aging mouse skeletal muscle.
  15. Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia.
  16. The Role of Extracellular Vesicles MicroRNAs in Sarcopenia: From Aging to Multi-Morbidity.
  17. p75 neurotrophin receptor preserves neuromuscular synapse stability and muscle strength during aging.
  18. 15-PGDH Inhibition Overcomes Muscle Regenerative Deficit Seen With GLP1-Receptor Agonist-Induced Weight Loss.
  19. Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
  20. Pro-inflammatory cytokine-driven molecular signaling in skeletal muscle during cancer cachexia.
  21. Resolution of Skeletal Muscle Inflammation: Role of Specialized Pro-resolving Lipid Mediators in the Recovery from Exercise, Injury, and Disease.
  22. GDF10 exacerbates metastatic burden and cachexia in murine models of cancer.
  23. GBT1118 voxelotor analog improves skeletal muscle function, phenotype and significantly reduced serum myopathy biomarker GDF15 in sickle cell disease mice.
  24. Dysferlin's C2A domain supports normal Ca2+ signaling and membrane repair in dysferlin-null myofibers.
  25. Frequent expression of aberrant chimeric Cdkn2a transcripts in mouse models of muscular dystrophy.
  26. A full-length single nuclei transcriptomic atlas of human skeletal muscle insulin resistance.
  27. Update: Is exercise-induced oxidative stress a friend or foe?
  28. Voluntary running sustains the correction of inflammation-related gene expression conferred by AAV gene therapy in mdx mice.
  29. YAP Acts as a Negative Regulator of Mini Utrophin-Based Gene Therapy for Duchenne Muscular Dystrophy in Mdx Mice.
  30. Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.
  31. A Workflow for Spatial Transcriptomic Analysis from Intra-operative Human Skeletal Muscle Biopsies.
  32. Differential Branched-Chain Amino Acid Metabolism in Tissues of Tumor-Bearing Male Mice.
  33. Exercise and Skeletal Muscle-Derived Extracellular Vesicles: Their Cargo, Release, and Role in Metabolic Regulation.
  34. Toward bioengineered muscle-fat microphysiological systems for sports medicine and obesity therapeutics.
  35. Assessment of DNA Variations From Two In Vivo Skeletal Muscle Disorder Mouse Models Using Complementary Square-Wave Voltammetry and LC-MS/MS Analysis.
  36. Inhibition of Ornithine Decarboxylase 1 Mitigates Denervation-Induced Muscle Atrophy by Suppressing Proteolysis and Preserving Muscle Stem Cell Homeostasis.
  37. Human multi-tissue transcriptomics identifies galectin-1 and follistatin-like 1 as exerkines with distinct transcript-to-serum coupling after exercise.
  38. BMP4 derived from human gastrointestinal carcinoma cells impairs myogenic differentiation: A possible in vitro mechanism of cancer‑induced cachexia.
  39. Emerin is necessary for microtubule-organizing center translocation to the nuclear envelope of muscle cells.
  40. PTM encoding: decoding the mechanisms of exercise-induced metabolic memory through spatiotemporal modification networks.
  41. Combined single-cell RNA sequencing and mendelian randomization to identify biomarkers associated with circadian rhythm in sarcopenia.
  42. MyoRep: A Novel Reporter System to Detect Early Muscle Atrophy In Vitro and In Vivo.
  43. Estrogen deficiency induces pelvic floor muscle atrophy via ERα/GLUT4 pathway.
  44. Myostatin Research: From Molecular Understanding to Clinical Translation for Musculoskeletal and Metabolic Disorders.
  1. Best Pract Res Clin Endocrinol Metab. 2026 May 09. pii: S1521-690X(26)00037-0. [Epub ahead of print] 102115
    Key hormones for the control of muscle mass: Myokines.
    Hao Gu, Elke Albrecht, Zijun Deng, Steffen Maak.
      Skeletal muscle is an active metabolic tissue, and muscle health is crucial for maintaining quality of life. During muscle contraction, skeletal muscle cells secrete various proteins called myokines, which participate in the autocrine regulation of muscle and modulate structure and metabolism of other tissues and organs. Myokines have been identified to regulate skeletal muscle glucose and lipid metabolism, protein synthesis and degradation, as well as muscle regeneration, playing a crucial role in maintaining muscle mass and preserving muscle metabolic homeostasis, and alleviating muscle atrophy. In this review, we summarize the various biological functions of classical myokines, with a particular focus on their role in maintaining muscle mass and function, which may help us understand the effects of myokines on skeletal muscle physiology and pathology.
    Keywords:  muscle mass; muscle metabolism; myokines; skeletal muscle
    DOI:  https://doi.org/10.1016/j.beem.2026.102115
  2. Acta Physiol (Oxf). 2026 Jun;242(6): e70251
    Ryanodine Receptor Ca2+ Leak-Induced Redistribution of Ca2+ in Dystrophic mdx Mouse Muscle.
    Rhayanna B Gaglianone, Cedric R Lamboley, Taylor Dick, Aldo Meizoso-Huesca, Daniel P Singh, Bradley S Launikonis.
       AIM: The dystrophic mdx mouse is a widely used model of Duchenne muscular dystrophy. Altered Ca2+ handling is a key feature, including increased Ca2+ leak through the ryanodine receptor (RyR1's), the primary Ca2+ release channel in skeletal muscle. Such leak has important downstream consequences for intracellular Ca2+ homeostasis. Here, we quantified basal compartmentalized Ca2+ levels in mdx muscle compared with wild-type (WT).
    METHODS: Single extensor digitorum longus muscle fibers from WT and mdx mice were mechanically skinned. Transverse tubule Ca2+ dynamics were assessed using confocal microscopy with fluorescent Ca2+ indicators during caffeine-induced RyR1-mediated Ca2+ release. Sarcoplasmic reticulum (SR) and mitochondrial Ca2+ contents were quantified using established depletion protocols combined with force measurements.
    RESULTS: Consistent with previous reports, mdx fibers exhibited increased RyR1 Ca2+ leak. Absolute quantification revealed a reduction in SR Ca2+ content accompanied by a ~4-fold increase in mitochondrial Ca2+ content. These shifts indicate a redistribution of intracellular Ca2+, triggered by the RyR1 Ca2+ leak to lower SR Ca2+ content and increase the Ca2+ permeability of the t-system membrane, leading to an elevation in cytoplasmic and mitochondrial Ca2+ levels in mdx muscle.
    CONCLUSION: Redistribution of Ca2+ is a regulated process, proportional to RyR1 Ca2+ leak. In mdx muscle fibers, there is reduced SR and elevated mitochondrial and cytoplasmic Ca2+ compared to WT fibers. These alterations contribute to the dystrophic muscle pathology, likely through promotion of oxidative stress through increased reactive oxygen species production.
    Keywords:  Ca2+; confocal; muscular dystrophy; ryanodine receptor; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.70251
  3. FASEB J. 2026 May 31. 40(10): e71893
    TAK1 Regulates Skeletal Muscle Mass, Hypertrophic Signaling, and Metabolic Homeostasis in Male and Female Mice.
    Meiricris Tomaz da Silva, Aniket S Joshi, Anirban Roy, Troy A Hornberger, Ashok Kumar.
      Skeletal muscle is the most abundant tissue in the human body and is essential for locomotion and the regulation of whole-body metabolism. The maintenance of skeletal muscle mass is essential for health, yet the molecular and signaling mechanisms that control skeletal muscle mass remain poorly understood. Transforming growth factor-β-activated kinase 1 (TAK1) is a key signaling protein that regulates multiple intracellular pathways. Recent studies have demonstrated that TAK1 is a critical regulator of skeletal muscle mass. However, the mechanisms by which TAK1 regulates muscle mass and whether its role is sex-dependent remain incompletely understood. In this study, we show that targeted inactivation of TAK1 induces muscle atrophy more rapidly in male than in female mice. Loss of TAK1 activity also abolished mechanical overload-induced phosphorylation of p70S6K and rpS6, and the induction of myofiber hypertrophy in both sexes. RNA-Seq analysis further revealed that TAK1 inactivation in skeletal muscle disrupts the gene expression of various molecules involved in catabolic processes, calcium signaling, muscle structure development, and aerobic respiration. Moreover, TAK1 inactivation impairs fatty acid oxidation and promotes lipid accumulation in skeletal muscle of adult mice in a sex-independent manner. Collectively, our findings demonstrate that TAK1 regulates skeletal muscle mass and growth by coordinating distinct intracellular pathways in both male and female mice.
    Keywords:  hypertrophy; oxidative phosphorylation; signaling; skeletal muscle growth; unfolded protein response
    DOI:  https://doi.org/10.1096/fj.202601212R
  4. J Physiol Biochem. 2026 May 14. pii: 51. [Epub ahead of print]82(1):
    Chrono overexpression blunts exercise-induced improvement in muscular glucose metabolism by inhibiting the BMAL1 transcriptional activity in high-fat diet-fed mice.
    Lei Xu, Jie Jia, Lu Yan, Yangwenjie Wang, Shudan Miao, Ying Zhang.
      Aerobic exercise improves systemic insulin sensitivity by modulating muscle glucose metabolism. The CHRONO/BMAL1 pathway constitutes a core component of the endogenous molecular clock and participates in glucose metabolic regulation; however, whether it mediates exercise-induced metabolic benefits under high-fat diet (HFD) conditions remains unclear. We therefore investigated the role of this pathway in conferring protective effects of aerobic exercise against HFD-induced glucose metabolic dysfunction in skeletal muscle, by subjecting wild-type (WT) and inducible muscle-specific Chrono overexpression (Chrono IMOE) mice to an HFD with or without 12-week exercise. Unlike in WT mice, exercise failed to ameliorate adipose mass, dyslipidemia, and insulin resistance in HFD-fed Chrono IMOE mice. Mechanistically, in skeletal muscle of Chrono IMOE mice, Chrono overexpression suppressed exercise-induced reductions in CHRONO expression and CHRONO-BMAL1 binding, as well as the increase in BMAL1 levels. Consequently, despite elevated p-TBC1D1Ser237 and GLUT4 expression, exercise failed to promote GLUT4 sarcolemmal colocalization or upregulate gene expression of key enzymes for glycolysis and glycogen metabolism in skeletal muscle of Chrono IMOE mice. These findings demonstrate that preventing CHRONO‑BMAL1 dissociation via muscle-specific Chrono overexpression abrogates exercise-induced GLUT4 membrane trafficking, transcriptional activation of glycolytic/glycogen metabolic genes, and systemic insulin sensitivity improvements in HFD-fed mice, establishing CHRONO‑BMAL1 dissociation as a required step for these exercise adaptations.
    Keywords:  Aerobic exercise; CHRONO/BMAL1 pathway; Glucose metabolism; High-fat diet; Skeletal muscle
    DOI:  https://doi.org/10.1007/s13105-026-01191-1
  5. J Physiol Biochem. 2026 May 11. pii: 50. [Epub ahead of print]82(1):
    Exercise-induced modulation of the unfolded protein response: a therapeutic avenue for muscle wasting disorders.
