bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–09–27
forty-five papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.
  2. Macroscopic to ultrastructural analyses identify the loss of myofibrils as the primary mediator of ageing- and disuse-induced muscle fibre atrophy.
  3. Aging of Skeletal Muscle: From Molecular Mechanisms to Therapeutic Interventions.
  4. Integrated Transcriptomic Analysis Identifies a Candidate INHBA/Activin A-Associated Macrophage-MuSC Communication Axis in Human Skeletal Muscle Ageing.
  5. A quantitative redox proteome of the human muscle response to exercise.
  6. State-Dependent FGF Signaling in Satellite Cell-Mediated Skeletal Muscle Regeneration and Pathological Remodeling.
  7. Reassessing the Role of Progenitor Cells in Muscle Wasting in Cancer Cachexia.
  8. The circadian clock component NPAS2 is modulated by AMPK and regulates substrate utilization and mitochondrial function in human skeletal muscle cells.
  9. Skeletal Muscle Stem Cells: Aging and Rejuvenation.
  10. Emerin loss of function inhibits MyoD-driven differentiation of human iPSCs into skeletal myotubes.
  11. β-hydroxy-β-methylbutyrate improves fast-twitch muscle function, histopathology and mitochondrial respiration in the D2.mdx dystrophic mouse.
  12. Revisiting Culture Conditions of Satellite Cells In Vitro for Skeletal Muscle Regeneration and Therapeutic Applications.
  13. Sarcopenia and Skeletal Muscle Dysfunction in Liver Cirrhosis: Clinical Perspectives of Myostatin Inhibition.
  14. Aerobic Exercise Attenuates High-Fat Diet-Induced Skeletal Muscle Atrophy by Suppressing Oxidative Stress, Inflammation, and Drp1-Associated Mitochondrial Fission.
  15. A semi-automated pipeline for quantitation of Pax7+, myonuclei, and cross-sectional area by fiber type.
  16. The ageing microenvironment in sarcopenia: early alterations and targeted therapeutic strategies.
  17. Preliminary findings on the enhancement of skeletal muscle structure and function in aged male mice by P7C3 activation of nicotinamide phosphoribosyl transferase (NAMPT).
  18. Extracellular-matrix mediated stresses spatially bias myoblast fusion and myotube growth.
  19. AngioNet: a systems biology approach to regulation of microvascular remodelling in response to skeletal muscle activity.
  20. Crk/Crk-L-mediated Rapgef1 recruitment couples MuSK signaling to AChR anchoring at the neuromuscular junction.
  21. Long-term imoxin treatment does not attenuate disease severity in dystrophic diaphragm of male mice.
  22. High-resolution spatial transcriptomic atlas of mouse soleus muscle: Unveiling single cell and subcellular heterogeneity in health and denervation.
  23. Dosage-sensitive regulation of Cofilin-1 and LIMK signaling controls myoblast differentiation and fusion.
  24. Transcriptomic Profiling Reveals Early Molecular Adaptations to Resistance Exercise During Disuse Muscle Atrophy with Complementary Automated H&E-Based Muscle Morphometry.
  25. Skeletal muscle dedifferentiation requires centrosomes.
  26. Damage-associated molecular patterns in skeletal muscle: a double-edged sword - from sterile inflammation initiation to precision targeted therapeutic strategies.
  27. Genetic and regenerative contexts specify distinct soft tissue sarcoma identities from Twist2+ progenitors.
  28. Cross-Species Transcriptomic Integration Identifies a Conserved Molecular Core and Regulatory ceRNA Network in Duchenne Muscular Dystrophy.
  29. The Myokine Landscape: Sources, Signaling, and Context-Dependent Actions.
  30. Skeletal Muscle Transcriptomic Responses to Concurrent Training With Polyphenols in Ageing Adults: A Randomized Trial.
  31. Pancreatic Cancer Disrupts Circadian Patterns of Gene Expression in Cardiorespiratory Muscles.
  32. Hesperetin Attenuates Experimentally Induced Skeletal Muscle Dysfunction by Modulating Time-of-Day-Dependent Gene Expression and Mitochondrial Redox-Related Markers.
  33. Gene-Corrected Human iPSC-Derived Cardiomyocytes and Skeletal Muscles Reveal Partial Dystrophin Dp427 Preservation and Cardiac Dp116 Expression in Duchenne Muscular Dystrophy Patient With a Splice-Site Mutation in Intron 68 (c.9975-1G>T).
  34. Integrated Multi-Omics Network by Physical Exercise Across Aging: Molecular Adaptation Beyond Single Signaling Pathways.
  35. Bioengineered Skeletal Muscle Construct Using A Cell-Seeded Decellularized Diaphragm Muscle Scaffolding System For Pelvic Muscle Regeneration.
  36. Fermented protein foods as modulators of the gut-muscle axis: mechanisms, evidence, and future directions.
  37. The effect of infrared radiation emitting garments on the acute skeletal muscle molecular signalling responses to high-intensity interval exercise.
  38. Tumor-derived MG53 aggravates gastrointestinal cancer cachexia related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway.
  39. β-Nicotinamide Mononucleotide Inhibits Cellular Senescence in Mouse C2C12 Skeletal Muscle Cells.
  40. Biomechanical strain alters the microRNA cargo of primary myogenic cell-derived extracellular vesicles associated with a differentiation phenotype.
  41. "Improving the beneficial effects of HDAC8 inhibition by simultaneously activation of SIRT1 in a zebrafish model of Duchenne muscular dystrophy.
  42. Exploring the Impact of Urolithins A and B on Muscle Health: A Transcriptomic Analysis in Human Myotubes.
  43. Chronic Contractile Activity Remediates Lysosomal Dysfunction in a Muscle Cell Lysosomal Disease Model.
  44. Skeletal Muscle Effects of GLP 1 Receptor Agonists: Molecular Mechanisms and Comparative Insights on Semaglutide and Tirzepatide, a Narrative Review.
  45. Skeletal muscle function does not differ between menstrual cycle phases: A prospective cohort study across three cycles.
  1. J Physiol. 2026 Sep 24.
    Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.
    Maya Semel, Cole Lukasiewicz, Sarah Skinner, Mark R Viggars, Sung Gi Noh, Martin Picard, Abbey-Gale Mannings, Michael S Cohen, Dennis W Wolan, Terence E Ryan, Russell T Hepple.
      Skeletal muscle in wasting conditions often exhibits atrophy, mitochondrial respiratory dysfunction and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. The accompanying alterations in mitochondrial morphology suggest that mitochondria may be involved in muscle pathology in these conditions. To address this gap, we tested an established pathological mechanism in ischaemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle: mitochondrial permeability transition (mPT). We tested if mPT recapitulated phenotypes common in wasting conditions, whether tumour-conditioned media (TCM) could promote mPT and compared differentially expressed genes (DEGs) induced by mPT with DEGs observed in a mouse model of pancreatic cancer cachexia. Inducing mPT in mouse skeletal muscle bundles progressively altered mitochondrial cristae morphology, culminating in a breach of the outer mitochondrial membrane. Inducing mPT in mouse muscle fibres increased mitochondrial reactive oxygen species (mROS) and caspase 3 activity and caused atrophy. Inducing mPT caused a complex I mitochondrial respiratory impairment, increased lysosome-mitochondrion colocalization and fragmented the AChR cluster at the muscle endplate. The Ca2+ threshold for mPT, mitochondrial calcein colocalization and mitochondrial membrane potential were reduced by TCM in skeletal muscle or C2C12 myoblasts, respectively. Knockout of the mPT-regulating protein CypD attenuated the reduction in Ca2+ threshold for mPT by TCM. Inhibitors of mPT attenuated atrophy with TCM in C2C12 and human primary myotubes. Finally, there was overlap between the DEGs of mPT and diaphragm muscle in a mouse model of pancreatic cancer cachexia during the muscle-wasting phase. We conclude that mPT should be explored as a therapeutic target in muscle-wasting disorders. KEY POINTS: Mitochondrial permeability transition (mPT) induces marked alterations in mitochondrial morphology and muscle phenotypes that are common in wasting conditions. mPT is promoted by tumour-derived factors in a manner that depends in part on the mPT-regulating protein CypD. mPT generates transcriptional alterations that overlap with cachectic muscle in a mouse model of pancreatic cancer, particularly during the period of muscle wasting. Pharmacological targeting of mPT attenuates or prevents atrophy in C2C12 and human primary myotubes, respectively.
    Keywords:  mitochondrial permeability transition; mitophagy; muscle atrophy; muscle wasting; neuromuscular junction
    DOI:  https://doi.org/10.1113/JP291213
  2. J Physiol. 2026 Sep 25.
    Macroscopic to ultrastructural analyses identify the loss of myofibrils as the primary mediator of ageing- and disuse-induced muscle fibre atrophy.
    Ramy K A Sayed, Anthony N Lange, Hector G Paez, Jamie E Hibbert, Marius Meinhold, Corey G K Flynn, Jared Hartung, Matilde B Z Santibanez, Isabell Dobrzycki, David J Wrucke, Carlos S Zepeda, Jessica J James, Christopher W Sundberg, Troy A Hornberger.
      Ageing and disuse are two of the most clinically relevant conditions associated with the loss of skeletal muscle mass, yet the ultrastructural adaptations that drive these losses remain poorly defined. Indeed, even the most basic questions, such as whether radial atrophy of muscle fibres is driven primarily by reductions in myofibril size, and/or the loss of myofibrils, remain unanswered. To address this gap, skeletal muscle structure was assessed at the macroscopic, microscopic and ultrastructural levels in young and older humans and mice. In humans, magnetic resonance imaging was used to measure quadriceps muscle volume and cross-sectional area (CSA), whereas vastus lateralis biopsies underwent standard immunohistochemistry for microscopic evaluations, coupled with a next-generation fluorescence imaging pipeline for ultrastructural analyses. Parallel experiments were conducted in mice, including a unilateral immobilization model of disuse-induced atrophy. Ageing in humans was associated with lower muscle volume and CSA, along with radial atrophy of SERCA1-positive fibres, whereas SERCA2-positive fibre CSA was preserved. Notably, the radial atrophy of SERCA1 fibres was largely explained by a lower number of myofibrils, rather than a smaller size of the myofibrils. Similar alterations were observed in aged mice, although SERCA1 fibres also exhibited slightly smaller myofibril size. In mice, disuse likewise caused radial muscle fibre atrophy that was again almost exclusively associated with a lower number of myofibrils. Collectively, these findings identify the loss of myofibrils as a central and conserved mechanism that mediates radial muscle fibre atrophy during ageing and disuse, highlighting a potential therapeutic target for preserving skeletal muscle mass. KEY POINTS: Skeletal muscles atrophy with ageing and disuse, and the loss of muscle mass increases the risk of falls, disability and all-cause mortality. Skeletal muscles are composed of long cells called muscle fibres, and each fibre is densely packed with thread-like structures called myofibrils; however, whether muscle fibre atrophy is primarily driven by reductions in the size of the myofibrils, and/or the loss of myofibrils, is not known. Using a next-generation imaging pipeline, this study examined muscle samples from young and older adults, as well as from young and old mice. The results show that muscle fibre atrophy during both ageing and disuse is mainly associated with a lower number of myofibrils, rather than a smaller size of the myofibrils. Identifying the loss of myofibrils as the primary mechanism underlying muscle fibre atrophy highlights a specific therapeutic target for preserving muscle as people age or recover from injury.
    Keywords:  FIM‐ID; atrophy; immobilization; muscle fibre; myofibrils; sarcopenia
    DOI:  https://doi.org/10.1113/JP291728
  3. MedComm (2020). 2026 Oct;7(10): e70995
    Aging of Skeletal Muscle: From Molecular Mechanisms to Therapeutic Interventions.
    Ting Liu, Yaomin Hu.
      Skeletal muscle aging is a major cause of frailty, metabolic dysfunction, and loss of independence in later life, yet it cannot be explained by muscle mass loss alone. Recent single-cell, multi-omics, and translational studies show that aged muscle is shaped by coordinated changes in myofibers, stem and stromal cells, immune and vascular compartments, neuromuscular control, and systemic metabolism. This review describes skeletal muscle aging as a gradual loss of tissue resilience rather than a simple decline in muscle mass. Impaired proteostasis, mitochondrial dysfunction, chronic inflammation, and cellular senescence are discussed as major, closely linked processes that contribute to defective regeneration, matrix remodeling, fibro-adipogenic conversion and denervation, and are influenced by endocrine, metabolic, liver-, adipose-, gut-, and brain-derived signals. Current therapeutic evidence is reviewed with an emphasis on exercise and nutritional optimization as the clinical foundation, while mitochondrial, anabolic, senescence-directed, and regenerative strategies are considered as emerging or investigational approaches. By bringing these findings together, this review highlights how studies of muscle aging can move beyond descriptive changes in mass and strength toward a clearer understanding of the biological processes that limit muscle function in later life.
    Keywords:  molecular mechanisms; muscle health; sarcopenia; skeletal muscle aging; therapeutic intervention
    DOI:  https://doi.org/10.1002/mco2.70995
  4. Int J Mol Sci. 2026 Sep 17. pii: 8283. [Epub ahead of print]27(18):
    Integrated Transcriptomic Analysis Identifies a Candidate INHBA/Activin A-Associated Macrophage-MuSC Communication Axis in Human Skeletal Muscle Ageing.
    Xuanchen Liu, Zehui Li, Yutong Yuan, Nuo Si, Ningbei Yin.
      Skeletal muscle ageing is accompanied by impaired regeneration and remodelling of the multicellular niche, yet how age-related immune changes relate to altered muscle stem cell (MuSC) states in humans remains unclear. Here, we integrated bulk RNA-sequencing, scRNA-seq and an independent older adult cohort analysis to characterize age-associated changes in human skeletal muscle and identify candidate macrophage-MuSC signalling interactions. Bulk transcriptomic analysis revealed inflammatory activation, reduced mitochondrial and metabolic programmes, and increased macrophage-associated signatures in aged muscle. Single-cell analysis resolved distinct myeloid and MuSC states. Among aged myeloid populations, inflammatory macrophages exhibited the highest SenMayo score, whereas donor-level pseudobulk analysis identified age-related early-primed MuSCs (epMuSC) remodelling involving inflammatory, interferon-related, and extracellular matrix-associated programmes. Ligand-target modelling prioritized inhibin subunit beta A (INHBA)/Activin A as a candidate signal linking inflammatory macrophages to the aged epMuSC programme. This prediction was further supported by an independent older adult human muscle scRNA-seq cohort showing concordant INHBA expression in inflammatory macrophages and Activin receptor expression in epMuSCs. In primary human MuSCs, Activin A induced Activin-responsive genes and suppressed myogenic regulators, and these effects were attenuated by SB431542, a small-molecule inhibitor of ALK4/5/7 signalling. Together, these findings support a candidate INHBA-associated, cell state-resolved communication framework between inflammatory macrophages and epMuSC remodelling in aged human muscle, providing a potential link between immune remodelling and altered regenerative cell states.
    Keywords:  INHBA/Activin A signalling; cell–cell communication; macrophages; muscle stem cells; single-cell RNA sequencing; skeletal muscle ageing
    DOI:  https://doi.org/10.3390/ijms27188283
  5. bioRxiv. 2026 Sep 17. pii: 2026.09.15.751463. [Epub ahead of print]
    A quantitative redox proteome of the human muscle response to exercise.
    Yu Lei, Jonathan J Petrocelli, Anita Reddy, Carlos Henríquez-Olguin, Nils Burger, Sanghee Shin, Bingsen Zhang, Taylor Covington, Markus Waldeck-Weiermair, Jiuchun Zhang, Shelley M Wei, Thomas E Jensen, Christian T Voldstedlund, Christian S Carl, Bente Kiens, Erik A Richter, Edward T Chouchani.
      Reactive oxygen species (ROS) regulate protein function through reversible cysteine oxidation. In human skeletal muscle, exercise-induced ROS initiates adaptations such as mitochondrial biogenesis, increased insulin sensitivity, and hypertrophy. However, specific protein targets of ROS regulation during exercise remain unclear owing to longstanding challenges in analyzing redox proteomes in vivo . We applied cysteine derivatization and multiplexed proteomics to map muscle protein cysteine oxidation in humans during exercise. The OxiMuscle dataset quantifies reversible modifications across 9,177 unique cysteine sites on 2,782 proteins, comprising 17,492 individual cysteine site measurements in young men undergoing three types of exercise, providing the first comprehensive, site-resolved and quantitative analysis of the exercise-regulated redox cysteine proteome in humans. We systematically define cysteine oxidation targets regulated by at least one form of exercise, many of which reside in proteins with established roles in muscle physiology. Among these sites is a redox-regulated cysteine on the autophagy receptor protein p62. We demonstrate that reversible oxidation of this cysteine regulates p62-mediated autophagy upon myotube contraction and mouse muscle adaptation to exercise in vivo . Together, these results define a redox-driven mechanism linking exercise-induced autophagy to muscle adaptation. More broadly, our findings offer a comprehensive resource on redox-signaling networks in human muscle, accessible at http://oximuscle-alb-1899330623.us-east-1.elb.amazonaws.com/ .
    DOI:  https://doi.org/10.64898/2026.09.15.751463
  6. Biomolecules. 2026 Aug 26. pii: 1238. [Epub ahead of print]16(9):
    State-Dependent FGF Signaling in Satellite Cell-Mediated Skeletal Muscle Regeneration and Pathological Remodeling.
    Shuying Fu, Yuhuan Meng, Keying Liang, Meiying Feng.
      Skeletal muscle regeneration depends on coordinated transitions of muscle stem cells (MuSCs), also known as satellite cells, from quiescence through activation and proliferative expansion to differentiation and fusion, while self-renewal replenishes the quiescent MuSC pool within a dynamically remodeled niche. Fibroblast growth factor (FGF) signaling regulates these transitions, but its effects vary as MuSCs and their niche change across regenerative stages. FGF output is shaped by ligand availability and extracellular presentation, fibroblast growth factor receptor (FGFR) isoform expression and coreceptor availability, receptor trafficking, intracellular feedback, and the state of the responding cell. Following acute injury, FGF inputs can support MuSC activation and expansion; signaling is subsequently reconfigured during differentiation, fusion, self-renewal, and return to quiescence. Aging-associated regenerative decline, chronic injury and dystrophic remodeling, denervation, and metabolic dysfunction disrupt this coordination and can uncouple FGF activity from productive repair. Rhabdomyosarcoma provides a distinct malignant context in which the FGF network is rewired to sustain oncogenic myogenic cell states. Here, we integrate molecular, cellular, and niche-level evidence across these settings to explain why FGF signaling produces divergent outcomes and to clarify how cellular context and timing should inform therapeutic modulation.
    Keywords:  aging; fibroblast growth factor; muscle stem cells; pathological remodeling; regenerative niche; rhabdomyosarcoma; skeletal muscle regeneration; state-dependent signaling
    DOI:  https://doi.org/10.3390/biom16091238
  7. Am J Physiol Cell Physiol. 2026 Sep 19.
    Reassessing the Role of Progenitor Cells in Muscle Wasting in Cancer Cachexia.
    Spencer G Miller, Abasi-Ama Udeme, Emma Funk, Carlos Alfaro-Quinde, Suganya Subramanian, Stefano Berto, Jian Ouyang, David J Wang, Michael C Ostrowski, Teresa A Zimmers, Denis C Guttridge.
      Skeletal muscles contain myogenic and non-myogenic progenitor cells that proliferate and differentiate after tissue damage to restore myofiber, connective tissue, and blood vessel homeostasis. We previously showed that cancer-induced muscle wasting involves myofiber damage and impaired differentiation of myogenic progenitors, coincident with the aberrant accumulation of mesenchymal progenitor cells expressing both myogenic (Pax7) and non-myogenic (Sca1, Pdgfrα) progenitor markers. Here, we combined lineage tracing and scRNA-seq to more deeply explore muscle resident progenitor cells during cancer cachexia. Colon-26 (C-26) carcinoma cells were injected into adult (≥12-weeks-old) Pax7-CreER; Rosa26-LSL-tdTomato mice, and tamoxifen was administered after tumors were established but prior to cachexia. At cachexia endpoint, scRNA-seq analysis was performed on muscle mononuclear cells. In both control and C-26 muscles, Pax7 and tdTomato transcripts were restricted to myogenic progenitors, whereas Sca1 and Pdgfrα were restricted to non-myogenic progenitors. These results were confirmed by flow cytometry and suggest that mesenchymal progenitor cells do not commit to a myogenic fate during cancer cachexia. However, consistent with earlier findings, our transcriptomic analyses validated that myogenic progenitors from tumor-bearing mice were impaired to differentiate. When we repeated Pax7-lineage tracing and scRNA-seq on young mice (6-week-old) still undergoing developmental muscle growth similar results were obtained, but interestingly, by flow cytometry we detected a small population of Sca1+; tdTomato+ cells, not present in adult muscles. Thus, non-myogenic progenitors might indeed be capable of adopting a myogenic fate during cancer cachexia, but this contributes to only a minor fraction of Pax7+ cells and likely to be age dependent.
    Keywords:  Cancer cachexia; atrophy; mesenchymal progenitor cells; muscle stem cells; myogenesis; regeneration; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00144.2026
  8. Mol Metab. 2026 Sep 19. pii: S2212-8778(26)00130-4. [Epub ahead of print] 102446
    The circadian clock component NPAS2 is modulated by AMPK and regulates substrate utilization and mitochondrial function in human skeletal muscle cells.
    David Rizo-Roca, Logan A Pendergrast, Prasad Kamble, Dimitrius Santiago P S F Guimarães, Lucile Dollet, Marie Björnholm, Juleen R Zierath.
      The molecular circadian clock coordinates cellular and systemic metabolism across the day, yet how it integrates with energy-sensing pathways in human skeletal muscle remains incompletely understood. AMP-activated protein kinase (AMPK) functions as a cellular energy sensor and has been implicated in circadian regulation; however, its role in coupling clock components to metabolic programming in human muscle has not been established. Here, we investigated the interaction between AMPK signaling and the circadian machinery in primary human myotubes, focusing on the downstream clock components NPAS2 and DBP. Silencing of the AMPKα subunit altered core clock gene expression, increasing CRY1 and CRY2 while reducing NPAS2 and DBP expression, with rhythmicity preserved. To determine the functional relevance of these changes, we examined metabolic phenotypes following siRNA-mediated silencing of NPAS2. NPAS2 knockdown reduced basal oxidative metabolism, decreased abundance of electron transport chain subunits, and increased β-oxidation flux, while maximal mitochondrial respiratory capacity remained intact. These alterations occurred independently of canonical AMPK-ACC signaling but were associated with reduced HIF1A expression. In contrast, DBP silencing reduced glucose oxidation but did not recapitulate the broader metabolic remodeling observed with NPAS2 knockdown. Together, these findings identify NPAS2 as a downstream mediator linking AMPK-dependent circadian signaling to skeletal muscle metabolic regulation. Disruption of this axis alters substrate utilization and impairs mitochondrial function, revealing a mechanism by which circadian clock components contribute to metabolic regulation in human skeletal muscle.
    Keywords:  Circadian clock; Glucose and lipid metabolism; Metabolic regulation; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.molmet.2026.102446
  9. Cold Spring Harb Perspect Biol. 2026 Sep 21. pii: a041479. [Epub ahead of print]
    Skeletal Muscle Stem Cells: Aging and Rejuvenation.
    Joana Neves, Pedro Sousa-Victor, Pura Muñoz-Cánoves.
      Stem cells are central for tissue homeostasis and regeneration after stress, and their function depends on interactions with neighboring niche cells. In skeletal muscle, the resident stem cells (also called satellite cells [SCs]) decline in number and function with age, leading to loss of regenerative capacity and, eventually, deterioration of muscle integrity and physiology. Aged SCs lose the capacity to preserve quiescence or to activate and expand upon injury, in part due to changes in the local and systemic environment. Here, we focus on the age-associated intrinsic changes of SCs and the causes of their cellular and molecular decline. We discuss results from single-cell omics technologies that have shed light on the interactions between SCs and niche cells and how far-reaching signals impact SC function. We present future perspectives on rejuvenating interventions to counter age-dependent regenerative decline and the open questions in muscle stem cell aging.