    Ao Ke, Zhuo Jinyuan, Lijuan Xiang, Zhanguo Su.
      Muscle wasting, prevalent in various pathological conditions including cancer, cardiac dysfunction, and neurodegeneration, is typified by sustained protein depletion in muscle and a compromised ability of the tissue to repair and regenerate effectively. Triggered by disruptions in protein folding in the endoplasmic reticulum (ER), the unfolded protein response (UPR) represents a key regulatory system that sustains intracellular proteostasis under conditions of stress. While the UPR is crucial for cellular survival, prolonged activation or dysfunction of the pathway can contribute to muscle atrophy and the progression of muscle wasting diseases. Recent evidence suggests that exercise, through its impact on cellular stress responses, can modulate the UPR in muscle cells, promoting a protective response that enhances protein folding capacity, reduces ER stress, and stimulates muscle regeneration. This review explores how exercise influences the UPR in muscle cells, focusing on the activation of key UPR sensors, including IRE1, PERK, and ATF6, and their downstream effects on protein quality control, autophagy, and muscle fiber maintenance. We also examine the role of exercise in promoting adaptive responses in muscle cells, including increased mitochondrial function, autophagy, and the activation of stress resistance pathways, all of which can counteract muscle wasting. The review also emphasizes exercise as an effective strategy to influence ER stress pathways and attenuate muscle atrophy associated with pathological conditions, offering critical insights into the molecular benefits of physical activity for muscle preservation.
    Keywords:  Autophagy; Endoplasmic reticulum stress; Exercise; Muscle wasting; Unfolded protein response
    DOI:  https://doi.org/10.1007/s13105-026-01190-2
  6. J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70309
    Heme Metabolism-Derived Carbon Monoxide Regulates Skeletal Muscle Function.
    Rodrigo W Alves de Souza, Hyo In Kim, Paula Ketilly Nascimento Alves, Ailma Oliveira da Paixão, Ashlee Rasmussen, Sidharth Shankar, James Harbison, Vanessa Azevedo Voltarelli, Leo E Otterbein.
       BACKGROUND: Heme oxygenases, HO-1 (Hmox1) and HO-2 (Hmox2), regulate skeletal muscle homeostasis by degrading heme and generating carbon monoxide (CO), a bioactive signalling molecule. Although HO-1 is known to influence muscle fibre composition and mitochondrial function, the role of HO-2 in activity-dependent neuromuscular plasticity remains poorly understood. This study aimed to define the distinct contributions of each isoform and test whether CO could restore muscle function in HO-deficient states.
    METHODS: We generated Hmox1/2 double-knockout mice (Hmox1/2-/-) and compared their skeletal muscle phenotype with that of single HO-1 or HO-2 knockouts and wild-type (WT) controls under sedentary and exercised conditions. We evaluated endurance capacity using treadmill running (n = 8-12 per group), assessed fibre-type distribution and neuromuscular junction (NMJ) morphology via immunohistochemistry and measured mitochondrial function using high-resolution respirometry. Primary neuronal cultures were analysed using multielectrode array recordings to assess firing dynamics. Inhaled CO was administered to test its capacity to rescue muscle phenotype and performance.
    RESULTS: HO-1 deficiency led to a significant reduction in oxidative fibres (Type I and IIa), decreased mitochondrial respiratory capacity (reduced by ~30%, p < 0.01) and diminished treadmill endurance (-40% running time vs. WT, p < 0.001). Hmox2 deficiency was associated with NMJ remodelling, increased acetylcholine receptor expression, reduced Sox2 transcription and heightened burst firing. The double deletion of HO-1/HO-2 produced an additive phenotype characterized by severe mitochondrial dysfunction, increased glycolytic fibre content and NMJ remodelling. We identify CO, a by-product of HO-1, as a crucial modulator of skeletal muscle adaptation, capable of compensating for HO deficiency. Treatment with CO in Hmox1/2-/- mice restored fibre-type distribution toward oxidative fibres (increased by 25%, p < 0.01), improved mitochondrial respiratory parameters and doubled endurance performance (p < 0.001). CO also normalized mitochondrial protein expression and modulated key metabolic pathways, including nucleotide metabolism, the TCA cycle and redox balance.
    CONCLUSIONS: HO-1 and HO-2 have distinct roles in regulating muscle phenotype and metabolic adaptation. HO-1 modulates mitochondrial content and muscle plasticity, whereas Hmox2 regulates, in part, activity-dependent neuromuscular plasticity and responsiveness to exercise. Exogenous CO effectively restores mitochondrial and functional deficits in HO-deficient muscle, mimicking endurance exercise adaptations. These findings support the therapeutic potential of CO in conditions of muscle disuse, aging or disease where exercise is limited or not feasible.
    Keywords:  carbon monoxide; exercise adaptation; heme oxygenase; mitochondrial dysfunction; neuromuscular junction; skeletal muscle metabolism
    DOI:  https://doi.org/10.1002/jcsm.70309
  7. Exp Physiol. 2026 May 10.
    Recent advances in understanding skeletal muscle ageing: Functional, morphological and omics perspectives.
    Oscar Horwath, William Apró.
      
    Keywords:  DNA methylation; muscle atrophy; myosin heavy chains; plasticity; sarcopenia
    DOI:  https://doi.org/10.1113/EP093857
  8. Biomed Pharmacother. 2026 May 12. pii: S0753-3322(26)00540-8. [Epub ahead of print]199 119504
    Dysregulation of the ubiquitin-proteasome system in aging skeletal muscle.
    Gunju Song, Boo-Yong Lee, Kwang-Hyun Baek.
      Protein homeostasis (proteostasis) is essential for maintaining skeletal muscle integrity, and its disruption is a central feature of aging related sarcopenia. The ubiquitin-proteasome system (UPS) is the primary pathway responsible for selective protein degradation in muscle. However, its regulation during physiological aging remains incompletely understood. Most studies have focused on muscle-specific E3 ubiquitin ligases, particularly MuRF1 and MAFbx/atrogin-1, which are widely used as molecular markers of muscle atrophy. However, changes in E3 ligase expression do not consistently correspond to proteasome activity, suggesting a disconnect between ubiquitination signals and proteolytic capacity in aging muscle. In this review, we synthesize current evidence on age-related alterations in key components of the UPS, including proteasome activity, E3 ubiquitin ligases, and deubiquitinating enzymes (DUBs). We highlight that these components are differentially regulated across muscles and conditions. We further discuss DUBs as an additional regulatory layer that remains poorly understood in skeletal muscle aging. These findings emphasize the need to move beyond single-marker interpretations of UPS activity. Overall, current evidence indicates that aging skeletal muscle is characterized not by a simple increase in protein degradation, but by multi-layered dysregulation of proteostasis networks. A more integrated evaluation of UPS components will be required to better understand protein turnover in aging muscle.
    Keywords:  Deubiquitinating enzymes; E3 ubiquitin ligases; Muscle atrophy; Protein degradation; Proteostasis; Sarcopenia
    DOI:  https://doi.org/10.1016/j.biopha.2026.119504
  9. Biochem Biophys Res Commun. 2026 Jul 09. pii: S0006-291X(26)00674-1. [Epub ahead of print]821 153910
    Type 2A fibers exhibit higher mitochondrial content than type 1 fibers in mouse skeletal muscles across physiological conditions.
    Eiji Wada, Nao Susumu, Kotaro Ariga, Yukiko K Hayashi.
      Skeletal muscle is composed of a heterogeneous mixture of oxidative slow-twitch type 1 fibers and glycolytic fast-twitch type 2 fibers (2A, 2XD, and 2B), defined by their myosin heavy chain isoform. Among the defining characteristics of muscle fiber types, a high mitochondrial content is classically associated with type 1 fibers in human skeletal muscles. In addition, mitochondrial adaptations occur according to the energy demands of each fiber type. In contrast, type 1 fibers exhibit lower mitochondrial enzyme activities than type 2A fibers in rodent limb muscles, and fiber type-specific adaptation of mitochondrial content in rodent models remains unclear. In this study, we comprehensively examined mitochondrial content at the single-myofiber level across multiple muscle regions in mice and investigated fiber type-dependent changes of mitochondrial content under various physiological conditions. We demonstrate that type 2A fibers possess higher mitochondrial content than type 1 fibers across different skeletal muscle regions in mice. Importantly, this relationship was maintained under different physiological conditions, including aging and exercise. In addition, our study identified type 2XD fibers as a metabolically plastic population that responds dynamically to physiological stimuli. These findings suggest that mitochondrial content in each skeletal muscle isotype is both species-specific and context-dependent.
    Keywords:  Mitochondrial adaptation; Mitochondrial content; Mouse skeletal muscle; Muscle fiber type; SDH and COX staining; Single myofiber
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153910
  10. Cell Death Dis. 2026 May 09.
    EMILIN1 emerges as a TGFβ/SETDB1-regulated secreted biomarker in Duchenne muscular dystrophy.
    Maeva Zamperoni, Laura Muraine, Minh-Y Tran, Alice Granados, Anne Bigot, Valentin Petit, Mona Bensalah, Jessica Ohana, Véronique Legros, Ekaterina Boyarchuk, Johanna Bruce, Guillaume Chevreux, Véronique Joliot, Elisa Negroni, Maryline Moulin, Capucine Trollet, Slimane Ait-Si-Ali.
      Duchenne muscular dystrophy (DMD) is an incurable muscle-wasting disorder characterized by chronic membrane damage, inflammation, and progressive fibrosis. Fibrosis in DMD is driven by sustained TGFβ signaling, which promotes extracellular matrix (ECM) accumulation. We previously showed that SETDB1 sustains the TGFβ-induced fibrotic response in DMD myotubes. Here, we further show that SETDB1 modulates the TGFβ-induced secretome, particularly by regulating ECM-related proteins. Comparison of the basal secretome from DMD patient-derived myotubes and healthy controls revealed a distinct disease-specific profile. Integrating both secretome analyses, we identified EMILIN1, an ECM glycoprotein not previously studied in skeletal muscle, as a robust shared candidate; EMILIN1 is enriched in the DMD secretome, further upregulated by TGFβ, and downregulated upon SETDB1 depletion. We confirmed EMILIN1 overexpression in DMD patient muscle biopsies, validating its pathological relevance. Functionally, EMILIN1 depletion modulated myogenic differentiation and reduced expression of the fibrotic marker SERPINE1. These findings establish EMILIN1 as a novel secreted regulator of myogenesis and fibrosis, and implicate SETDB1 in shaping the TGFβ-dependent secretome in DMD. Our integrative proteomic approach provides new insights into the molecular drivers of impaired regeneration in DMD and highlights potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s41419-026-08825-8
  11. Cells. 2026 Apr 22. pii: 744. [Epub ahead of print]15(9):
    Cell Death in Skeletal Muscle Diseases: Diverse Roles and Pathological Processes.