    DOI:  https://doi.org/10.1101/cshperspect.a041479
  10. bioRxiv. 2026 Sep 16. pii: 2026.09.14.750687. [Epub ahead of print]
    Emerin loss of function inhibits MyoD-driven differentiation of human iPSCs into skeletal myotubes.
    Tracy A Knight, Jessica Mella, Daniel Chen, Rodolfo S Ferreira, Helen C Miranda, Abigail Buchwalter.
      Loss of function of the nuclear lamina-associated protein emerin causes Emery-Dreifuss muscular dystrophy (EDMD). Efforts to define emerin's essential functions in skeletal muscle have been limited by poor concordance between mouse models and human disease phenotypes. Here, we adapt transgene-driven differentiation of human induced pluripotent stem cells (hiPSCs) into skeletal muscle (iSMs) as a tractable human model for emerin loss of function. We find that EMD knockout (KO) hiPSCs are poorly responsive to combined overexpression of MyoD and Baf60c and produce fewer mature iSMs, indicating that emerin influences muscle differentiation downstream of these differentiation factors. While MyoD acetylation and heterodimerization with E-box proteins are unaffected by emerin loss, MyoD targets including p21 and myogenin are downregulated, and EMD KO cells exhibit impaired cell cycle exit in response to differentiation signals. Transcriptomic analysis of EMD KO iSMs revealed persistent expression of cell cycle genes and decreased expression of terminal muscle differentiation genes. Dysregulated genes do not overlap with lamina-associated domains (LADs) but are instead enriched for targets of polycomb repressive complex 2 (PRC2), which deposits H3K27 trimethylation. Altogether, our data indicate a functional overlap between emerin and PRC2-mediated regulation of terminal muscle differentiation.
    DOI:  https://doi.org/10.64898/2026.09.14.750687
  11. J Physiol. 2026 Sep 19.
    β-hydroxy-β-methylbutyrate improves fast-twitch muscle function, histopathology and mitochondrial respiration in the D2.mdx dystrophic mouse.
    Nicholas Giourmas, Hannah Lalunio, Memphis Calzoni, Ryan Bagaric, Craig A Goodman, Alan Hayes.
      Duchenne muscular dystrophy (DMD) is a severe inherited muscle disorder caused by mutations that eliminate the protein, dystrophin, resulting in disrupted protein homeostasis, mitochondrial dysfunction, chronic inflammation and progressive muscle degeneration. The leucine metabolite, β-hydroxy-β-methylbutyrate (HMB), has shown therapeutic potential in dystrophic muscle. We previously reported that HMB supplementation improves fast-twitch muscle histopathology and function in juvenile mdx mice during their peak damage phase (3-6 weeks). However, the mdx model exhibits a relatively mild pathology compared to human DMD, limiting clinical relevance. Here, we investigated 8 weeks of HMB supplementation (1 mg g-1 day-1 via drinking water) in the more severe D2.mdx mouse model at 3 and 6 months of age, representing skeletal muscle pathologies consistent with chronic inflammation and advanced muscle fibrosis, respectively. HMB-treated D2.mdx mice had improved grip strength compared to controls, whereas isolated fast-twitch extensor digitorum longus (EDL) muscles displayed increased fibre size, reduced tissue infiltrate and enhanced force production ex vivo. Mechanistically, HMB increased the phospho-to-total ratio of direct downstream mammalian target of rapamycin complex 1 (mTORC1) targets p70S6K1 and 4EBP1, consistent with enhanced anabolic signalling. Mitochondria assessed from treated flexor digitorum brevis muscles exhibited improved respiration and ATP production, with functional improvements aligning with elevated complex II succinate dehydrogenase activity in HMB-treated EDL muscles. By contrast, no significant HMB-induced effects were observed in the slow-twitch soleus muscle. This study is the first to demonstrate that HMB enhances in vivo and ex vivo muscle function, downstream mTORC1 signalling, and mitochondrial performance in the severe D2.mdx model, supporting its potential as a therapeutic strategy for DMD. KEY POINTS: β-Hydroxy-β-methylbutyrate (HMB) supplementation improves skeletal muscle function in the D2.mdx mouse model of Duchenne muscular dystrophy. HMB treatment increased voluntary grip strength and enhanced force production in isolated extensor digitorum longus extensor digitorum longus muscles in 3- and 6-month-old D2.mdx mice. Functional improvements were accompanied by reduced tissue infiltrate, increased mean muscle fibre size, and elevated succinate dehydrogenase activity. Τηεδδ adaptations coincided with increased markers of mammalian target of rapamycin complex 1 signalling, mitochondrial respiration and ATP production, suggesting improved metabolic capacity in dystrophic muscle.
    Keywords:  Duchenne muscular dystrophy; extensor digitorum longus; histopathology; mitochondria; β‐hydroxy‐β‐methylbutyrate
    DOI:  https://doi.org/10.1113/JP291639
  12. Ann Anat. 2026 Sep 23. pii: S0940-9602(26)00602-3. [Epub ahead of print] 153381
    Revisiting Culture Conditions of Satellite Cells In Vitro for Skeletal Muscle Regeneration and Therapeutic Applications.
    Pooja Kumari, Aayushi Raval, Pranav Rana, Rishabh Rai Kaushik, Ajay Kumar Sahi, Shravanya Gundu, Sanjeev Kumar Mahto.
      Skeletal muscle fibers are largely post-mitotic in adulthood yet retain robust regenerative capacity through satellite cells (SCs), quiescent muscle stem cells located beneath the basal lamina that are activated after injury, proliferate as myoblasts, differentiate, fuse into myotubes, and mature via tightly regulated cues. Given the burden of muscle-wasting and neuromuscular diseases, including Duchenne muscular dystrophy (DMD) (driven by dystrophin defects and impaired SC function), amyotrophic lateral sclerosis (ALS) (with progressive atrophy and evidence of SC perturbation), and myasthenia gravis (autoimmune neuromuscular junction failure), physiologically relevant and scalable in vitro SC systems are essential for mechanistic studies and future cell-therapy development. This review revisits culture conditions and workflows used to isolate, enrich, and differentiate rodent and human skeletal muscle progenitors, integrating key regenerative signalling (hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met), nitric oxide (NO), fibroblast growth factor (FGF)-mitogen-activated protein kinase (MAPK) modulated by Sprouty-1, insulin-like growth factor (IGF)-driven Akt/mechanistic target of rapamycin (mTOR) hypertrophy, inflammatory cytokines including interleukin-6 (IL-6) signal transducer and activator of transcription 3 (STAT3)-cyclin D1, and differentiation switches involving Notch/Wnt, glycogen synthase kinase 3 (GSK3), and mitogen-activated protein kinase (p38α MAPK)) with practical culture variables. Two principal isolation strategies are compared: explant outgrowth, which preserves tissue architecture and injury-mimicking activation but can be slow and yield-limited without matrix support, and enzymatic dissociation (e.g., collagenase, dispase, pronase, protease XIV), which accelerates release from the basal lamina and supports high-throughput needs but requires optimization to minimize trauma and fibroblast contamination. Across reported protocols, matrix choice (notably Matrigel or poly-L-lysine/Matrigel), differential pre-plating, and medium composition (serum levels, chick embryo extract (CEE), basic fibroblast growth factor (bFGF)) strongly influence SC quiescence, migration, survival, and myotube formation, with high purities achievable (e.g., ~97.6% Pax7+ after explant plus differential adherence; ~90% α7-integrin+/SCA-1-/CD31-/CD45-; up to ~98% after preplating; and ~95% in several optimized workflows) and differentiation occurring within ~1-7 days depending on conditions. The isolation of human SCs is constrained by the limited availability of tissue, inconsistent biopsy quality, and the absence of reliable markers to differentiate SCs from other mononuclear cells. Induced pluripotent stem cell (iPSC)-derived muscle organoids present a patient-specific alternative; however, they predominantly produce fetal-like PAX7+ progenitors instead of mature adult SCs. Overall, explant-based systems best retain physiological fidelity for niche and matrix studies, whereas enzymatic and hybrid approaches maximize efficiency and yield, underscoring that culture strategy should be selected based on the experimental objective rather than presumed universal superiority.
    Keywords:  Differentiation; Muscle progenitor cells; Muscle stem cells; Regeneration; Satellite cells; Skeletal muscle; proliferation
    DOI:  https://doi.org/10.1016/j.aanat.2026.153381
  13. Biomedicines. 2026 Sep 16. pii: 2082. [Epub ahead of print]14(9):
    Sarcopenia and Skeletal Muscle Dysfunction in Liver Cirrhosis: Clinical Perspectives of Myostatin Inhibition.
    Olga Sukocheva, Damian Harding, Tsai-Wing Ow, Edmund Tse.
      Liver cirrhosis is frequently complicated by sarcopenia, a progressive and systemic loss of skeletal muscle mass and function that contributes substantially to increased morbidity, mortality, and healthcare utilisation. The pathogenesis of sarcopenia in cirrhosis is multifactorial, involving hyperammonaemia, altered protein turnover, hormonal and cytokine dysregulation, chronic inflammation, malnutrition, and broader metabolic disturbances. Increasing evidence suggests that these convergent pathological processes are mediated, at least in part, through dysregulation of myokine signalling pathways, particularly those involving myostatin. Myostatin, in concert with downstream effectors such as mechanistic target of rapamycin (mTOR), plays a central role not only in skeletal muscle homeostasis but also in systemic metabolic regulation, highlighting its relevance beyond muscle biology alone. Therapeutic strategies targeting myostatin signalling have been developed, with several myostatin inhibitors advancing into clinical trials. Emerging data indicate that these agents may increase skeletal muscle mass, reduce adiposity, and improve glucose metabolism in patients with sarcopenia and other metabolic disorders, supporting their pleiotropic metabolic effects. However, the mechanistic role and therapeutic implications of myostatin modulation in the specific context of coexisting cirrhosis and sarcopenia remain incompletely understood. This review summarises current knowledge on myokine-mediated regulation of muscle metabolism in cirrhosis, with a focus on the myostatin-mTOR axis. We critically evaluate existing and emerging myostatin-targeting approaches, including pharmacological inhibition and gene-based therapies, as potential strategies to restore muscle mass and function. Finally, we outline future directions for translational research aimed at modulating myostatin signalling in cirrhosis-associated sarcopenia, emphasising the need to elucidate its systemic metabolic effects to identify novel therapeutic targets and improve clinical outcomes in this population.
    Keywords:  cirrhosis; gene therapy; mTOR; myokines; myostatin; sarcopenia; testosterone
    DOI:  https://doi.org/10.3390/biomedicines14092082
  14. Antioxidants (Basel). 2026 Aug 31. pii: 1102. [Epub ahead of print]15(9):
    Aerobic Exercise Attenuates High-Fat Diet-Induced Skeletal Muscle Atrophy by Suppressing Oxidative Stress, Inflammation, and Drp1-Associated Mitochondrial Fission.
    Yiwen Yuan, Zhenxian An, Min Hu, Xuebin Li, Jiahao Wang, Xuejing Liu, Wenhao Zhang, Zujie Xu, Xiaoqin Zhao.
      High-fat diet (HFD)-induced skeletal muscle atrophy is characterized by impaired muscle mass and function, mitochondrial dysfunction, redox imbalance, and increased inflammation. Previous research has shown that aerobic exercise ameliorates HFD-induced skeletal muscle atrophy, but the underlying mechanisms remain unclear. Dynamin-related protein 1 (Drp1) is a key GTPase that mediates mitochondrial fission, maintains mitochondrial homeostasis, and regulates reactive oxygen species (ROS) production and inflammatory responses. This study investigated the potential involvement of Drp1-associated mitochondrial fission in the protective effects of aerobic exercise against HFD-induced skeletal muscle atrophy. HFD-fed mice underwent an 8-week aerobic exercise intervention, and Mdivi-1, a commonly used mitochondrial fission inhibitor, was administered intraperitoneally to further examine the involvement of mitochondrial fission. Assessments included grip strength, endurance testing, body composition, histology, transmission electron microscopy, immunofluorescence, DHE staining, antioxidant assays, Western blotting, and qPCR. Aerobic exercise reduced Drp1 phosphorylation, oxidative stress, and inflammatory responses in the skeletal muscle of HFD-fed mice and attenuated skeletal muscle atrophy. Mdivi-1 treatment produced similar protective effects, including attenuation of skeletal muscle atrophy, oxidative stress, and inflammatory responses. Together, these findings suggest that Drp1 phosphorylation and associated mitochondrial fission may contribute to the protective effects of aerobic exercise against HFD-induced skeletal muscle atrophy.