    Ya-Lan Yang, Liang Guo.
      Skeletal muscle is vital for movement and metabolism, and its dysfunction underpins disorders like muscular dystrophy and sarcopenia, severely impacting life quality. In these diseases, various cell death pathways are pivotal, driving core pathological features such as fiber loss and chronic inflammation. This study reviews the central role of cell death in skeletal muscle diseases, and analyzes its roles and mechanisms in genetic muscle disorders such as Duchenne muscular dystrophy (DMD), glycogen storage diseases (GSD), mitochondrial myopathies, as well as acquired muscle disorders such as idiopathic inflammatory myopathy, sarcopenia, rhabdomyolysis, and myasthenia gravis (MG). We also explore the potential of cell death-related molecules as biomarkers and discuss emerging therapeutic strategies that target these pathways, aiming to provide new insights for diagnosis and treatment.
    Keywords:  Duchenne muscular dystrophy; cell death; glycogen storage diseases; idiopathic inflammatory myopathy; mitochondrial myopathies; myasthenia gravis; rhabdomyolysis; sarcopenia
    DOI:  https://doi.org/10.3390/cells15090744
  12. Geroscience. 2026 May 14.
    Brain senescence drives sarcopenia-like transcriptomic remodeling in skeletal muscle.
    Shoba Ekambaram, Roland Patai, Rafal Gulej, Tamas Kiss, Siva Sai Chandragiri, Dorina Nagy, Kiana Vali Kordestan, Tamas Lakat, Stefano Tarantini, Peter Mukli, Andriy Yabluchanskiy, Anna Ungvari, Zoltán Benyó, Anna Csiszar, Zoltan Ungvari.
      Aging is accompanied by a progressive decline in skeletal muscle mass and function, culminating in sarcopenia, a major contributor to frailty, disability, and mortality in older adults. While skeletal muscle aging has traditionally been attributed to cell-autonomous and local tissue mechanisms, increasing evidence suggests that systemic, cell non-autonomous processes play a central role in coordinating aging across organs. The brain, particularly the hypothalamus, has emerged as a key regulator of organismal aging, yet its contribution to skeletal muscle aging remains poorly defined. Here, we tested the hypothesis that senescence confined to the brain is sufficient to induce aging-like molecular remodeling in skeletal muscle via systemic mechanisms. To model brain senescence, young mice were subjected to fractionated whole-brain irradiation (WBI), a well-established approach that induces widespread cellular senescence and neuroinflammation in the brain while sparing peripheral tissues. Two months after WBI, transcriptomic profiling of quadriceps muscle was performed and compared with that of naturally aged mice. WBI-induced robust gene expression changes in skeletal muscle that closely mirrored those observed during chronological aging. Pathway-level analyses revealed marked downregulation of mitochondrial organization, respiratory chain assembly, and metabolic processes, alongside enrichment of remodeling- and stress-associated pathways. Upstream regulator analysis identified FOXO1, FOXO3, KLF15, and STAT3, which are key drivers of muscle catabolism and atrophy, as central mediators of the observed transcriptional program. Semantic similarity analysis further demonstrated a high concordance between WBI-induced and aging-associated biological processes. Collectively, these findings demonstrate that brain senescence is sufficient to drive sarcopenia-like transcriptomic remodeling in skeletal muscle, implicating central nervous system aging as an upstream regulator of peripheral muscle decline. This brain-muscle aging axis may contribute to frailty in individuals with accelerated brain aging and in cancer survivors exposed to cranial irradiation, highlighting brain senescence as a potential therapeutic target to mitigate systemic aging and skeletal muscle dysfunction.
    Keywords:  Accelerated aging; Cell non-autonomous aging; FOXO signaling; Frailty; Irradiation; Mitochondrial dysfunction; Sarcopenia; Senescence; Senescence-associated secretory phenotype (SASP); Skeletal muscle aging; Systemic aging; Transcriptomics
    DOI:  https://doi.org/10.1007/s11357-026-02205-y
  13. J Physiol. 2026 May 15.
    Tauroursodeoxycholic acid (TUDCA) ameliorates age-related skeletal muscle loss.
    Marina S Carvalho, Leticia Barssotti, Lohanna M B Dos Santos, Lucas R O Rosa, Maria Cristina C Gomes-Marcondes, Everardo M Carneiro, Helena C L Barbosa, Lucas Zangerolamo.
      Ageing leads to changes in body composition, including increased adiposity and reduced skeletal muscle mass and force. The alterations in ageing skeletal muscle result from impaired proteostasis driven by factors such as chronic inflammation, hormonal changes and reduced nutrient absorption. Those age-related changes in body composition and skeletal muscle compromise mobility and increase the risk of falls, fractures and metabolic disorders. Tauroursodeoxycholic acid (TUDCA), a bile acid with known benefits in chronic diseases, has been shown by our group to improve cognition and metabolic homeostasis in ageing and Alzheimer's disease mouse models. Interestingly, in previous studies, TUDCA treatment was also associated with increased skeletal muscle mass in ageing mice, leading us to hypothesize that TUDCA could target skeletal muscle to reduce age-related muscle loss. To explore this, we treated 18-month-old C57BL/6 mice with TUDCA or vehicle for 20 days, using 3-month-old mice as a young control group. We demonstrate that TUDCA treatment decreases body weight while increasing skeletal muscle mass, restores muscle fibre size and preserves functional integrity. Additionally, TUDCA enhances skeletal muscle insulin sensitivity through increased AKT activation and reduces tissue inflammation. Such improvements collectively support the restoration of skeletal muscle proteostasis, as indicated by increased protein synthesis and phosphorylation of key anabolic signalling pathways, including ribosomal protein S6 kinase beta-1 (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These findings contribute to a better understanding of TUDCA's actions on skeletal muscles of ageing mice and highlight its role as a promising strategy against age-related muscle loss. KEY POINTS: Tauroursodeoxycholic acid (TUDCA) treatment attenuates skeletal muscle loss in ageing mice. TUDCA improves skeletal muscle insulin sensitivity and restores AKT signalling. TUDCA exerts an anti-inflammatory effect in skeletal muscle of ageing mice. TUDCA emerges as a potential therapy for age-related skeletal muscle loss.
    Keywords:  ageing; ageing‐related skeletal muscle loss; bile acids; skeletal muscle; tauroursodeoxycholic acid
    DOI:  https://doi.org/10.1113/JP290683
  14. Front Aging. 2026 ;7 1824237
    Sex differences in mitochondrial function in aging mouse skeletal muscle.
    Angelina Holcom, Ashley Liao, Kaitlyn G Holden, Anne M Bronikowski, Ashley E Webb.
       Introduction: Sex differences in lifespan and age-associated phenotypes are pervasive across species, yet the mechanisms remain poorly understood. Mitochondrial dysfunction is a major hallmark of aging, but whether skeletal muscle mitochondria age along sex specific trajectories remains incompletely defined.
    Methods: Here, we profiled mitochondrial bioenergetics and DNA integrity in flexor digitorum brevis (FDB) muscle from young (3-4 months) and aged (20-24 months) male and female C57BL/6 mice. We quantified cellular respiration in intact myofibers, measured mitochondrial DNA (mtDNA) copy number, and assessed expression of genes involved in mitochondrial dynamics, electron transport chain (ETC) function, and mtDNA maintenance.
    Results: Cellular respiration differed by sex at baseline and changed with age in a sex-dependent manner. Aged females exhibited a lower basal and ATP-linked respiration than aged males. In contrast, spare respiratory capacity increased in aged females relative to aged males, consistent with age- and sex-specific remodeling of the bioenergetic reserve. mtDNA copy number increased with age in both sexes, with a greater increase in mtDNA content in aged males. Gene-expression analyses revealed age- and/or sex-dependent changes, including lower Pink1 expression in females compared to males, an age-related increase in the mtDNA maintenance gene Polg2 only in males, though most genes were not significantly different. As an exploratory systemic readout, we additionally assessed DNA damage responsiveness in whole-blood leukocytes using the alkaline comet assay following oxidative challenge; young females exhibited greater induced DNA damage than young males.
    Discussion: Together, these data define sex- and age-associated mitochondrial remodeling in FDB and provide an initial assessment of sex-dependent inducible DNA damage responses in blood, underscoring the importance of sex as a biological variable in studies of aging.
    Keywords:  alkaline comet assay; flexor digitorum brevis (FDB); mitochondria bioenergetics; mitochondrial DNA copy number; sex differences; skeletal muscle aging
    DOI:  https://doi.org/10.3389/fragi.2026.1824237
  15. Am J Physiol Cell Physiol. 2026 May 12.
    Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia.
    Jeremy B Ducharme, Scott M Ebert, Miles E Cameron, Martin M Schonk, Chandler S Callaway, Andrew C D'Lugos, John J Talley, Sarah M Judge, Christopher M Adams, Andrew R Judge.
      Skeletal muscle atrophy is a devastating and defining feature of cancer cachexia that reduces quality of life, treatment tolerance, and survival, but cannot be prevented or reversed by current management strategies. Ursolic acid is a natural dietary compound that has been shown to inhibit atrophy-associated changes in skeletal muscle mRNA expression in rodents and dogs, leading to beneficial changes in skeletal muscle structure and function. We hypothesized that dietary supplementation with ursolic acid might help support skeletal muscle mass and function during cancer. To test this hypothesis, we investigated ursolic acid's effects in five in vivo mouse models of cancer cachexia that are driven by pancreatic, colon, and lung cancer cells of mouse and human origin. We found that dietary supplementation with ursolic acid has broad-spectrum effects towards cancer-induced skeletal muscle atrophy, significantly preserving muscle mass in all five cancer cachexia models. Ursolic acid's positive effects on muscle mass and muscle fiber size led to significant improvements in grip strength and muscle tetanic force, persisted in the presence of chemotherapy, and were not associated with discernable changes in food intake or tumor growth. Ursolic acid appeared to generate its beneficial effects in skeletal muscle by acting directly on muscle cells, inhibiting catabolic effects of tumor-derived secreted factors, and inhibiting > 90% of cancer-induced changes in skeletal muscle mRNA expression. These results strongly nominate ursolic acid as a promising potential nutritional approach for supporting muscle mass and function in individuals with cancer.
    Keywords:  cancer cachexia; muscle atrophy; nutrition; skeletal muscle; ursolic acid
    DOI:  https://doi.org/10.1152/ajpcell.00159.2026
  16. Aging Med (Milton). 2026 Apr;9(2): 185-195
    The Role of Extracellular Vesicles MicroRNAs in Sarcopenia: From Aging to Multi-Morbidity.
    Bingyu Huang, Zhao Peng, Lin Kang.
      Sarcopenia, defined as progressive loss of skeletal muscle mass and function, occurs during aging and has also been recognized for its detrimental effects in various disease states. Its prevention and management represent a critical aspect of geriatric care and multi-morbidity management. As a systemic disorder, extracellular vesicle-transported miRNAs mediate both intrinsic muscle pathology and multifaceted organ crosstalk. This review comprehensively summarizes and discusses the roles of EVs-miRNAs in sarcopenia under physiological aging and pathological conditions, and their emerging potential as diagnostic biomarkers and engineered therapeutic targets.