    Keywords:  Drp1; ROS; aerobic exercise; inflammation; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/antiox15091102
  15. Physiol Rep. 2026 Sep;14(18): e71097
    A semi-automated pipeline for quantitation of Pax7+, myonuclei, and cross-sectional area by fiber type.
    Helia G Megowan, Madeline Luu, Adam Shuaib, Kaitlyn B Augienello, Adam C Fries, Jake Searcy, Hans C Dreyer.
      Manual analysis of skeletal muscle cross-sections is time-consuming and subject to error and user bias. To overcome these limitations, we developed and validated a semi-automated, quantitative, and reproducible image-analysis pipeline specifically tailored to quantify Pax7+ satellite cells, myonuclei, and cross-sectional area by fiber type. The workflow combines Fiji/ImageJ-based image preprocessing with CellProfiler, Cellpose, and a custom Python script to process and analyze immunohistological images of muscle tissue cross-sections. Outcomes include Pax7+ satellite cells and myonuclei quantified per fiber by fiber type, along with cross-sectional area, perimeter, and fiber type classification. This semi-automated approach provides a robust and efficient platform for high-throughput analysis of muscle tissue cross-sections from large datasets.
    Keywords:  CellProfiler; automated analysis; muscle stem cells; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.71097
  16. Front Immunol. 2026 ;17 1929891
    The ageing microenvironment in sarcopenia: early alterations and targeted therapeutic strategies.
    Liangping Zhang, Guangyang Li, Long Long, Lei Pan, Yun Bai, Ligang Ni, Linqiu Han, Rongqi Cao.
      Sarcopenia is a progressive skeletal muscle disorder associated with ageing and characterized by declines in muscle strength, mass and function. Increasing evidence suggests that its development is not driven solely by myofiber atrophy or impaired protein metabolism, but also by early remodeling of the ageing skeletal muscle microenvironment. This Review summarizes key early alterations in sarcopenia, including dysregulated immune homeostasis, cellular senescence and the senescence-associated secretory phenotype, depletion and dysfunction of muscle satellite cells, disruption of the regenerative niche, mitochondrial dysfunction, impaired proteostasis and neuromuscular junction degeneration. In aged skeletal muscle, chronic low-grade inflammation, oxidative stress, extracellular matrix stiffening and reduced regenerative capacity reinforce one another, establishing a self-amplifying cycle of inflammation, senescence and regeneration failure. This cycle may first impair muscle quality and contractile performance, resulting in early muscle weakness, and subsequently promote myofiber atrophy, fibrosis, fatty infiltration and overt functional decline. Accordingly, therapeutic strategies for sarcopenia should move beyond interventions aimed only at end-stage muscle loss and instead target the ageing microenvironment at earlier, potentially reversible stages. Potential approaches include exercise and nutritional interventions, modulation of inflammation, senescent cell clearance or suppression of the senescence-associated secretory phenotype, improvement of mitochondrial function and restoration of the muscle satellite cell niche. Biomarker- and omics-based population stratification may further support early detection, precision intervention and individualized management of sarcopenia.
    Keywords:  ageing microenvironment; cellular senescence; early alterations; inflammaging; muscle regeneration; sarcopenia
    DOI:  https://doi.org/10.3389/fimmu.2026.1929891
  17. Exp Gerontol. 2026 Sep 20. pii: S0531-5565(26)00306-2. [Epub ahead of print] 113327
    Preliminary findings on the enhancement of skeletal muscle structure and function in aged male mice by P7C3 activation of nicotinamide phosphoribosyl transferase (NAMPT).
    Ravikumar Manickam, Gaurav Shingote, Janani Prasanna, Srinivas M Tipparaju, David W Russ.
      Nicotinamide phosphoribosyl transferase (NAMPT) activation is a key enzyme in the NAD+ salvage pathway that mediates major metabolic changes in skeletal muscle and during aging. The Nampt activator P7C3 provides beneficial effects to both cardiac and skeletal muscle in diabetes, but the effects on aging remain unknown.
    HYPOTHESIS: In the present study we hypothesized that Nampt activation via P7C3 administration would enhance skeletal muscle structure and function in aged mice.
    METHODS: Two-year-old male C57BL/6 mice were treated daily with 10 mg/Kg body weight P7C3 or an equivalent volume of vehicle (DMSO) for 4 weeks. Measurements of ex vivo force frequency relationship (FFR), grip strength, myofiber cross-sectional area (CSA), and Western blotting were conducted to assess muscle responses in old age.
    RESULTS: FFR showed P7C3 provided clear improvement in muscle contractility in EDL and Soleus, though muscle fatigue was unaffected. Volitional grip strength was maintained after 4 weeks of treatment with P7C3, while it declined in the vehicle treatment group. Distribution of muscle fiber CSA in the Tibialis anterior muscle was significantly shifted toward larger fibers in P7C3 treated group. Nampt expression as well as p-Akt/total-Akt protein levels were increased in EDL muscle from the mice treated with P7C3.
    CONCLUSION: Overall, the present study demonstrates for the first time that Nampt activation via P7C3 injections allows for improved fast and slow skeletal muscle function in aged mice with increased muscle quality, myofiber CSA and preserved grip strength.
    Keywords:  Contractility; Muscle fiber; NAD+; Sarcopenia
    DOI:  https://doi.org/10.1016/j.exger.2026.113327
  18. Nat Commun. 2026 Aug 22. pii: 10057. [Epub ahead of print]17(1):
    Extracellular-matrix mediated stresses spatially bias myoblast fusion and myotube growth.
    Yoann Le Toquin, Sushil Dubey, Aleksandra Ardaševa, Lakshmi Balasubramaniam, Emilie Delaune, Valérie Morin, Amin Doostmohammadi, Christophe Marcelle, Benoît Ladoux.
      Myoblast fusion into multinucleated myotubes is essential for skeletal muscle development and repair, yet how tissue-scale mechanics contributes to this process remains poorly understood. Here, we show that primary myoblasts behave as an evolving active nematic system in which actomyosin-dependent stresses, extracellular-matrix (ECM) remodeling and fusion-driven myotube growth are dynamically coupled. As myoblasts fuse into elongated myotubes, orientational order increases and the nematic field is progressively reshaped. We identify a strong coupling between cellular and ECM nematic organization, whereby cytoskeleton-dependent ECM remodeling stabilizes topological defects and reinforces their associated stress patterns. Fusion events preferentially accumulate near comet-shaped +1/2 defects, which correspond to regions of high compressive stress predicted by our theoretical model. Our findings support a model in which the intrinsic fusion machinery provides fusion competence, while ECM-stabilized nematic stress patterns spatially bias the localization of fusion events. Fusion-driven myotube growth then feeds back on the mechanical landscape, increasing nematogen length and stress magnitude. Together, these results reveal a self-reinforcing biomechanical mechanism that contributes to the organization of myoblast fusion and myotube growth, with potential relevance for developmental and regenerative morphogenesis.
    DOI:  https://doi.org/10.1038/s41467-026-76967-6
  19. Am J Physiol Cell Physiol. 2026 Sep 18.
    AngioNet: a systems biology approach to regulation of microvascular remodelling in response to skeletal muscle activity.
    Roger W P Kissane, Lukas Steuernagel, Peter G Tickle, Natalie E Doody, Michela Bonomo, Francesco Falciani, Peter K Davidsen, Stuart Egginton.
      Exercise remodels skeletal muscle microvasculature, yet the transcriptional programs that distinguish functionally meaningful angiogenesis from stochastic increases in capillary number remain unclear. Here, we integrate human exercise transcriptomics with reductionist rat models to develop AngioNet, a network-based framework that resolves stimulus-specific angiogenic programmes. Human endurance and resistance training datasets generated exercise mode specific angiogenic neighbourhoods, showing that canonical mediators, including VEGF-related signalling, occupy divergent network contexts across training modes. Using rat models designed to emphasise mechanical or metabolic exercise stimuli, we highlight the multitude of interactive signals capable of expanding the capillary network. However, not all microvascular expansion promotes improved oxygen delivery dynamics that translated to improvements in fatigue resistance. This functional divergence was explained by local capillary supply and distribution rather than capillary number alone. Overlaying rat transcriptomes onto AngioNet revealed that functional gains preferentially engaged extracellular matrix remodelling, vessel-matrix interaction and coordinated endothelial-matrix programmes, whereas shear-dominant stimuli produced capillary expansion without comparable matrix-remodelling network activation or improvement in fatigue resistance. Hub-set signatures, rather than individual genes, better linked transcriptional remodelling to local-capillary supply area, predicted PO₂ and fatigue resistance. AngioNet therefore provides a mechanistically grounded framework to interpret heterogeneity in exercise-induced vascular adaptation and prioritise pro-functional angiogenic stimuli.
    Keywords:  Angiogenesis; Capillary; Exerecise; Skeletal muscle; Transcriptomics
    DOI:  https://doi.org/10.1152/ajpcell.00397.2026
  20. Cell Chem Biol. 2026 Sep 22. pii: S2451-9456(26)00324-7. [Epub ahead of print]
    Crk/Crk-L-mediated Rapgef1 recruitment couples MuSK signaling to AChR anchoring at the neuromuscular junction.
    Cinzia Barresi, Eleonora Maino, Weiqiang Chen, Jakob J Prömer, Alexia Bock-Pereda, Markus Hartl, Markus A Rüegg, Ruth Herbst.
      The neuromuscular junction (NMJ) is established through reciprocal signaling between motoneurons and skeletal muscle, a process critically dependent on the receptor tyrosine kinase MuSK. Although MuSK activation by Agrin, Lrp4, and Dok-7 is well characterized, the temporal organization of downstream signaling remains unclear. Here, we define the MuSK proximity proteome using TurboID-based proximity labeling combined with mass spectrometry. We identified 74 MuSK-associated proteins, including known substrates and previously unreported interactors. Among early signaling components, the adapter Crk-L emerged as a central hub linking MuSK to small GTPase pathways. We further identified Rapgef1 as a Crk-L-associated effector required for Agrin-dependent acetylcholine receptor (AChR) phosphorylation and clustering. Rapgef1 loss in adult muscle led to NMJ fragmentation. We propose that these defects result from reduced cytoskeletal anchorage of AChRs due to compromised Rapsyn/AChR interaction. These findings uncover Rapgef1 as a key regulator of MuSK-mediated signaling and highlight dynamic mechanisms governing NMJ formation and maintenance.
    Keywords:  AChR clustering; C3G; MuSK; NMJ formation; Rapgef1; TurboID; neuromuscular junction; proximity-dependent labeling; signal transduction; skeletal muscle
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.014
  21. Physiol Rep. 2026 Sep;14(18): e71115
    Long-term imoxin treatment does not attenuate disease severity in dystrophic diaphragm of male mice.
    Ji Heun Lee, Morgan E Vorwald, Melissa Roths, Joshua T Selsby, Rudy J Valentine.
      Duchenne muscular dystrophy (DMD) is characterized by chronic skeletal muscle injury and degeneration. We discovered activation of protein kinase R (PKR; EIF2AK2), a regulator of the integrated stress response, in dystrophic muscle; however, its role in DMD remains unknown. We hypothesized that the PKR inhibitor imoxin (IMX) would improve muscle force and attenuate fibrosis, inflammatory signaling, and ER stress in diaphragms from mdx mice. C57 and mdx mice were treated with vehicle or IMX for ~24 wks (0.5 mg/kg, subcutaneous, 5 times/wk). Specific force was decreased (p < 0.001), and dynamic passive force was increased (p = 0.001) by disease, but there were no IMX effects. Disease-increased fibrotic area was decreased by IMX (p = 0.038); however, IMX failed to reduce fibronectin, collagen, or TGF-β1 signaling proteins. PKR and phosphorylated (p)PKR (thr446) were increased in mdx (p < 0.001) and maintained despite IMX treatment. Similarly, PKR regulators (total PACT, pPACT (ser18), TRBP, and PP1α), and PKR substrates (total eIF2α and peIF2α (ser51)) were also increased with disease (p < 0.001), but unaffected by IMX. Likewise, IMX did not attenuate disease-mediated elevations in inflammatory signaling and ER stress markers. Overall, the dose of IMX was insufficient to attenuate PKR activation and failed to improve muscle function or prevent pathology in dystrophic skeletal muscle.
    Keywords:  DMD; Duchenne muscular dystrophy; ER stress; dystrophin; protein kinase R
    DOI:  https://doi.org/10.14814/phy2.71115
  22. FEBS J. 2026 Sep 21.
    High-resolution spatial transcriptomic atlas of mouse soleus muscle: Unveiling single cell and subcellular heterogeneity in health and denervation.
    Jer-En Hsu, Lloyd Ruiz, Yongha Hwang, Steve D Guzman, Chun-Seok Cho, Weiqiu Cheng, Yichen Si, Peter Macpherson, Angelo Anacleto, Qingyang Zhao, Xiaoya Zhao, Mitchell Schrank, Goo Jun, Hyun Min Kang, Myungjin Kim, Susan V Brooks, Jun Hee Lee.
      Skeletal muscle exhibits pronounced cellular and subcellular heterogeneity, but comprehensive spatial mapping has been constrained by cell/nuclei dissociation-based methods that lose tissue architecture and by spatial platforms with insufficient resolution or limited transcriptome coverage. Here, we present a high-resolution spatial transcriptomic atlas of mouse soleus muscle in longitudinal sections with unbiased whole-transcriptome coverage, enabling myofiber-resolved transcriptomes while preserving subcellular expression domains across the length of fibers. Combining histology-guided myofiber segmentation with unbiased grid-based mapping, we recover canonical fiber types and reveal widespread hybrid myofiber states in situ, including type IIb-associated signatures that are rare in soleus muscle and evident only when intramyofiber heterogeneity is assessed. At subcellular scale, we delineate the neuromuscular junction (NMJ) as a multicompartment niche comprising postsynaptic myonuclei and spatially distinct perisynaptic and myelinating Schwann cell-associated regions, each with characteristic gene programs. Applying this framework to denervation (3 and 7 days) identifies robust fiber-type-specific stress responses, coordinated remodeling of macrophage and fibroblast transcriptomes, and marked intramyofiber heterogeneity, including spatially nonuniform activation of damage-response genes along individual myofibers, with distinct transcriptional domains proximal and distal to the NMJ and associated degenerative histological features. Together, this atlas provides a high-resolution reference for muscle biology and clarifies how denervation reshapes myofiber, synaptic, and stromal-immune programs across cells and within cells in intact tissue.
    Keywords:  Seq‐Scope; denervation; neuromuscular junction; skeletal muscle; spatial transcriptomics
    DOI:  https://doi.org/10.1111/febs.70726
  23. Cell Mol Life Sci. 2026 Sep 18. pii: 338. [Epub ahead of print]83(1):
    Dosage-sensitive regulation of Cofilin-1 and LIMK signaling controls myoblast differentiation and fusion.
    Dora Gjirlić, Anja Weber, Guido Posern, Anurag Kumar Singh.
      Skeletal muscle differentiation requires coordinated cytoskeletal remodeling and transcriptional reprogramming. Members of the actin-depolymerizing factor/Cofilin family regulate actin filament turnover, yet the isoform-specific functions of Cofilin-1 and Cofilin-2 during myogenesis remain incompletely understood. Murine C2C12 myoblasts were used to investigate the expression and function of Cofilin isoforms during differentiation. CRISPR/Cas9-mediated knockout, shRNA-mediated knockdown, immunofluorescence, gene expression analyses, MRTF reporter assays, and pharmacological inhibition of LIM kinase were used to assess myogenic progression and signaling. Myogenic differentiation was accompanied by a pronounced isoform transition characterized by progressive downregulation of Cofilin-1 and Actin-Depolymerizing Factor together with increased expression of Cofilin-2. Loss of Cofilin-1 resulted in marked morphological abnormalities, impaired cell-cycle exit, elevated MRTF activity, and reduced myotube formation, whereas Cofilin-2 deficiency produced comparatively mild effects during early differentiation. Importantly, partial reduction of Cofilin-1 enhanced myoblast fusion, while stronger depletion impaired differentiation, demonstrating a dosage-sensitive requirement for Cofilin-1. In addition, Cofilin-1 activity was dynamically regulated by transient LIM kinase-mediated phosphorylation during early differentiation, and inhibition of this pathway disrupted myogenic progression. Analyses of mRNA and protein stability indicated that isoform switching is primarily regulated at the level of gene expression. Cofilin-1 functions as a dosage-sensitive regulator of myogenic progression that links cytoskeletal remodeling to signaling pathways controlling proliferation and differentiation. Coordinated regulation of Cofilin-1 expression and activity, together with the transition to Cofilin-2, is required for efficient myoblast fusion and muscle formation.
    Keywords:  Actin cytoskeleton; Cell fusion; Cofilin-1; Cofilin-2; Cytoskeletal regulation; LIM Kinase; MRTF signaling; Myoblast differentiation; Myogenesis
    DOI:  https://doi.org/10.1007/s00018-026-06437-1
  24. Life (Basel). 2026 Aug 25. pii: 1403. [Epub ahead of print]16(9):
    Transcriptomic Profiling Reveals Early Molecular Adaptations to Resistance Exercise During Disuse Muscle Atrophy with Complementary Automated H&E-Based Muscle Morphometry.
    Hub E Fatima, Chien-Lin Lin, Yu-Jung Cheng.
      Although resistance exercise effectively attenuates disuse muscle atrophy, studies examining both quantitative muscle morphometry and transcriptomic responses during early adaptation remain limited. To comprehensively evaluate these adaptations, we performed automated Hematoxylin and Eosin stain (H&E)-based quantitative morphometry alongside transcriptomic profiling in a mouse model of hindlimb immobilization with or without resistance exercise. Resistance exercise partially restored muscle fiber atrophy and restored muscle morphology. Transcriptomic profiling identified 76 differentially expressed genes and revealed coordinated alterations involving metabolic regulation, immune/inflammatory responses, and extracellular matrix remodeling, rather than a single dominant signaling pathway. Functional enrichment analysis further highlighted cytokine-mediated signaling, extracellular matrix organization, and metabolic pathways associated with the early response to resistance exercise. Together, these findings demonstrate that automated H&E-based morphometry, alongside transcriptomic profiling, provides complementary structural and molecular insights into the early adaptive response to resistance exercise and offers a practical framework for future studies of skeletal muscle remodeling.
    Keywords:  disuse muscle atrophy; muscle fiber morphology; quantitative morphometry; resistance exercise; transcriptomics
    DOI:  https://doi.org/10.3390/life16091403
  25. NPJ Regen Med. 2026 Sep 25. pii: 38. [Epub ahead of print]11(1):
    Skeletal muscle dedifferentiation requires centrosomes.
    Elaiyaraja Subramanian, Anoop Kumar, Ketan Mishra, Gonçalo Brito, Matthew Kirkham, András Simon.
      Multinucleated skeletal muscle cells are stably withdrawn from the cell cycle in most vertebrates. Muscle dedifferentiation, however, naturally occurs during limb regeneration in newts and can be experimentally induced in mammalian myotubes. Here we addressed the dynamics of centrosomes, which are key organelles for cell proliferation during myogenic differentiation and dedifferentiation in a cross-species comparative setting. We show that, unlike their mammalian counterparts, newt muscle cells retain centrosomes during differentiation, and their abrogation during regeneration interferes with myogenic dedifferentiation as well as blastema formation in newts. Mammalian myotubes, which are experimentally induced to dedifferentiate, give rise to progeny that regain centrosomes through a process that depends on inhibition of the tumor suppressor, p53. We also find that regulation of the subcellular localization of Polo-Like Kinase 4, rather than its expression level, is a hallmark of myogenic differentiation and dedifferentiation, revealing a novel cellular process underlying the plasticity of the differentiated state.
    DOI:  https://doi.org/10.1038/s41536-026-00509-3
  26. Biochem Pharmacol. 2026 Sep 25. pii: S0006-2952(26)00838-5. [Epub ahead of print] 118496
    Damage-associated molecular patterns in skeletal muscle: a double-edged sword - from sterile inflammation initiation to precision targeted therapeutic strategies.
    Zihui Gao, Xia Li, Yanan Ji, Jitai Zhang, Zhanzhan Li, Yong Cai, Hualin Sun.
      Skeletal muscle repair after injury depends on a tightly coordinated cascade of inflammatory and regenerative responses. Damage-associated molecular patterns (DAMPs) link tissue damage to innate immune activation, but their effects are highly context dependent. This review summarizes the major cellular sources of DAMPs, including nuclear, cytoplasmic, mitochondrial, and extracellular matrix-derived molecules, and discusses their release through regulated cell death pathways such as necroptosis, pyroptosis, ferroptosis, and apoptosis. We further examine major DAMP-sensing systems relevant to skeletal muscle, including TLR2/4/9, the NLRP3 inflammasome, and the cGAS-STING pathway. Transient DAMP signaling can support inflammatory recruitment, tissue clearance, and regenerative responses, whereas persistent or excessive signaling may contribute to chronic inflammation, fibrosis, and muscle wasting. Exercise-associated DAMP signaling is similarly context dependent and is influenced by exercise modality, intensity, duration, training status, and recovery. We also discuss major barriers to clinical translation, including spatiotemporal heterogeneity, pathway redundancy, limited muscle-specific pharmacology, and discrepancies between experimental models and chronic human muscle diseases. Emerging strategies include targeted nanodelivery, engineered extracellular vesicles, selective modulation of regulated cell death, immunometabolic remodeling, gene- and cell-based approaches, and precision exercise. Molecular docking analyses of representative pathway inhibitors are considered hypothesis-generating tools for proposing potential binding modes rather than evidence of target engagement or therapeutic efficacy. Overall, DAMP-directed intervention in skeletal muscle will likely require selective and context-dependent modulation that limits pathological inflammation while preserving physiological repair and regeneration.
    Keywords:  Damage-associated molecular patterns; Pattern recognition receptors; Precision therapy; Regulated cell death; Skeletal muscle; Sterile inflammation
    DOI:  https://doi.org/10.1016/j.bcp.2026.118496
  27. Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2624530123
    Genetic and regenerative contexts specify distinct soft tissue sarcoma identities from Twist2+ progenitors.
    Alinne C Costa, Akansha M Shah, Maria Gabriela Morales, Runzhe Xu, Efrain Sanchez-Ortiz, Eric N Olson, Ning Liu.
      Soft tissue sarcomas (STS) comprise diverse mesenchymal malignancies whose developmental origins and mechanisms of subtype specification remain poorly understood. Whether distinct sarcoma subtypes can arise from a common progenitor through distinct oncogenic and tissue contexts has remained unresolved. Here, we show that skeletal muscle progenitors marked by expression of the Twist2 transcription factor generate distinct STS subtypes in response to defined genetic and microenvironmental cues. Activation of Kras together with Trp53 loss maintained a mesenchymal cell identity and drove highly penetrant undifferentiated pleomorphic sarcoma (UPS), whereas Trp53 loss or Hedgehog pathway activation in regenerating skeletal muscle preferentially induced fusion-negative rhabdomyosarcoma (FN-RMS). Single-nucleus RNA sequencing revealed fundamentally distinct tumor cell-state landscapes, with UPS enriched for mesenchymal-like states and FN-RMS spanning a continuum of myogenic differentiation states. Comparative analysis demonstrated that both models faithfully recapitulate the cellular hierarchies observed in their respective human STS subtypes. These findings reveal how oncogenic and microenvironmental contexts direct malignant lineage identity from a shared progenitor, providing a powerful platform for defining the developmental mechanisms and therapeutic vulnerabilities underlying STS subtype specification.