    Keywords:  MicroRNAs; exosomes; extracellular vesicles; multi‐morbidity; sarcopenia
    DOI:  https://doi.org/10.1002/agm2.70078
  17. NPJ Aging. 2026 May 16.
    p75 neurotrophin receptor preserves neuromuscular synapse stability and muscle strength during aging.
    Viviana Pérez, Sebastián Aedo-Cares, Francisca Bermedo-García, Jessica Mella, Camila Uribe-Martínez, Francisca C Bronfman, Juan Pablo Henríquez.
      Age-related decline of the neuromuscular junction (NMJ), the peripheral synapse that controls muscle contraction, contributes to muscle weakness and impaired motor function in aging. The NMJ comprises a motor axon terminal, a skeletal muscle fibre, and terminal Schwann cells (tSC). Neurotrophin signalling is essential for mature NMJ organisation, with the p75 receptor acting as a key regulator of its morphology and function. However, the potential contribution of p75 to age-related NMJ decline remains unexplored. In this study, we used germline p75 knockout (p75⁻/⁻) mice to examine how the lifelong absence of p75 impacts NMJ stability and muscle function during aging through quantitative morphometric analyses, postsynaptic receptor dynamics, muscle histology, and functional strength testing. Although NMJ morphology was preserved, aged p75⁻/⁻ mice exhibited pronounced denervation and reduced tSC coverage, hallmarks of age-associated NMJ degeneration. Moreover, postsynaptic domains of aged p75⁻/⁻ mice displayed reduced stability of membrane-bound acetylcholine receptors. Glycolytic muscle fibres also showed signs of atrophy. Notably, aged p75⁻/⁻ mice exhibited a significant reduction in muscle strength compared with age-matched controls. Together, our findings are consistent with cumulative effects of persistent p75 deficiency on NMJ integrity and function during aging, supporting its potential relevance for interventions aimed at preventing age-associated neuromuscular decline.
    DOI:  https://doi.org/10.1038/s41514-026-00399-1
  18. bioRxiv. 2026 Feb 28. pii: 2026.02.26.708119. [Epub ahead of print]
    15-PGDH Inhibition Overcomes Muscle Regenerative Deficit Seen With GLP1-Receptor Agonist-Induced Weight Loss.
    Minas Nalbandian, Jameel Lone, Emmeran Le Moal, Ireh Kim, Yutong Kelly Li, Peggy Kraft, Meng Zhao, Kassie Kolacar, Zeyuan Zhang, Katrin J Svensson, Helen M Blau.
      Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including long-acting semaglutide, are revolutionary anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that an inhibitor of the gerozyme 15-hydroxyprostaglandin dehydrogenase (PGDHi), which boosts PGE2 levels, increases skeletal muscle mass, strength, and regeneration in the presence of semaglutide. We find that in a high fat diet-induced mouse model of obesity, semaglutide alone induces significant loss of muscle mass, while retaining contractile function. However, muscle regeneration and recovery of strength post-injury are hindered by semaglutide. This regenerative deficit is due to impeded stem cell function, which is overcome if mice are treated with a combination of PGDHi and semaglutide. Our data show that GLP-1-mediated weight loss interferes with this key muscle-building function, which PGDHi co-treatment counteracts to promote proper muscle regeneration and restored strength.
    DOI:  https://doi.org/10.64898/2026.02.26.708119
  19. Nat Aging. 2026 May 14.
    Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
    David E Lee, Lauren K McKay, Akshay Bareja, JiaCheng Yang, Wentao He, Demitrius A Hill, James R Bain, Shihuan Kuang, Guo-Fang Zhang, Christopher B Newgard, James P White.
      Sarcopenia and the age-related decline in muscular strength and regenerative capacity contribute directly to loss of autonomy, greater risk for hospitalization and healthcare utilization. One contributing cellular phenotype associated with skeletal muscle aging is a loss in the function and number of resident muscle stem cells (MuSCs) or satellite cells. MuSC activation leads to dramatic changes in cellular architecture and metabolic reprogramming, including both mitochondrial biogenesis and increased glycolysis. Despite these changes to increase energy production, high energy demands may not be fully met during periods of MuSC activation. Here we used in vitro and in vivo approaches in mice to demonstrate the function of glutaminase for age-related changes in MuSC function. By combining fluorescence-activated cell sorting (FACS) isolation with metabolomics and stable isotope tracing, we show an age-related decline in reductive (counterclockwise) flux of glutamine through the tricarboxylic acid (TCA) cycle, a pathway by which MuSCs build cellular fatty acid stores as necessary biomass for MuSC function.
    DOI:  https://doi.org/10.1038/s43587-026-01120-3
  20. Biochem Soc Trans. 2026 May 27. 54(5): 547-559
    Pro-inflammatory cytokine-driven molecular signaling in skeletal muscle during cancer cachexia.
    Benudhara Pati, Nibedita Nandy, Birendra Kumar Bindhani, Naresh Chandra Bal.
      Cancer cachexia is a multifactorial syndrome characterized by the progressive loss of muscle and fat, commonly observed among patients with cancer. It is very distinct from other skeletal muscle wasting such as sarcopenia and malnutrition and is known to reduce cancer treatment effectiveness. Cachexia progression is driven by a combination of factors, including hormonal dysregulation, anorexia, tumor-derived catabolic factors (in cancer cachexia), and systemic or muscular inflammation, all of which worsen overall muscle health. In this review, we will probe the role of pro-inflammatory cytokines, such as IL-6, IFN-γ, TNF-α, TGF-β, IL-1β, and IL-8, in driving the systemic inflammation and disruption of muscle metabolic homeostasis that support the development of cachexia. These cytokines may be produced from various organs, including the adipose depots that contribute to muscle wasting and metabolic dysfunction by disrupting the equilibrium between anabolic and catabolic processes. The ubiquitin-proteasome system, NF-κB, and JAK/STAT3 are important molecular pathways that mediate cytokine-induced catabolic signaling. The review further analyzes the context-dependent dual functions of these cytokines and the molecular mechanisms underlying the loss of their regulatory control during cancer progression. The limited success of current therapeutic approaches for cancer cachexia highlights the urgent need for evaluation of more targetable mechanisms for the treatments. Here, one of our main objectives is to probe whether suppression of pro-inflammatory cytokine signaling and activation of anti-inflammatory pathways can be utilized to modulate the tumor microenvironment, thereby countering cancer cachexia.
    Keywords:  Cancer cachexia; JAK/STAT3 pathway; Muscle wasting; NF-κB pathway; Pro-inflammatory cytokines; adipocytes
    DOI:  https://doi.org/10.1042/BST20260486
  21. Curr Top Microbiol Immunol. 2026 May 15.
    Resolution of Skeletal Muscle Inflammation: Role of Specialized Pro-resolving Lipid Mediators in the Recovery from Exercise, Injury, and Disease.
    Xinyue Lu, Hamood Rehman, James F Markworth.
      This chapter examines the resolution biology and pharmacology of skeletal muscle inflammation across the physiological contexts of exercise, acute injury, and chronic musculoskeletal disease. Central to these processes are specialized pro-resolving lipid mediators (SPMs), bioactive metabolites of omega-6 (n-6) arachidonic acid (ARA), omega-3 (n-3) eicosapentaenoic acid (EPA), and n-3 docosahexaenoic acid (DHA), formed by the coordinated action of mammalian lipoxygenase (LOX) enzymes. Unlike traditional anti-inflammatory mechanisms that passively dissipate, SPMs actively coordinate resolution by limiting polymorphonuclear neutrophil (PMN) infiltration, stimulating efferocytosis, and orchestrating the macrophage (MΦ) transition from a pro-inflammatory to a reparative phenotype. We explore how physical activity serves as a natural stimulus for these pathways, as acute resistance or endurance exercise triggers transient SPM biosynthetic circuits, while chronic training primes the immune system for enhanced resolution. A critical focus is placed on "resolution-interference" caused by nonsteroidal anti-inflammatory drugs (NSAIDs), which may delay repair by suppressing endogenous mediators and impairing muscle stem cell (satellite cell) activity. Furthermore, we review a significant paradigm shift involving the discovery that lipid mediator class switching is an intrinsic requirement for the myogenic differentiation program. By evaluating preclinical models of "resolution deficit," including sarcopenia, muscular dystrophy, and volumetric muscle loss, we highlight the therapeutic potential of pharmacological "immunoresolvents." Ultimately, leveraging these pathways represents a sophisticated therapeutic frontier that moves beyond simple inflammation suppression to directly drive stem cell-mediated muscle regeneration and functional recovery.
    Keywords:  Immunoresolvent; Inflammation; Macrophage; Myogenesis; Regeneration; Resolution; Skeletal muscle; Specialized pro-resolving lipid mediator
    DOI:  https://doi.org/10.1007/82_2026_344
  22. Front Physiol. 2026 ;17 1773275
    GDF10 exacerbates metastatic burden and cachexia in murine models of cancer.
    Lauren S James, Alastair A E Saunders, Chris Karagiannis, Hongwei Qian, Robin L Anderson, Rachel E Thomson, Craig A Goodman, Paul Gregorevic.
      Metastasis and cancer-induced cachexia significantly reduce survivorship and quality of life for cancer patients. GDF10 (BMP3b) is a TGF-ß superfamily ligand with little knowledge of its role in cancer progression. Some studies have shown that GDF10 exerts tumor-suppressive effects in a range of cancer types and also plays a protective role against muscle wasting. Basal transcription of GDF10 was described previously to be downregulated in both primary tumors and cachectic muscle. Here, we set out to investigate the therapeutic potential of GDF10 in the 4T1.2 mouse model of breast cancer metastasis and in the C-26 mouse model of cancer cachexia, hypothesizing that GDF10 would ameliorate both metastatic and cachectic disease pathology. Systemic rAAV6:GDF10 administration to mice did not alter primary tumor growth; however, metastatic burden was increased in the mice bearing 4T1.2 tumors. Similarly, increased intramuscular rAAV6:GDF10 expression exacerbated skeletal muscle wasting in C-26 tumor-bearing mice. These results contradicted our initial hypothesis and highlight the complexity of signaling mechanisms utilized by BMP family ligands. Our data point to the need for more research to understand how to target GDF10 in anti-cancer therapy.
    Keywords:  BMP3b; GDF10; adeno-associated virus; cachexia; cancer; metastasis; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2026.1773275
  23. Biochem Biophys Res Commun. 2026 May 13. pii: S0006-291X(26)00701-1. [Epub ahead of print]822 153937
    GBT1118 voxelotor analog improves skeletal muscle function, phenotype and significantly reduced serum myopathy biomarker GDF15 in sickle cell disease mice.
    Marja M Hurley, Wei He, Liping Xiao.
      We examined the effect of GBT1118, a sickle hemoglobin polymerization inhibitor on skeletal muscle grip strength and phenotype in Townes sickle cell disease (SCD) mouse model. Control male and female mice were fed with control Vehicle-chow for 2-months, while SCD male and female mice were fed with Vehicle-chow or 2-hydroxy-6-[(2S)-1-(pyridine-3-carbonyl)piperidin-2yl]methoxy (GBT1118)-chow for 2-months. We first confirmed significantly reduced hematocrit in both SCD males and females, that was significantly improved with GBT1118. Analysis of muscle function by grip strength measurement revealed significantly decreased grip strength in both SCD male and female mice that was significantly rescued by GBT1118. To assess whether there was phenotypic evidence of damaged skeletal muscle, histologic analysis of tibialis anterior muscle was performed. Muscle size determined using Laminin 2a stained muscle sections revealed significantly decreased fiber cross-sectional area in SCD females that was significantly increased by GBT1118. However, fiber size was similar in Control and SCD male mice and was not modulated by GBT1118. Hematoxylin Eosin staining revealed markedly increased fibrosis and inflammatory cells in tibialis anterior muscle of both sexes of SCD mice that was not reduced by GBT1118. Picrosirius-red staining revealed markedly increased collagen accumulation in muscle of both sexes that was reduced with GBT1118. Interestingly Oil red-O staining revealed markedly increased fat accumulation in tibialis muscle of SCD mice of both sexes that was markedly reduced with GBT1118. We made the novel observation that Growth and Differentiation Factor 15 (GDF15) a serum biomarker of muscle pathology that was significantly increased in serum of SCD mice of both sexes was significantly reduced by GBT1118. We conclude that GBT1118 might has the potential to enhance certain parameters of skeletal muscle dysfunction in older SCD mice.
    Keywords:  GDF-15; Hemoglobin allosteric modifier; Sickle cell disease; Skeletal muscle grip strength; Voxelotor analog GBT1118
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153937
  24. J Gen Physiol. 2026 07 06. pii: e202513844. [Epub ahead of print]158(4):
    Dysferlin's C2A domain supports normal Ca2+ signaling and membrane repair in dysferlin-null myofibers.
    Valeriy Lukyanenko, Joaquin Muriel, Kassidy K Banford, Thomas A Kwiatkowski, Hannah R Bulgart, Noah Weisleder, Robert J Bloch.
      Dysferlin is required for the health of skeletal muscle, where it mediates at least two seemingly distinct processes, repair of the sarcolemmal membrane and stabilization of Ca2+ release after injury. Dysferlin is a ∼230-kDa protein comprised of multiple C2 domains, Fer and Dysf domains, and a transmembrane domain that anchors it to the transverse tubule membrane at the triad junction (TJ). Here we show that replacing C2A with other C2 domains yields fusion proteins that are less active in supporting Ca2+ signaling than WT dysferlin. We also show that the most N-terminal of dysferlin's C2 domains, C2A (DysfC2A), is sufficient to support normal Ca2+ signaling and sarcolemmal repair in dysferlin-null muscle, though it accumulates at TJs inefficiently. The C2A domains of myoferlin and PKCα, though homologous, are less active. The C2 domain of PKCα (PKCαC2) targets the TJ more efficiently than DysfC2A, however. Fusion proteins containing one or two PKCαC2 domains accumulate at the TJ and are active in sarcolemmal membrane repair, but they do not support normal Ca2+ signaling unless linked to DysfC2A Control of Ca2+ signaling is fully restored when the PKCαC2 domain, alone or in pairs, is linked to DysfC2A. This suggests that the DysfC2A is sufficient to support two major functions of dysferlin in skeletal muscle, and that its effect on Ca2+ signaling is specific. We propose that the PKCαC2-PKCαC2-DysfC2A fusion protein is a promising candidate for future viral gene therapy treatment for dysferlinopathy.
    DOI:  https://doi.org/10.1085/jgp.202513844
  25. Sci Rep. 2026 May 13.
    Frequent expression of aberrant chimeric Cdkn2a transcripts in mouse models of muscular dystrophy.
    Michael Wolfram, Katharina Reiter, Harald Höger, Reginald E Bittner, Wolfgang M Schmidt.
      Muscular dystrophies (MDs) are rare hereditary disorders, characterized by progressive muscle weakness due to loss of functional muscle tissue and its replacement by fat and connective tissue. MD mouse models, such as mdx-mice harboring a nonsense variant in the murine dystrophin gene (Dmd), are prone to develop age-related skeletal muscle-derived sarcomas, which is in line with multiple lines of evidence that MD related genes like Dmd act as tumor suppressors in mice and men. Previously, we proposed that genetic instability and cancer-like mutations might arise early in dystrophic muscle. Here, we show that microscopic tumors in dystrophic muscle occur frequently in mice without clinically overt sarcomas. Representing sarcoma pre-stages, these "microsarcomas" share a subset of recurrent MD-specific genetic number alterations. The majority of MD sarcomas and microsarcomas harbor heterozygous Cdkn2a deletions, due to a deletion breakpoint hotspot within the downstream gene Gm12606, a long intergenic non-coding RNA (lincRNA). This lincRNA gene was also found to be involved in expression of aberrant chimeric RNA fusion transcripts, consisting of the first coding exon of the Cdkn2a gene (corresponding to either p19Arf or p14Ink4a) fused to an exon of Gm12606. Remarkably, expression of these fusion transcripts was highly specific to MD muscles and sarcomas and was never observed in muscle from healthy wild-type mice. In addition, muscles from MD double-mutants displayed an increased incidence of fusion transcript expression. Because readthrough transcription was associated with fusion transcript expression also in sarcomas lacking deletions at the Cdkn2a locus, expression of these chimeric RNA transcripts might be the result of dystrophy-induced stress on transcription. We propose that genetic alterations of the Cdkn2a locus, both at the DNA and RNA level, constitute hallmark events in the dystrophy-cancer continuum.
    Keywords:   Cdkn2a ; Gm12606 ; MD-Arf ; MD-Ink4a ; Mdx ; Fusion transcript; Microscopic tumour; Muscular dystrophy; Readthrough transcription; Sarcoma
    DOI:  https://doi.org/10.1038/s41598-026-52724-z
  26. bioRxiv. 2026 Feb 28. pii: 2026.02.26.708250. [Epub ahead of print]
    A full-length single nuclei transcriptomic atlas of human skeletal muscle insulin resistance.
    Katie L Whytock, Adeline Divoux, James Vazquez, Meghan Hopf, Mark R Viggars, Miguel A Gutierrez-Monreal, Courtney H Ruggiero, Felix R Jimenez-Rondan, Francielly Morena, Polina Krassovskaia, Nicholas T Broskey, Yifei Sun, Martin J Walsh, Robert J Cousins, Joseph A Houmard, Lauren M Sparks, Bret H Goodpaster.
      Skeletal muscle (SkM) insulin resistance is a central defect in T2D, yet cell specific molecular determinants remain incompletely understood. Here, we integrate full-length single-nucleus transcriptomics with gold-standard stable isotope-labeled hyperinsulinemic-euglycemic clamps to generate a nucleus-resolved transcriptomic atlas of SkM insulin resistance. We identify previously unrecognized myonuclear populations whose proportions associate with insulin sensitivity across independent cohorts, revealing MYH7B+ myonuclei are metabolically favorable over EGF+ myonuclei. Modeling transcriptional variation against tracer-derived glucose disposal uncovers highly nucleus-specific molecular programs that are obscured when using surrogate fasting indices. Mechanistically, we identify zinc transporter ZIP14 as a positive regulator of insulin-stimulated glucose uptake and implicate EGF signaling in impaired branched-chain amino acid catabolism and inflammatory cross-talk within the SkM niche. Together, these findings redefine SkM insulin resistance as a multicellular, nucleus-resolved process and highlight new cell type specific targets for metabolic intervention.
    DOI:  https://doi.org/10.64898/2026.02.26.708250
  27. Sports Med Health Sci. 2026 May;8(3): 229-239
    Update: Is exercise-induced oxidative stress a friend or foe?
    Scott K Powers, Mari Carmen Gomez-Cabrera.
      Free radicals (radicals) are highly reactive atoms or molecules that contain one or more unpaired electrons in their outermost shell. The first evidence that muscular exercise increases radical production and promotes oxidative damage to tissues was reported almost five decades ago. Following this milestone discovery, many studies have corroborated the finding that exercise increases the production of radicals and other reactive oxygen species (ROS) resulting in oxidative damage to macromolecules in muscles and other tissues. Although exercise-induced ROS production is associated with oxidative damage in many tissues, growing evidence reveals that ROS produced in contracting muscles act as signaling molecules to promote healthy exercise-induced adaptations in skeletal muscles and other tissues. These adaptive responses include increased mitochondrial volume, improved antioxidant capacity, and expression of cytoprotective proteins. Therefore, a key question emerges: "Is exercise-induced ROS production a friend or foe?" This review provides a state-of-the-art discussion of both the positive and negative effects of exercise-induced ROS production by examining the consequences of both oxidative damage to cellular macromolecules and the redox signaling-induced adaptations that occur in muscle fibers. To address the question of whether exercise-induced ROS production is a friend or foe we conclude with a risk/benefit analysis of the biological effects of exercise-induced production of ROS.
    Keywords:  Fatigue; Oxidants; Radicals; Reactive oxygen species; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.smhs.2026.03.006
  28. Mol Ther Adv. 2026 Mar 12. 34(1): 201679
    Voluntary running sustains the correction of inflammation-related gene expression conferred by AAV gene therapy in mdx mice.
    Claire Yuan, Shelby E Hamm, David L Mack, Jean-Baptiste Dupont, Robert W Grange.
      Duchenne muscular dystrophy is a fatal disease characterized by persistent skeletal muscle degeneration, inflammation, and fibrosis. Gene therapy using an adeno-associated virus-derived vector and a microdystrophin transgene is currently under investigation in patients, but the impact of physical activity on long-term therapeutic outcome remains poorly understood. Recently, we reported that 21 weeks of voluntary wheel running complemented the positive endurance and muscle function outcomes of gene therapy in mdx mice. In the present study, we performed a transcriptomic analysis of the gene expression changes associated with functional recovery in the diaphragm with a focus on genes and signaling pathways related to the inflammatory response. RNA sequencing and bioinformatic analysis revealed 2,881 dysregulated genes in untreated and unexercised mdx mice including inflammatory and fibrotic signaling pathways frequently affected in Duchenne muscular dystrophy patients. Among the dysregulated genes, 774 were rescued toward WT level after adeno-associated virus microdystrophin injection. Importantly, 93% of the rescued genes were maintained by voluntary running, which indicates that physical exercise has no significant impact on the outcome of gene therapy-rescued genes in the mdx diaphragm. Our study provides vital information that could help guide DMD patient follow-up protocols after treatment with gene therapy.