    Keywords:  cell of origin; soft tissue sarcoma; tumor heterogeneity
    DOI:  https://doi.org/10.1073/pnas.2624530123
  28. Genes (Basel). 2026 Aug 27. pii: 1017. [Epub ahead of print]17(9):
    Cross-Species Transcriptomic Integration Identifies a Conserved Molecular Core and Regulatory ceRNA Network in Duchenne Muscular Dystrophy.
    Abdolvahab Ebrahimpour Gorji, Tomasz Sadkowski.
       BACKGROUND: Duchenne muscular dystrophy (DMD) is a monogenic disorder caused by dystrophin deficiency, but its downstream molecular consequences involve complex and interconnected regulatory networks.
    METHODS: In this study, we performed a cross-species integrative transcriptomic analysis of skeletal muscle RNA-seq datasets from humans, mice, and rats to identify conserved molecular signatures of DMD.
    RESULTS: Differential expression analysis identified 1367 shared differentially expressed genes (DEGs) across the three datasets, of which 62 showed concordant directionality in all species. After ortholog filtering, which excluded five genes lacking confirmed one-to-one orthologs across all three species, 57 conserved genes were retained as the conserved DMD-associated gene (DAG) set. Functional enrichment (GO/KEGG) was performed on the cross-species shared DEG set, and the 57 conserved genes were subsequently mapped onto these enrichment outputs. The DAG-containing categories included focal adhesion, apoptosis, and calcium signaling, which remained significant after Benjamini-Hochberg correction, together with nominally enriched Rap1 signaling. Integration of circRNA, miRNA, and mRNA data further identified a candidate, computationally inferred hub-dominated ceRNA network involving DMD, RYR3, KLF4, ID1, TIMP4, and CASP7.
    CONCLUSIONS: Together, these findings support a model in which conserved core molecular programs are superimposed on species- and context-dependent transcriptional responses, prioritizing the conserved genes and candidate circRNA-related network components for future mechanistic and translational studies.
    Keywords:  Duchenne muscular dystrophy; RNA-seq; ceRNA network; circRNA; cross-species analysis; miRNA; orthologs; skeletal muscle
    DOI:  https://doi.org/10.3390/genes17091017
  29. Cells. 2026 Sep 17. pii: 1682. [Epub ahead of print]15(18):
    The Myokine Landscape: Sources, Signaling, and Context-Dependent Actions.
    Carme Casadevall, Alba Ramírez-Sarmiento, Ramon Camps-Ubach, Esther Barreiro, Mauricio Orozco-Levi, Joaquim Gea.
      In addition to its contractile role, skeletal muscle has important secretory functions and communicates with local and distant tissues through myokines, a heterogeneous group of cytokines, chemokines, growth factors, peptides, and extracellular-matrix-associated proteins released by muscle cells. Their production is regulated by contraction, mechanical loading, energy availability, hypoxia, inflammation, injury, and mitochondrial or metabolic stress. Through autocrine, paracrine, and endocrine mechanisms, myokines influence satellite-cell activity, myogenesis, protein turnover, muscle mass, metabolism, mitochondrial function, angiogenesis, immune-cell recruitment, extracellular-matrix remodeling, and inter-organ communication. This review provides a structured overview of current knowledge on the production, regulation, and biological actions of approximately 25 major myokines, with particular emphasis on the strength of evidence supporting their classification as bona fide muscle-derived factors. We distinguish local muscle signaling from changes in circulating concentrations of uncertain tissue origin and highlight the context-dependent nature of myokine actions. The same mediator may support adaptation and repair when transiently and locally produced but contribute to inflammation, metabolic dysfunction, fibrosis, or muscle wasting when signaling is excessive, prolonged, or disease-associated. Defining cellular sources, temporal regulation, receptor availability, and interactions within the muscle secretome will be essential for clarifying physiological relevance and translating myokine biology into biomarkers and therapeutic strategies.
    Keywords:  exercise; muscle regeneration; muscle secretome; myokines; skeletal muscle
    DOI:  https://doi.org/10.3390/cells15181682
  30. J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70391
    Skeletal Muscle Transcriptomic Responses to Concurrent Training With Polyphenols in Ageing Adults: A Randomized Trial.
    A Guadalupe-Grau, D Gudra, D Lismane, J Raudeniece, G Akuratere, K Viksne, L Gailite, B Vilne, O Pivovarova-Ramich, M Flensted-Jensen, F Dela, D Reihmane.
       BACKGROUND: Transcriptomic adaptations of ageing skeletal muscle to concurrent resistance training (RT) and high-intensity interval training (HIIT) remain insufficiently characterized. We investigated the effects of a 12-week concurrent RT + HIIT intervention on the vastus lateralis transcriptome in middle-aged and older adults and whether polyphenol supplementation modulated these responses.
    METHODS: Thirty-eight adults (55-70 years; 17 polyphenol [PP], 21 placebo [PLA]) with paired skeletal muscle RNA-sequencing data participated in a randomized, double-blind trial. Participants completed a 30-day supplementation phase followed by a 12-week supervised RT + HIIT programme with continued supplementation. Muscle biopsies were obtained before (PRE) and after (POST) training. Differential expression analyses were adjusted for age, sex and muscle fibre type composition. Differential expression was assessed using FDR ≤ 0.05, with |log2FC| > 1 applied as an additional effect-size criterion.
    RESULTS: Baseline transcriptomic differences between PP and PLA groups were minimal, with three FDR-significant transcripts, of which only HMOX1 additionally exceeded |log2FC| > 1 (FDR = 0.011; log2FC = 1.16). The group-by-time interaction analysis identified 14 FDR-significant transcripts, of which eight additionally exceeded |log2FC| > 1; these signals were characterized by low or sparse expression and high inter-individual variability, without a coherent supplementation-related transcriptional response. In the pooled paired PRE-POST analysis, 60 transcripts reached FDR significance, of which seven additionally exceeded |log2FC| > 1, including upregulation of CLLU1 (log2FC = 3.10; FDR = 0.0155), PRND (log2 log2FC = 2.60; FDR = 0.02) and LOX, and downregulation of MYH1 (log2FC = -1.3; FDR = 0.0001). Most FDR-significant transcripts showed relatively small estimated effect sizes, and functional enrichment analyses did not identify robust pathway-level adaptations.
    CONCLUSIONS: In middle-aged and older adults, 12 weeks of concurrent RT + HIIT induced a predominantly low-magnitude skeletal muscle transcriptional response. Selected transcript-level changes were consistent with processes related to extracellular matrix remodelling and contractile regulation; however, the absence of robust pathway-level enrichment limits conclusions regarding coordinated biological pathway adaptations. Polyphenol supplementation did not meaningfully influence the transcriptional response to exercise training.
    Keywords:  ageing; polyphenols; skeletal muscle transcriptomics; training
    DOI:  https://doi.org/10.1002/jcsm.70391
  31. J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70383
    Pancreatic Cancer Disrupts Circadian Patterns of Gene Expression in Cardiorespiratory Muscles.
    Jeremy B Ducharme, Martin M Schonk, Miguel A Gutierrez-Monreal, Leonardo F Ferreira, Karyn A Esser, Andrew R Judge, Sarah M Judge.
       BACKGROUND: Cancer cachexia, a debilitating syndrome characterized by muscle wasting, significantly impacts survival in gastrointestinal cancers like pancreatic cancer. Emerging evidence suggests a link between cancer cachexia and disrupted circadian rhythms in peripheral tissues, including locomotor muscles. However, circadian dysregulation in cardiorespiratory muscles-whose functional decline are suspected to contribute to increased morbidity and mortality in patients experiencing cachexia-remains largely unexplored.
    METHODS: Herein, we investigated circadian gene expression patterns in cardiorespiratory muscles during cachexia using the orthotopic KPC pancreatic cancer model. To do this, circadian transcriptomes were generated from diaphragm and heart tissues collected from Sham and KPC mice every 4 h over 24 h, beginning on Day 12 postinoculation, which, based on our prior work, reflects the onset of cachexia in this model. Rhythmically expressed genes (REGs) (Pc < 0.01) were identified using the LR_rhythmicity R package, which evaluates the goodness-of-fit (R2) to a 24-h sinusoidal model of transcript oscillations. Differences in circadian patterns, including changes in amplitude, phase and basal expression, were assessed using the LR_diff R package with p < 0.05.
    RESULTS: We found that ~60% of rhythmic genes lost their circadian rhythmicity in both tissues, with distinct shifts in gene networks. Diaphragm disruptions centred on repression in basal expression and/or amplitude of core clock components and rest-phase-dependent disruptions to gene networks governing lipid and oxidative programs of metabolism and proteostasis, which were linked to an upregulation and gain of rhythmicity in inflammatory networks that peaked during the rest phase. Circadian disruptions in the heart involved loss of rhythmicity in gene networks governing cardiac function, including beta-adrenergic and cAMP signalling, cellular responses to insulin and neurogenesis, with a similar, but more limited upregulation of inflammatory networks.
    CONCLUSIONS: These findings demonstrate that pancreatic cancer cachexia is associated with widespread circadian dysregulation in cardiorespiratory muscles, potentially contributing to both muscle wasting and functional decline.
    Keywords:  cancer cachexia; circadian rhythm; circadian transcriptome; diaphragm; heart; muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.70383
  32. Antioxidants (Basel). 2026 Sep 17. pii: 1185. [Epub ahead of print]15(9):
    Hesperetin Attenuates Experimentally Induced Skeletal Muscle Dysfunction by Modulating Time-of-Day-Dependent Gene Expression and Mitochondrial Redox-Related Markers.
    Suhyeon Lee, Yumin Sim, Minkyeong Lee, Eunju Kim.
      Skeletal muscle aging is characterized by impaired myogenic differentiation, mitochondrial dysfunction, oxidative stress, and circadian rhythm disruption, contributing to sarcopenia and muscle atrophy. Hesperetin, a natural flavonoid, has antioxidant and mitochondrial protective effects; however, its role in skeletal muscle circadian regulation during aging remains unclear. This study investigated the effects of hesperetin (20 µM or 100 mg/kg b.w.) using D-galactose (D-gal, 20 g/L)-induced senescent C2C12 myotubes, a D-gal (150 mg/kg b.w., i.p.)-induced aging mouse model, and a dexamethasone (Dex, 20 mg/kg b.w., i.p.)-induced muscle atrophy model. In D-gal-treated mice, hesperetin improved hanging test performance and increased SDH-positive area, particularly during the active phase. Hesperetin also partially modulated core clock gene expression and mitochondrial function-related gene expression. In D-gal-induced senescent C2C12 myotubes, hesperetin improved myotube formation, reduced SA-β-gal-positive cells, DCF-DA fluorescence, and MDA levels, enhanced antioxidant enzyme activities, and improved mitochondrial-associated functional indicators, including ATP levels, mitochondrial membrane potential-related fluorescence, pMitoTimer-based mitochondrial oxidation-associated signals, and Ppargc1a expression patterns. These findings suggest that hesperetin may protect against experimentally induced skeletal muscle dysfunction by modulating time-dependent gene expression, mitochondrial-related activities, and muscle-related functional markers.
    Keywords:  circadian rhythm; hesperetin; mitochondrial function; oxidative stress; skeletal muscle aging
    DOI:  https://doi.org/10.3390/antiox15091185
  33. Circ Genom Precis Med. 2026 Sep 25. e005376
    Gene-Corrected Human iPSC-Derived Cardiomyocytes and Skeletal Muscles Reveal Partial Dystrophin Dp427 Preservation and Cardiac Dp116 Expression in Duchenne Muscular Dystrophy Patient With a Splice-Site Mutation in Intron 68 (c.9975-1G>T).
    Marta Białobrzeska, Marta Przymuszała, Paweł Ferdek, Iryna Viestia, Anna Potulska-Chromik, Anna Kostera-Pruszczyk, Katarzyna Łuczak-Woźniak, Jacek Stępniewski, Urszula Florczyk-Soluch, Józef Dulak.
       BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease caused by mutations in the DMD gene, leading to the absence or dysfunction of dystrophin. Although cardiac and skeletal muscles are both affected, tissue-specific differences in disease manifestation and dystrophin regulation remain poorly understood.
    METHODS: To investigate these differences, we established a human induced pluripotent stem cell model of DMD from peripheral blood mononuclear cells of a patient (DMD patient with a point mutation in intron 68 (c.9975-1G>T) investigated in the study [DMB15]) carrying a splice-site mutation in intron 68 (c.9975-1G>T). An isogenic control line was generated via clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 correction. Both repaired and DMD human induced pluripotent stem cells were differentiated into cardiomyocytes (DMB15-CMs) and skeletal muscle cells (DMB15-derived skeletal muscle cells); the skeletal muscle lineage included a myoblast (DMB15-derived myoblasts) stage. Transcript and protein analyses were performed, along with functional assessments using microelectrode array recordings and calcium handling analysis.
    RESULTS: Transcript analysis revealed an in-frame deletion of 2 amino acids (Tyr3325 and Arg3326) due to skipping of the first 6 nucleotides of exon 69. Despite this, near full-length Dp427 (full-length dystrophin isoform of 427 kDa) was detected by Western blot, along with expression of Dp116 (dystrophin isoform of 116 kDa) in DMB15-CMs. Dystrophin levels were preserved in DMD DMB15-CMs but markedly reduced in DMB15-derived skeletal muscle cells, suggesting tissue-specific regulation. Analysis of DMB15-derived myoblasts demonstrated possible changes in myogenic program activation, alongside inconsistent expression of utrophin, the dystrophin paralogue. Functional analysis showed altered β-adrenergic responsiveness in DMD DMB15-CMs, with increased beating frequency and accelerated repolarization on isoproterenol stimulation. DMB15-CMs showed largely preserved basal Ca2+ cycling but failed to maintain a normal amplitude response under β-adrenergic stimulation.
    CONCLUSIONS: Our study identifies a splice-site DMD gene mutation that preserves high levels of dystrophin expression in cardiac muscle but reduced in skeletal muscle and reveals Dp116 expression in cardiomyocytes. These findings highlight the importance of tissue context in DMD and demonstrate the power of human induced pluripotent stem cell-based systems for dissecting mutation-specific effects.
    Keywords:  cardiomyopathies; induced pluripotent stem cells; muscular dystrophy, Duchenne; mutation; utrophin
    DOI:  https://doi.org/10.1161/CIRCGEN.125.005376
  34. Physiol Genomics. 2026 Sep 21.
    Integrated Multi-Omics Network by Physical Exercise Across Aging: Molecular Adaptation Beyond Single Signaling Pathways.
    Guilherme da Silva Rodrigues, Ivo Vieira de Sousa Neto, Takuji Kawamura, Ruither de Oliveira Carolino, Ana Paula Pinto, Jessica Denielle Matos Dos Santos, Dennys Esper Cintra, Eduardo Rochete Ropelle, José Rodrigo Pauli, Ellen Cristini de Freitas, Yasuyuki Taki, Zsolt Radak, Adelino Sanchez Ramos da Silva.
      Aging is characterized by progressive molecular dysregulation across interconnected biological systems, involving alterations in epigenetic regulation, gene expression, protein homeostasis, and metabolic function. Although physical exercise is widely recognized as one of the most effective non-pharmacological interventions to promote healthy aging, the integrative molecular mechanisms underlying its systemic effects remain incompletely understood. This review proposes a multi-omic framework in which exercise acts as a coordinated biological stimulus capable of remodeling age-associated molecular dysfunction across genomic, epigenomic, transcriptomic, proteomic, and metabolomic layers. We discuss evidence showing that exercise modulates DNA methylation patterns associated with inflammation, oxidative stress, and tissue regeneration. Epigenetically, exercise is associated with attenuation of age-associated hypermethylation in promoter regions and modulation of genes involved in oxidative stress defense and tissue regeneration. Transcriptomic studies further show that exercise is associated with more youthful expression patterns while attenuating inflammatory and senescence-related gene programs. Proteomic studies reveal that training is associated with mitochondrial metabolism, extracellular matrix remodeling, and muscle contractile protein abundance, reducing proteostatic dysfunction. Metabolomic analyses demonstrate that exercise improves metabolic flexibility and remodels cellular energy networks. Importantly, the unique contribution of this review lies in synthesizing emerging evidence that these adaptations are highly cell- and tissue-specific, involving immune cells, skeletal muscle satellite cells, endothelial cells, microglia, and intestinal stem cells. Rather than acting through isolated pathways, exercise may induce convergent adaptations across interconnected molecular systems, supporting the concept that healthy aging is dynamically regulated and that age-associated molecular dysfunction retains a degree of biological plasticity.
    Keywords:  bioenergetics; exercise; mitochondrial adaptation; molecular plasticity; omics
    DOI:  https://doi.org/10.1152/physiolgenomics.00089.2026
  35. Acta Biomater. 2026 Sep 24. pii: S1742-7061(26)00642-2. [Epub ahead of print]
    Bioengineered Skeletal Muscle Construct Using A Cell-Seeded Decellularized Diaphragm Muscle Scaffolding System For Pelvic Muscle Regeneration.
    Michael Won S Kim, Hyeongjin Lee, Erika Billman, Ickhee Kim, Young Min Ju, Anthony Atala, James J Yoo, Ji Hyun Kim.
      Pelvic floor muscle injury often leads to dysfunction of the entire pelvic urogenital system, negatively impacting the patient's quality of life. Current treatment options include autologous muscle transfer and biomaterial-based meshes and slings; however, adequately restoring muscle function remains a significant challenge. With advances in skeletal muscle tissue engineering, bioengineered skeletal muscle constructs have emerged as promising therapeutic solutions for treating various types of muscle injuries. Recently, these strategies have been expanded to address injuries involving pelvic musculature. In this study, we developed a bioengineered skeletal muscle construct by seeding human muscle progenitor cells (hMPCs) onto a decellularized skeletal muscle scaffold to regenerate damaged pelvic muscle tissues. Allogeneic decellularized diaphragm muscle tissue was employed as a biological scaffold due to its structural and mechanical similarities to native pelvic muscle tissues. We demonstrated that the decellularized diaphragm retained aligned skeletal muscle matrix microstructures and preserved mechanical properties. hMPCs seeded on the decellularized scaffold remained viable and differentiated into aligned muscle fibers. The feasibility of the bioengineered muscle construct was investigated in a rat model of extensive pelvic muscle injury. Our in vivo results demonstrated that the implanted construct supported the formation of new skeletal muscle tissue with vascular and neural integration and improved recovery of muscle weight and function. To our knowledge, this is the first approach using decellularized diaphragm muscle tissue matrices as a biologic scaffold for pelvic muscle repair. With further advances, this approach may offer an alternative strategy for repairing pelvic muscle injuries. STATEMENT OF SIGNIFICANCE: Pelvic floor muscle injury significantly impairs quality of life, yet current mesh- and sling-based treatments are limited by poor structural and biological integration. Here, we developed a bioengineered skeletal muscle construct using human muscle progenitor cells seeded onto a decellularized diaphragm scaffold, given its biomimetic architecture and mechanical properties that closely resemble native pelvic floor muscle. In a rat model of pelvic floor injury, this construct promoted muscle regeneration, vascularization, and neural integration while improving muscle mass and function. To our knowledge, this is the first use of decellularized diaphragm tissue for pelvic muscle reconstruction. This approach may provide a promising strategy for supporting structural and functional muscle repair.
    Keywords:  bioengineered skeletal muscle construct; decellularized diaphragm muscle; pelvic muscle regeneration; regenerative medicine; tissue engineering
    DOI:  https://doi.org/10.1016/j.actbio.2026.09.040
  36. Commun Biol. 2026 Sep 25. pii: 1252. [Epub ahead of print]9(1):
    Fermented protein foods as modulators of the gut-muscle axis: mechanisms, evidence, and future directions.
    Dominic N Farsi, Paul D Cotter, Orla O'Sullivan.
      Skeletal muscle has a profound influence on metabolic health, functional capacity and resilience across the lifespan. Beyond dietary protein and physical activity, the gut microbiome may have the capacity to impact skeletal muscle mass and function through the bidirectional network termed the gut-muscle axis (GMA). Fermented protein foods (FPFs) are protein rich matrices transformed by microbial activity that integrate modified protein structures, bioactive peptides, and live microorganisms, or components thereof, which could modulate skeletal muscle physiology. Here, we review mechanistic, preclinical and human evidence concerning the potential of FPFs to influence skeletal muscle health through GMA modulation. Although emerging human studies suggest favourable effects on metabolic regulation, inflammatory pathways and gut microbial ecology, direct evidence that FPFs impact muscle protein synthesis, muscle mass or function remains limited. Furthermore, the literature is characterised by considerable heterogeneity in interventions and outcome measures. Studies integrating comprehensive microbiome characterisation, multi-omics approaches and direct skeletal muscle phenotyping are needed to determine whether FPFs confer advantages over conventional protein foods or more established microbiome targeted strategies such as probiotic supplementation. Such studies will be essential to elucidate their role in targeted nutritional strategies for ageing, metabolic disease, muscle atrophy, and physical performance.
    DOI:  https://doi.org/10.1038/s42003-026-10941-2
  37. J Appl Physiol (1985). 2026 Sep 21.
    The effect of infrared radiation emitting garments on the acute skeletal muscle molecular signalling responses to high-intensity interval exercise.
    Jack W Bond, Patrick T Harrison, Hannah F Dugdale, Neil R W Martin, Stephen J Bailey, Tim Brownstone, Richard A Ferguson.
      Infrared radiation (IR) has previously been demonstrated to activate signalling pathways involved in mitochondrial biogenesis and angiogenesis. We tested the hypothesis that IR emitting fabric (IREF) would enhance translocation and phosphorylation of proteins, and mRNA expression of genes, associated with mitochondrial biogenesis and angiogenesis in response to high-intensity interval exercise (HIIE) compared to non-IREF. Eleven males (age, 22 ± 4 yrs, V̇O2peak, 48.0 ± 4.6 ml·kg-1·min-1) completed two HIIE sessions consisting of 10 x 3 min intervals at a power output equivalent to 60% of the difference between gas exchange threshold and peak power output. Each interval was interspersed by 3 min at 25 W. In a repeated-measures, counter balanced, single-blind design, participants wore IREF and non-IREF clothing (SHAM) before, during and following HIIE. Muscle biopsies were obtained pre (Baseline), immediately post (PE) and 3 hours post exercise (3hPE). Cytosolic and Nuclear p-CaMKII content were both greater PE in IREF compared to SHAM (P = 0.001 and P = 0.003 respectively). Cytosolic and Nuclear p-p38 MAPK content increased from baseline to PE in IREF (P = 0.008 and P = 0.005, respectively) but not SHAM. NRF1 and TP53 mRNA expression were greater in IREF compared to SHAM PE (P ≤ 0.013) and 3hPE in NRF1 only (P = 0.002). There was no change in the phosphorylated protein content or gene expression of any angiogenesis related target in IREF compared to SHAM. Wearing IREF before, during and following HIIE augments some of the acute cellular signalling cascades associated with mitochondrial biogenesis.
    Keywords:  Angiogenesis; Gene expression; Mitochondrial biogenesis; Protein phosphorylation; Skeletal muscle adaptation
    DOI:  https://doi.org/10.1152/japplphysiol.00258.2026
  38. Front Oncol. 2026 ;16 1919475
    Tumor-derived MG53 aggravates gastrointestinal cancer cachexia related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway.
    Yong-Fei Wang, Yuan-Yuan Xin, Si-Yuan Wang, Zi-Yi An, Dong-Yang Qi, Wen- Li, Wei-Lin Jin, Wen-Zhen Yuan.