    Keywords:  AAV; RNA sequencing; exercise; inflammation; innate immune response; mdx; microdystrophin
    DOI:  https://doi.org/10.1016/j.omta.2026.201679
  29. Int J Mol Sci. 2026 May 04. pii: 4108. [Epub ahead of print]27(9):
    YAP Acts as a Negative Regulator of Mini Utrophin-Based Gene Therapy for Duchenne Muscular Dystrophy in Mdx Mice.
    Zhuo Li, Yafeng Song.
      Duchenne muscular dystrophy (DMD) is a fatal rare disease caused by dystrophin deficiency, with no effective clinical treatments available to date. Using mdx mice as a model, this study investigated the therapeutic efficacy and interaction of mini utrophin (a truncated utrophin) and Yes-associated protein (YAP) delivered via recombinant adeno-associated virus (rAAV). Results showed that mini utrophin was efficiently expressed in mdx mouse skeletal muscle, significantly increased phosphorylated YAP (p-YAP) levels, restored the expression of dystrophin-glycoprotein complex (DGC) components (α/γ-sarcoglycans), reduced serum creatine kinase (CK) leakage, alleviated pathological damages such as central nucleation and inflammatory infiltration, and comprehensively improved grip strength, treadmill endurance, and pole climbing ability in mice. However, the co-overexpression of YAP completely antagonized these therapeutic effects, resulting in no improvement in pathological phenotypes or motor function of mdx mice. This study confirms that mini utrophin can effectively reverse DMD-related phenotypes, while excessive YAP activation abrogates its therapeutic efficacy, suggesting that precise regulation of YAP activity is required in DMD treatment and providing experimental basis for optimizing gene therapy strategies.
    Keywords:  Duchenne muscular dystrophy; MyoAAV; YAP; gene therapy; mini utrophin
    DOI:  https://doi.org/10.3390/ijms27094108
  30. Am J Physiol Cell Physiol. 2026 May 13.
    Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.
    Klaudia Sztolsztener, Thulasi Mahendran, David A Hood.
      Protein homeostasis is critical for mitochondrial function and is maintained by proteases and chaperones that respond to stress and mediate adaptive changes such as the mitochondrial unfolded protein response (UPRmt), the integrated stress response (ISR) and antioxidant signaling. However, the mechanisms by which stressors regulate these retrograde responses remains uncharacterized in muscle. Thus, we examined the effect of mitochondrial stressors on the activation of these pathways in myoblasts and differentiated myotubes. Cells were exposed to either 1) CDDO, a LonP1 protease inhibitor, 2) GTPP, an HSP90 chaperone inhibitor, 3) CCCP, an energetic uncoupler, or 4) MB-10, an inhibitor of protein import, and responses were compared to those induced by acute contractile activity (ACA). LonP1 inhibition activated ATF4 and Nrf2 signaling, increased mitochondrial chaperones, and resulted in protein aggregation without elevating reactive oxygen species (ROS). In contrast, blocking HSP90 led to increases in mitochondrial ROS and activation of CHOP, indicating protein homeostasis-related stress with limited antioxidant signaling. ACA elicited responses similar to the inhibition of LonP1, including the activation of ATF4 and Nrf2, increased UPRmt markers, and a redox balance. Although CCCP and MB-10 both impaired protein import, they activated distinct downstream responses. CCCP resulted in ISR activation, while MB-10 induced Nrf2-mediated antioxidant responses. Together, these findings show that the type of mitochondrial stress determines the direction of the retrograde signaling pathways between protein homeostasis and redox signaling in muscle cells, and they provide insights on how muscle coordinates signaling pathways as part of mitochondrial adaptations to contractile activity.
    Keywords:  integrated stress response; mitochondrial biogenesis; mitochondrial proteostasis; mitochondrial unfolded protein response; muscle contractile activity
    DOI:  https://doi.org/10.1152/ajpcell.00167.2026
  31. bioRxiv. 2026 Feb 26. pii: 2026.02.24.707605. [Epub ahead of print]
    A Workflow for Spatial Transcriptomic Analysis from Intra-operative Human Skeletal Muscle Biopsies.
    Patricia S Pirbhoy, Vikram Murugan, Michael Hicks, Oswald Steward, Ranjan Gupta.
       Introduction: Successful reinnervation following peripheral nerve injury is highly variable, and the molecular programs underlying human muscle degeneration and recovery remain poorly defined. There is a critical need for high-resolution, spatially resolved gene expression data from human skeletal muscle obtained in clinically relevant settings. This study aimed to establish the feasibility of applying spatial transcriptomics to intra-operatively human muscle biopsies and to generate a framework for identifying gene expression signatures associated with reinnervation outcomes.
    Methods: To validate the workflow, we collected biopsies intraoperatively from upper-extremity muscles during standard-of-care orthopaedic surgical procedures 5 months after traumatic brachial plexus injury. The flash-frozen biopsy was processed using the 10x Genomics Visium HD high-resolution platform. Quality metrics confirmed high RNA integrity and robust transcript detection at 8 µm resolution.
    Results: Genes involved in neuromuscular junction formation, degeneration, and regeneration were identified at subcellular resolution and showed fiber-type-specific expression patterns. Analyses were performed using complementary approaches in Seurat and Loupe Browser.
    Conclusions: Together, these findings demonstrate the feasibility of spatial transcriptomics in human muscle, establish baseline gene-expression signatures, and provide a foundation for future studies aimed at identifying biomarkers associated with successful reinnervation and improved nerve-repair strategies.
    DOI:  https://doi.org/10.64898/2026.02.24.707605
  32. Am J Physiol Regul Integr Comp Physiol. 2026 May 13.
    Differential Branched-Chain Amino Acid Metabolism in Tissues of Tumor-Bearing Male Mice.
    Miriam Zerrouk, Luca J Delfinis, Christopher G R Perry, Olasunkanmi A J Adegoke.
      Cancer cachexia is a multifactorial syndrome characterized by involuntary loss of skeletal muscle and adipose tissue that is often resistant to nutritional support. The branched-chain amino acids (BCAA: leucine, isoleucine, and valine) stimulate protein synthesis, yet BCAA-targeted therapies have yielded limited clinical benefit and inconsistent results. This might be related to altered metabolism of BCAA in cachexia. In this study, a C26 tumor allograft mouse model was used to examine how tumor burden alters BCAA metabolism across tumor tissue, liver, kidney, adipose tissue and skeletal muscle. Tumor tissue at 4 weeks exhibited higher BCAA levels and elevated branched-chain α-ketoacid dehydrogenase (BCKD) activity compared to samples collected at 2 weeks. At 4 weeks, skeletal muscles from tumor-bearing mice showed reduced BCAA concentrations relative to control. In contrast, liver and adipose tissue did not demonstrate uniform reductions in BCAA content, indicating tissue-specific metabolic responses. Multiple peripheral tissues also displayed lower expression of the L-type amino acid transporter 1 (LAT1) and alterations in downstream mechanistic target of rapamycin complex 1 (mTORC1) signaling. Notably, the soleus muscle maintained elevated phosphorylated S6 (P-S6) levels despite reduced BCAA availability, suggesting muscle-specific adaptations. These findings demonstrate distinct tumor and peripheral tissue alterations in BCAA handling in C26 tumor bearing mice. The observed changes in BCAA metabolism may underlie the limited success of BCAA-based interventions in cachexia and highlight the need for therapies that address both tumor and host metabolism.
    Keywords:  Amino acid transporters; branched-chain amino acids; branched-chain α-keto acids; cancer cachexia; tissue metabolism
    DOI:  https://doi.org/10.1152/ajpregu.00320.2025
  33. J Extracell Biol. 2026 May;5 e70139
    Exercise and Skeletal Muscle-Derived Extracellular Vesicles: Their Cargo, Release, and Role in Metabolic Regulation.
    Jeremy Boulestreau, Scott K Ferguson, Luke Nelson, Noemi Polgar.
      The health benefits of exercise are well established in the prevention and management of metabolic disorders such as obesity and diabetes. Emerging evidence indicates that extracellular vesicles (EVs) may contribute to the beneficial effects of exercise. These membrane-bound nanoparticles carry bioactive molecules, such as proteins, lipids, and RNAs, and facilitate intercellular communication. Of note, exercise has been shown to significantly influence EV release and cargo, enhancing their ability to mediate metabolic benefits across various tissue types. Recent investigations have demonstrated that skeletal muscle-derived EVs (SkM-EVs) can improve insulin sensitivity, promote glucose homeostasis, and modulate lipid metabolism in recipient cells and tissues. Additionally, exercise-induced SkM-EVs are enriched in specific proteins and microRNAs that activate key signaling pathways essential for glucose homeostasis, thereby providing protective effects against insulin resistance, inflammation, and other hallmarks of metabolic dysfunction. In this review, we summarise the current understanding of the effects of exercise on SkM-EV release, molecular cargo, and the potential mechanisms by which they exert metabolic benefits. By doing so, we highlight the potential of SkM-EVs as therapeutic tools for treating diabetes and related metabolic disorders.
    Keywords:  T2DM; exercise; extracellular vesicle; metabolic disorders; skeletal muscle
    DOI:  https://doi.org/10.1002/jex2.70139
  34. Adv Drug Deliv Rev. 2026 May 14. pii: S0169-409X(26)00130-4. [Epub ahead of print] 115896
    Toward bioengineered muscle-fat microphysiological systems for sports medicine and obesity therapeutics.
    Min Young Kim, Anicca D Harriot, Deok-Ho Kim.
      Muscle injuries represent a major healthcare burden, yet we lack platforms capable of predicting human responses to exercise, injury, and therapeutic interventions. Muscle-on-chip (MoC) technologies can now reproduce physiological force generation, electrical activity, and repair processes. However, most existing systems still culture muscle in isolation, limiting their ability to capture physiological interactions. Such models overlook the bidirectional signaling between muscle and adipose tissue that regulates exercise performance and metabolic balance. Myokines released during exercise promote adipose lipolysis and browning, whereas adipokines associated with obesity can hinder muscle function and regeneration. Over the past two decades, microphysiological systems (MPS) have evolved from simple passive microfluidic channels into dynamic, responsive platforms that capture muscle contraction forces, cytokine secretion, and electrical responses in real time. An integrated muscle-adipose platform that preserves distinct culture environments and allows controlled cytokine exchange is still lacking. Beyond integration challenges, we highlight critical gaps in tissue maturation, standardization, neuromuscular innervation, and scalability. This review focuses on current skeletal muscle-on-chip technologies, emerging adipose-relevant modeling strategies, and the design requirements needed to build future integrated muscle-adipose microphysiological systems for sports medicine and obesity therapeutics.
    Keywords:  Microphysiologic system; Obesity; Sarcopenia; Skeletal muscle-on-a-chip; Sports medicine
    DOI:  https://doi.org/10.1016/j.addr.2026.115896
  35. Chembiochem. 2026 May 14. 27(9): e70368
    Assessment of DNA Variations From Two In Vivo Skeletal Muscle Disorder Mouse Models Using Complementary Square-Wave Voltammetry and LC-MS/MS Analysis.
    Elizabeth R LaFave, Grayson B Sink, Saphal Bhandari, Emma L Rayfield, Andrew T Readyoff, Espen E Spangenburg, Eli G Hvastkovs.
      Duchenne Muscular Dystrophy (DMD) and Ehlers-Danlos Syndrome (EDS) are characterized by genetic instability due to DNA damage leading to loss of muscular function. Genetic impacts of these diseases were probed by extracting DNA from selected muscle tissues of either a mouse model of X chromosome-linked muscular dystrophy (mdx, DMD model) or a heterozygous col5a1 (+/-) mouse (EDS model). Complementary square wave voltammetry (SWV) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) approaches were used to assess extracted DNA. SWV analysis was performed by immobilizing DNA layer-by-layer (LbL) on pyrolytic graphite (PG) electrodes before oxidation in the presence of Ru(bpy)3 2+. Changes in SWV peak currents (Ip) at ∼+1.05 V vs. SCE indicated significant DNA alterations in the genetically altered mouse tissues compared to wild type (WT) controls. Both mdx and heterozygous col5a1(+/-) samples exhibited statistically significant decreased Ip levels (p < 0.05) compared to WT DNA suggesting guanine content varied due to the genetic alterations, which was statistically more significant in leg muscle DNA. MS/MS validated and expanded on the SWV results. DNA base analysis showed increased oxidative damage alongside changes in undamaged base content in mdx mice. DNA from col5a1(+/-) leg muscles exhibited significant changes to undamaged base content, showcasing similar trends.
    DOI:  https://doi.org/10.1002/cbic.70368
  36. Cell Prolif. 2026 May 15. e70231
    Inhibition of Ornithine Decarboxylase 1 Mitigates Denervation-Induced Muscle Atrophy by Suppressing Proteolysis and Preserving Muscle Stem Cell Homeostasis.
    Mingming Zhang, Feifan Chang, Siliang Ge, Fuming Cao, Pincong Fu, Haobo Zhang, Ming Chen, Yi Li, Peifu Tang, Pengbin Yin.
      Neural innervation is of vital importance for muscle mass and function, and denervation induces progressive muscle atrophy, which lacks effective treatments. Polyamine metabolism is reported to be innervation responsive and involved in denervation-induced muscle atrophy, yet the effects of polyamine in denervated muscle atrophy remain unknown. In this study, using a sciatic nerve transection model, we observed progressive increases in putrescine and spermidine, alongside induction of polyamine metabolism enzymes, coincident with the early rapid atrophy phase post denervation. Pharmacological ODC1 inhibition lowered intramuscular polyamines and improved denervated muscle atrophy and fibrosis. In contrast, spermidine supplementation induced muscle atrophy and atrogene expression in healthy and denervated muscle, implicating spermidine as a pro-atrophic metabolite. Single-nucleus sequencing revealed an expansion of atrophic myonuclei and depletion of type IIb myonuclei post denervation. DFMO reduced the atrophic myonuclear fraction, increased MuSCs abundance, and suppressed FAPs derived FGF signalling dominated by the Fgf7-Fgfr2 axis to maintain MuSCs homeostasis. Taken together, our results demonstrate that dysregulated polyamine metabolism is a key contributor to denervation-induced muscle atrophy, and ODC1 inhibition mitigates muscle atrophy and fibrosis by restraining proteolysis and preserving MuSCs homeostasis, which will provide references for future clinical treatments.
    Keywords:  denervation; muscle atrophy; muscle stem cell; polyamine metabolism
    DOI:  https://doi.org/10.1111/cpr.70231
  37. J Physiol. 2026 May 15.
    Human multi-tissue transcriptomics identifies galectin-1 and follistatin-like 1 as exerkines with distinct transcript-to-serum coupling after exercise.
    Jaeseung Song, Eun-Suk Cho, Yu Rim Kwon, Jong Suk Park, Ji Sun Nam, YuSik Kim.
      Exercise-induced secreted factors (exerkines) are proposed to coordinate systemic health benefits, yet their human tissue sources and the physiological rules governing transcript-to-serum coupling remain incompletely defined. We integrated multi-tissue transcriptomics with matched serial serum profiling to identify exercise-regulated exerkines and determine whether tissue mass moderates their systemic appearance. Sixteen healthy, sedentary young men performed a single treadmill bout calibrated to expend 300 kcal at 70-75% of maximum heart rate. RNA sequencing was performed on periumbilical subcutaneous adipose tissue, vastus lateralis skeletal muscle and whole blood collected before and immediately after exercise, with serial serum quantification up to 120 min post-exercise. Acute exercise altered adipose and muscle transcriptomes, with a minimal whole-blood response, and upregulated LGALS1 (galectin-1), FSTL1 (follistatin-like 1), OGN (osteoglycin) and C1QTNF3 (C1q and tumour necrosis factor-related protein 3) in both tissues. Serum follistatin-like 1 and galectin-1 concentrations increased significantly immediately after exercise and during recovery. Despite robust transcript induction, OGN and C1QTNF3 did not translate into early circulating increases, indicating candidate-specific kinetics and constraints beyond transcript abundance. Moderation models revealed divergent transcript-to-serum coupling: follistatin-like 1 coupling was moderated by tissue mass in both muscle and adipose depots, whereas galectin-1 followed a muscle-dominant additive profile independent of mass scaling. These findings propose galectin-1 and follistatin-like 1 as human exerkines and indicate that body composition regulates systemic exerkine signatures after exercise, providing a mechanistic framework for understanding physiological variability in exercise-induced adaptations. KEY POINTS: Exercise releases circulating factors that may contribute to health benefits, but the human tissues responsible for their production remain unclear. RNA sequencing was performed in human skeletal muscle, subcutaneous adipose tissue and whole blood, with targeted serum protein quantification over 2 h after a single treadmill bout. Exercise increased LGALS1 and FSTL1 transcripts in skeletal muscle and adipose tissue, with concurrent increases in their circulating protein products immediately post-exercise and during recovery, whereas OGN and C1QTNF3 transcripts increased robustly without an early post-exercise elevation in their circulating protein products. Body composition moderated transcript-to-serum coupling: FSTL1 (follistatin-like 1) showed mass-sensitive coupling, whereas LGALS1 (galectin-1) displayed a muscle-dominant additive profile. Galectin-1 and follistatin-like 1 emerge as exercise-induced exerkines whose circulating responses vary with body composition, supporting their prioritization as candidate mediators of exercise-related health benefits and a framework for interpreting physiological heterogeneity in adaptation.
    Keywords:  C1q and tumour necrosis factor‐related protein 3; exercise; exerkine; follistatin‐like 1; galectin‐1; osteoglycin
    DOI:  https://doi.org/10.1113/JP291172
  38. Int J Oncol. 2026 Jul;pii: 78. [Epub ahead of print]69(1):
    BMP4 derived from human gastrointestinal carcinoma cells impairs myogenic differentiation: A possible in vitro mechanism of cancer‑induced cachexia.
    Kazuki Higure, Yoshihiko Kitajima, Naoya Kimura, Shota Ikeda, Shohei Matsufuji, Tomokazu Tanaka, Hirokazu Noshiro.
      Gastrointestinal cancer (GIC) frequently causes cancer cachexia, the major feature of which is the loss of skeletal muscle mass. The degradation of muscular proteins by cancer‑derived factors in the major pathogenesis of cancer‑induced muscle wasting is a known phenomenon. However, this mechanism has mainly been demonstrated using rodent cancer cells, and it may not always be applicable to human cancer types. Impaired skeletal muscle differentiation and regeneration have attracted attention as alternative inducers of cancer cachexia. The present study revealed that conditioned medium from four human GIC cell lines inhibited C2C12 myoblast differentiation by inducing the expression of the inhibitor of DNA binding (Id) proteins Id1 and Id3, which mediated via bone morphogenetic protein (BMP)‑Smad signaling. The results suggested that BMP‑Smad1/5/8‑Id signaling inhibited the expression of a MRF member, myogenin and its downstream myogenic genes, thus leading to unsuccessful differentiation into myotubes. Furthermore, the present study identified high levels of BMP4 secretion from these four human GIC cell lines and demonstrated that an inhibitor of BMP receptor, dorsomorphin or abrogation of BMP4 by siRNA in the GIC cells restored myogenic differentiation in C2C12 cells. The present study uncovered, for the first time, that BMP4 derived from human GIC cells exogenously inhibited myoblast differentiation by activating the Smad1/5/8‑Id signaling axis. In the future, this in vitro study may help to elucidate the complicated mechanisms underlying cancer‑induced cachexia in humans.
    Keywords:  bone morphogenetic protein; cachexia; gastrointestinal cancer; inhibitor of DNA binding; myogenic differentiation
    DOI:  https://doi.org/10.3892/ijo.2026.5891
  39. Cell Death Dis. 2026 May 12.
    Emerin is necessary for microtubule-organizing center translocation to the nuclear envelope of muscle cells.
    Elisabetta Mattioli, Vittoria Cenni, Patrizia Sabatelli, Elisa Schena, Spartaco Santi, Chiara Fiorillo, Claudio Bruno, Antonella Pini, Melania Giannotta, Marco Cavallo, Costantino Errani, Eleonora Cattin, Daniela Benati, Alessandra Recchia, Giovanna Lattanzi.
      During myogenic differentiation, the Microtubule-Organizing Center (MTOC) is relocated to the nuclear envelope by a molecular platform including Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins, A Kinase Anchoring Proteins (AKAP9 and AKAP6) and Pericentriolar Material 1 (PCM-1). Here, we show that emerin is required for centrosomal protein recruitment to the nuclear periphery of myonuclei and microtubule dynamics. In fact, in type 1 Emery-Dreifuss Muscular Dystrophy (EDMD1), loss of emerin was associated with altered pericentrin recruitment to the nuclear envelope, LINC protein impairment at the nuclear poles of myonuclei and microtubule organization defects. As a consequence, dynein, mitochondrial distribution and nuclear alignment along the longitudinal axis of the myotubes were altered in EDMD1 myotubes. Moreover, reduced levels of AKAP6 and PKA were detected at the nuclear periphery of EDMD1 myotubes, possibly contributing to an aberrant nuclear localization of the mechanosensing factor YAP. Upon rescue of emerin expression by CRISPR correction of mutated EMD gene: SUN1/2, pericentrin, AKAP6 and PKA were restored at the nuclear envelope and a correct YAP localization was observed in EDMD1 muscle cells. These results show that emerin is required for Nuclear Envelope-MTOC (NE-MTOC) organization in differentiating skeletal muscle cells and suggest that disruption of such complex is a key pathogenetic event in Emery-Dreifuss Muscular Dystrophy.
    DOI:  https://doi.org/10.1038/s41419-026-08819-6
  40. Front Sports Act Living. 2026 ;8 1769113
    PTM encoding: decoding the mechanisms of exercise-induced metabolic memory through spatiotemporal modification networks.
    Yinghao Shen, Zhujun Mao, Xinru Zhang, Yupeng Yang, Zhidong Shen, Haodong He, Cheng Chen, Junjie Liu.
      Post-translational modifications (PTMs) form a sophisticated regulatory layer that modulates cellular responses to physiological stimuli, notably exercise-triggered metabolic adaptations like skeletal muscle glucose uptake. Understanding PTM-mediated regulatory logic, namely how several well-characterized PTMs coordinate spatiotemporally to mediate distinct biological functions, has become a critical frontier in decoding metabolic memory mechanisms. Traditional paradigms focused on isolated signaling pathways struggle to account for the intricate network dynamics underlying these adaptations. This review synthesizes recent advances that clarify the role of PTM-mediated regulation in exercise-induced metabolic memory. We emphasize integrating cutting-edge technologies (single-cell multiomics, in situ mass spectrometry imaging). These tools enable constructing dynamic PTM profiles with exceptional spatial and temporal resolution. Innovations in fluorescence reporter probes additionally improve monitoring of PTM dynamics in vivo. We explore the molecular logic governing hierarchical PTM networks and interorgan communication, highlighting the central regulatory functions of AMPK/mTOR pathways. Additionally, we discuss emerging machine learning-based PTM clock models that provide quantitative frameworks to track metabolic states and advance precision exercise prescriptions. By bridging molecular insights with translational applications, this review offers a holistic view to advance our understanding of exercise-induced metabolic memory and facilitate developing personalized interventions. These conceptual and technological breakthroughs position PTM-mediated regulation as a transformative paradigm with notable academic value and clinical promise.
    Keywords:  AMPK/mTOR; PTM clock; in situ mass spectrometry imaging; interorgan communication; metabolic memory; post-translational modification (PTM) encoding; precision exercise prescription; single-cell multiomics
    DOI:  https://doi.org/10.3389/fspor.2026.1769113
  41. Mamm Genome. 2026 May 11. pii: 66. [Epub ahead of print]37(1):
    Combined single-cell RNA sequencing and mendelian randomization to identify biomarkers associated with circadian rhythm in sarcopenia.
    Yuli Huang, Lifeng Tang, Daoyuan Li, Long Chen, Wenjuan Wu, Dingcheng Zeng, Yanbiao Zhong, Maoyuan Wang.
      Sarcopenia refers to the involuntary loss of skeletal muscle mass and function with aging and is associated with multiple adverse health outcomes. Disruption of normal circadian rhythms due to shift work or nocturnal lifestyle is associated with the risk of several diseases such as metabolic syndrome and cancer. However, its role in sarcopenia remains unclear. The synergy of single-cell RNA sequencing and Mendelian randomization (MR) analysis provides an opportunity to reveal the important involvement of circadian rhythms in the pathogenesis of sarcopenia. Data quality control and normalisation were performed in the single-cell dataset, GSE167186. Then, different cell types were obtained by cell annotation through marker genes. Differentially expressed genes (DEGs) were further analyzed in different cell types. The intersection of DEGs and circadian-related genes in fast skeletal muscle cell were taken. Afterwards, the genes that had causal relationship with sarcopenia were selected as biomarkers by MR analysis. Variations in signaling pathways between different cell types were further analyzed. In GSE167186, 20 different cell populations identified by UMAP cluster analysis were further annotated to 8 cell types using maker genes. Afterwards, 44 DEGs were screened between fast skeletal muscle cell and circadian-related genes. Further MR Analysis yielded three genes with significant causal association with sarcopenia, which could be used as biomarkers in this study. SMARCD3 was found to have a protective effect against sarcopenia (OR = 0.9183, 95% CI = 0.8577-0.9832, p = 0.0144); in contrast, CPED1 (OR = 1.0292, 95% CI = 1.0089-1.0500, p = 0.0047) and FNBP4 (OR = 1.1096, 95% CI = 1.0316-1.1934, p = 0.0051) were associated with an increased risk of sarcopenia. The analysis of intercellular signaling revealed that the loss of the protective factor SMARCD3 in fast skeletal muscle cell triggers a specific upregulation of EGF signaling directed at FAPs. This study highlights the contribution of circadian rhythms in the pathogenesis of sarcopenia and further defines circadian rhythm-related biomarkers in sarcopenia, as demonstrated by MR analysis and scRNA-seq analysis. This suggests circadian rhythms as a focal point for pathogenesis research and potential therapeutic targeting in sarcopenia.
    Keywords:  Biomarkers; Circadian rhythm; Mendelian randomization; Sarcopenia; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1007/s00335-026-10231-6
  42. J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70296
    MyoRep: A Novel Reporter System to Detect Early Muscle Atrophy In Vitro and In Vivo.
    Andrea D Re Cecconi, Nicoletta Rizzi, Mara Barone, Federica Palo, Martina Lunardi, Mara Forti, Adriana Maggi, Paolo Ciana, Giulia Terribile, Michela Chiappa, Lorena Zentilin, Rosanna Piccirillo.
       BACKGROUND: Muscle atrophy occurs during physiological (i.e., fasting) and pathological conditions (i.e., cancer) and anticipates death. Since not all patients will undergo muscle wasting, it would be highly useful to identify them soon to intervene early. We aim to generate a reporter system to follow only pathological, but not physiological, muscle wasting through in vivo imaging.
    METHODS: Comparing the upstream non-coding regions of a subset of atrophy-related genes or atrogenes, using the MuRF1 promoter as a backbone, we cloned various promoters upstream of Firefly Luciferase. The best hits selected in vitro were further compared in in vivo imaging if able to sense early atrophy induced by MCG101 sarcoma or sciatic nerve resection through plasmid electroporation or AAV9 injections. The best promoter was used to generate the reporter mouse MyoRep, expressing the cassette in all skeletal and cardiac muscles using the loxP system.
    RESULTS: Luciferase assays showed that only the newly generated promoters of MuRF1, one containing glucocorticoid-responsive elements or GRE (TWIST) (p ≤ 0.01, 1.7 FC) and a GRE-less promoter (GREDEL) (p ≤ 0.0001, 1.6 FC), discriminated the supernatants from cachectic tumoural cells (C26) from non-cachectic ones (4T1). Comparing both reporters electroporated in leg muscles, we found that GREDEL, but not TWIST, anticipated atrophy by 6 days in MCG101 carriers (p ≤ 0.05) and by 8 days upon denervation (p ≤ 0.05), recapitulating MuRF1 inductions. TWIST, but not GREDEL, drove an undesirable bioluminescent signal in vitro to dexamethasone (p ≤ 0.001, 1.5 FC) and in vivo upon fasting (p = 0.0553, 3 FC). GREDEL-carrying AAV9 injected in the legs of ApcMin/+ mice unraveled sex-different cachexia and anticipated body emaciation by 1 week (p ≤ 0.001, 3.7 FC). GREDEL was then used to generate the MyoRep mouse. Dorsal view of bioluminescent signal of MCG101-carrying MyoRep mice increased already 6 days from tumour injection (p ≤ 0.01, 1.7 FC) when tumour is still unpalpable. Denervated MyoRep mice emitted a signal already 1 day after surgery (p ≤ 0.05, 1.4 FC), anticipating atrophy. Male ApcMin/+ mice display less musclin in their muscles (p ≤ 0.05, 0.4 FC) and plasma (p ≤ 0.01, 0.6 FC). Such mice, when expressing MyoRep in their muscle legs, were given the anti-catabolic myokine musclin. The emitted signal was decreased by 30% 3 weeks after musclin-AAV9 administration (p ≤ 0.05), supporting MyoRep useful to test anti-atrophic drugs.
    CONCLUSIONS: Since MyoRep detects only pathological atrophy anticipating wasting, it represents an unprecedented tool to predict it early in diseases with local or systemic atrophy. It could also be useful to identify early biomarkers of atrophy and new drugs at once.
    Keywords:  cancer cachexia; in vivo imaging; muscle atrophy; reporter mouse
    DOI:  https://doi.org/10.1002/jcsm.70296
  43. PLoS One. 2026 ;21(5): e0349371
    Estrogen deficiency induces pelvic floor muscle atrophy via ERα/GLUT4 pathway.
    Xiaoyu Huang, Mengqi Zhou, Ying Wang, Mao Chen, Ya Xiao, Lingyun Li, Fangyi Zhu, Liying Chen, Xiaoyu Tian, Shiman Wu, Bingshu Li, Li Hong.
      Pelvic floor dysfunction (PFD) is a common disease in women that seriously affects physical and psychological health. Menopause-associated estrogen reduction is one of the risk factors. However, the role and mechanism of estrogen in PFD remains unclear. In this study, we observed atrophy of both fast and slow muscle fibers in the pelvic floor muscle (PFM) of ovariectomized rats, accompanied by decreased expression of estrogen receptor α (ERα). Estrogen deficiency severely impaired the proliferation, differentiation, and mitochondrial function of C2C12 myoblasts and increased apoptosis, which could be rescued by ERα agonist. Mechanistically, estrogen deficiency led to the downregulation of ERα, which in turn suppressed the expression of glucose transporter 4 (GLUT4) and its trafficking regulator Rac family small GTPase 1 (RAC1). This disruption abolished the critical co-localization of GLUT4 with RAC1, resulting in defective glucose uptake, mitochondrial dysfunction, and ultimately impaired myoblast proliferation and differentiation. Both ERα activation and GLUT4 overexpression rescued these defects. Thus, our study delineates a novel ERα/GLUT4 pathway that mediates PFM atrophy under estrogen deficiency conditions, providing a potential therapeutic target for PFD.
    DOI:  https://doi.org/10.1371/journal.pone.0349371
  44. Int J Mol Sci. 2026 Apr 25. pii: 3836. [Epub ahead of print]27(9):
    Myostatin Research: From Molecular Understanding to Clinical Translation for Musculoskeletal and Metabolic Disorders.
    Chongguang Lei, Hewen Jiang, Xin Yang, Shijian Ding, Yuanyuan Yu, Zongkang Zhang, Luyao Wang, Chong Gao, Aiping Lyu, Ling Qin, Ge Zhang, Bao-Ting Zhang.
      Myostatin (Mstn), a well-characterized member of the transforming growth factor-β (TGF-β) superfamily, serves as a key negative regulator of skeletal muscle mass. Its overactivation is closely associated with the pathogenesis of various musculoskeletal and metabolic disorders. Over the past decades, inhibiting Mstn has emerged as a promising therapeutic strategy to promote muscle growth. A range of Mstn-targeted inhibitors has been developed, yielding encouraging preclinical and clinical outcomes. These include small molecules, monoclonal antibodies, peptibodies, and gene therapy-based approaches. This review summarizes the biological structure and function of Mstn, provides a comprehensive overview of recent advances in Mstn-targeted therapeutics, and offers critical insights into future directions for drug development and clinical translation.
    Keywords:  metabolic function; muscle atrophy; musculoskeletal disorders; myostatin; pro-myostatin
    DOI:  https://doi.org/10.3390/ijms27093836
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