       Background: Cancer cachexia is a multisystem syndrome characterized by progressive skeletal muscle atrophy, anorexia, and weight loss, imposing a substantial global health burden. Gastrointestinal cancer cachexia is highly prevalent, yet its pathogenesis remains poorly understood, and there is currently a lack of effective diagnostic methods and therapeutic strategies specifically targeting muscle atrophy. Identifying diagnostic and therapeutic targets for gastrointestinal cancer cachexia-related muscle atrophy represents a critical challenge.
    Methods: This study investigated the role of MG53 in gastrointestinal cancer cachexia. Serum MG53 levels were analyzed in patients, and experimental models examined tumor-derived MG53 effects on cancer cachexia-related muscle atrophy.
    Results: Elevated serum MG53 levels were found in gastrointestinal cancer cachexia patients. Tumor-derived MG53 aggravates cancer cachexia-related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway in muscle.
    Conclusions: MG53 is identified as a novel cancer cachexia factor driving gastrointestinal cancer cachexia-related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway in muscle. MG53 correlates with muscle atrophy, supporting its potential as a diagnostic biomarker and therapeutic target of gastrointestinal cancer cachexia.
    Keywords:  E3 ubiquitin ligases; MG53; PI3K/AKT/FOXO3a signaling pathway; cancer cachexia; cancer cachexia factors; inter-organ communication; muscle atrophy; skeletal muscle index
    DOI:  https://doi.org/10.3389/fonc.2026.1919475
  39. J Aging Res. 2026 ;2026 4970524
    β-Nicotinamide Mononucleotide Inhibits Cellular Senescence in Mouse C2C12 Skeletal Muscle Cells.
    Jing Mi, Chenxin Wang, Hongfei Gu, Mengxuan Wang, Weihua Zhang, Qiangqiang Zhou, Yuejiao Zhang, Jie Pan, Liming Yu.
      β-Nicotinamide mononucleotide (NMN), as the precursor of nicotinamide adenine dinucleotide (NAD+), has remarkable therapeutic potential in aging-associated diseases. Skeletal muscle exhibits not only reduced mass but also impaired strength and function during aging. However, the protective effects of NMN against skeletal muscle cell senescence remain to be fully elucidated. In this study, we used D-galactose (D-gal) to establish a senescence model in C2C12 cells. Our results demonstrate that aging C2C12 cells displayed a significant impairment in differentiation capacity, an effect that was ameliorated by NMN treatment, as indicated by an increase in myotube formation and elevated myosin heavy chain (MHC) expression. NMN significantly decreased reactive oxygen species (ROS) levels in both aged C2C12 myoblasts and myotubes. NMN treatment downregulated the mRNA expression of aging-associated markers, including tumor protein p53 (Trp53), poly (ADP-ribose) polymerases (PARPs), and interleukin-1α (IL-1α) in aged C2C12 myotubes. Immunofluorescence staining revealed that the expressions of p53 and interleukin-1β (IL-1β) were significantly upregulated in aged C2C12 myotubes, while NMN treatment significantly attenuated this elevation. Collectively, the present study demonstrates that NMN treatment attenuates D-gal-induced ROS accumulation, enhances myotube formation, and downregulates several senescence-associated molecules. Therefore, our findings suggest that NMN represents a promising therapeutic agent for mitigating skeletal muscle cell aging.
    Keywords:  D-galactose; cellular senescence; nicotinamide adenine dinucleotide; β-nicotinamide mononucleotide
    DOI:  https://doi.org/10.1155/jare/4970524
  40. Front Cell Dev Biol. 2026 ;14 1858881
    Biomechanical strain alters the microRNA cargo of primary myogenic cell-derived extracellular vesicles associated with a differentiation phenotype.
    Katherine B Williams, Laura Chubb, Shelby Osburn, Qian Zhang, Bradley Guilliams, Melinda Meyers, Thomas J LaRocca, Karyn L Hamilton, Nicole Ehrhart.
      Extracellular vesicles (EVs) are membrane-bound vesicles that regulate intercellular signaling by transporting cellular cargo including RNAs, proteins, and lipids. In recent years, EVs have emerged as promising biologic therapeutics for musculoskeletal repair, recapitulating many of the benefits of mesenchymal stromal cells. However, strategies to enhance the therapeutic potential of EVs remains limited. Here, we investigated how cyclic mechanical strain influences the microRNA (miRNA) cargo and function of EVs produced by primary C57BL/6 murine myogenic cells. Specifically, we aimed to determine how biomechanical strain regimens alter myogenic EV cargo and regulate the transcriptome of recipient myoblasts. We identified miR-222 as a miRNA that was significantly and selectively enriched in low-strain long-duration (LSLD) mechanically strained EVs compared to Static EVs and to high-strain short-duration (HSSD) EVs. Recipient primary myoblasts treated with LSLD EVs displayed distinct transcriptomic changes, characterized by a statistically significant overrepresentation of downregulated predicted target genes associated with miR-222-5p and miR-222-3p at 24 h and 72 h after LSLD EV treatment, respectively. This transcriptomic shift correlated with an increase in Myosin Heavy Chain (MyHC) expression in recipient myoblasts. Together, these findings demonstrate that biomechanical strain regulates the packaging of miRNAs within myogenic EVs, and that LSLD EV delivery is associated with a differentiation-related phenotype in recipient myoblasts. This work provides a foundation for future studies utilizing biomechanical cues to tune EV cargo for potential therapeutic applications in muscle repair and regeneration.
    Keywords:  differentiation; extracellular vesicles; mechanical strain; mechanobiology; microRNA; myoblast; myogenesis; skeletal muscle
    DOI:  https://doi.org/10.3389/fcell.2026.1858881
  41. Pharmacol Res. 2026 Sep 20. pii: S1043-6618(26)00392-0. [Epub ahead of print]233 108477
    "Improving the beneficial effects of HDAC8 inhibition by simultaneously activation of SIRT1 in a zebrafish model of Duchenne muscular dystrophy.
    S Carbone, A Brix, L Lociuro, L Belleri, O Gjana, E Cannone, S Bonusi, M Schiavone, A Marozzi, F Del Bene, C Braccia, A Andolfo, C De Palma, A Pezzotta, A Pistocchi.
      Duchenne Muscular Dystrophy (DMD) is a severe genetic disorder characterized by progressive skeletal muscle degeneration, chronic inflammation, fibrosis, and mitochondrial dysfunction. Although gene- and cell-based therapies hold great promise, significant limitations still restrict their broad application, highlighting the need for complementary pharmacological approaches targeting secondary pathological mechanisms. Histone deacetylase (HDAC) inhibitors and Sirtuin 1 (SIRT1) activators represent promising therapeutic strategies, as HDAC8 is involved in cytoskeletal remodeling, whereas SIRT1 mainly regulates mitochondrial metabolism and energy homeostasis. In this study, we investigated the therapeutic efficacy of combining selective HDAC8 inhibition (PCI-34051) with SIRT1 activation (SRT2104) in a zebrafish model of DMD. Combined treatment significantly improved muscle structure and function, reduced inflammatory cell recruitment, and enhanced mitochondrial activity compared with single-drug administration. Importantly, comparable therapeutic efficacy was achieved using reduced doses of both compounds. Proteomic and acetylomic analyses revealed distinct but complementary molecular signatures induced by the two treatments. HDAC8 inhibition predominantly modulated pathways associated with cytoskeletal organization, epigenetic regulation, ribosome biogenesis, and muscle structural remodeling, whereas SIRT1 activation mainly affected mitochondrial function, oxidative metabolism, amino acid catabolism, and cellular bioenergetics. Overall, these findings demonstrate that combined HDAC8 inhibition and SIRT1 activation effectively ameliorate key pathological features of DMD in zebrafish and provide mechanistic insights into the complementary pathways targeted by the two compounds. This work supports the development of combinatorial epigenetic strategies as potential therapeutic approaches for DMD.
    Keywords:  DMD; HDAC8; SIRT1; acetylome; mitochondria; zebrafish
    DOI:  https://doi.org/10.1016/j.phrs.2026.108477
  42. J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70385
    Exploring the Impact of Urolithins A and B on Muscle Health: A Transcriptomic Analysis in Human Myotubes.
    Yves Henrotin, Antoine Florin, Christelle Sanchez, Prescilia Centonze, Tiago Pinto Coelho, Sophie Bekisz, Jean-Emile Dubuc, Olivier Galand, Cécile Lambert.
       BACKGROUND: Urolithin A (UA) and urolithin B (UB) are gut microbiota-derived metabolites of ellagitannins reported to influence mitochondrial function, inflammation and muscle metabolism. Their comparative transcriptomic effects in human skeletal muscle cells remain undefined. We characterized UA- and UB-induced molecular responses in primary human myotubes.
    METHODS: Primary CD56+ satellite cells were isolated from vastus lateralis muscle of 9 donors (6 men, 3 women; age 55-96 years; mean 74.1 ± 13.8 years) and differentiated into myotubes. Cells were treated 24 h with UA or UB (5 μM). RNA sequencing generated ~20 million paired-end reads per sample. Differential expression analysis was performed using DESeq2 (design = ~Patient + Treatment). Differentially expressed genes were defined as adjusted p value (FDR) < 0.01 and |Log2FoldChange| > 0.32. Pathway enrichment was assessed using Ingenuity Pathway Analysis. Selected targets were validated by RT-qPCR and ELISA in 4 donors from the RNA-seq cohort using UA and UB at 1, 5 and 10 μM.
    RESULTS: UA and UB significantly modulated 1918 and 339 genes, respectively (FDR < 0.01; |log2FoldChange| > 0.32), demonstrating distinct transcriptomic reprogramming in human myotubes. Pathway analysis showed that UA predominantly affected oxidative phosphorylation, mitochondrial dysfunction, inositol phosphate metabolism and glycosylation pathways (N-linked glycosylation z score 2.11), whereas UB activated cholesterol biosynthesis (z score 2.45), mevalonate pathway (z score 2.00), adipogenesis (z score 1.41) and inhibited eicosanoid signalling (z score -2.71). At 5 μM (RNA-seq), UA increased NOTCH1 (+73%), MYMX (+70%), PANX1 (+50%) and MSTN (+64%), and decreased FGF9 (-75%), ICAM5 (-52%) and MRLN (-33%), whereas UB decreased IGFN1 (-75%), TGFBI (-60%) and STC2 (-35%) and increased TGM2 (+59%). UA increased LIF (+80%) and decreased PTGS1 (-41%) and IL17B (-49%), whereas UB decreased PTGS1 (-43%) and increased IL17B (+45%). RT-qPCR validation confirmed UA-induced increases in NOTCH1 (5 μM, p = 0.0471), MYMX (10 μM, p = 0.0363), and PANX1 (5 μM, p = 0.0012; 10 μM, p = 0.0065), dose-dependent reductions in FGF9 (r2 = 0.9389) and ICAM5 (r2 = 0.8804), and opposite regulation of IL17B (UA r2 = 0.8309; UB 10 μM, p = 0.0498) and PTGS1. Both UA and UB reduced TGFBI protein levels dose-dependently (UA r2 = 0.8582; UB r2 = 0.7415).
    CONCLUSIONS: UA and UB induce quantitatively and qualitatively distinct transcriptomic programmes in human myotubes. UA preferentially modulates mitochondrial and inflammatory pathways, whereas UB primarily affects lipid metabolism and muscle-related processes. These findings provide mechanistic insight into urolithin-mediated regulation of human muscle cell biology able Stro.
    Keywords:  RNA sequencing; inflammation; musculoskeletal biology; myotubes; urolithins
    DOI:  https://doi.org/10.1002/jcsm.70385
  43. J Cell Physiol. 2026 Sep;241(9): e70231
    Chronic Contractile Activity Remediates Lysosomal Dysfunction in a Muscle Cell Lysosomal Disease Model.
    Debasmita Bhattacharya, Neushaw Moradi, David A Hood.
      Lysosomes are important organelles for the degradation of unwanted biomolecules via autophagy. Lysosomal dysfunction is apparent in ageing tissues, and can cause various neurodegenerative diseases. It is imperative to understand the mechanisms and implications of lysosomal malfunction and to find strategies to ameliorate diseases. To investigate this, we induced lysosomal dysfunction with Bafilomycin A1 (BAF), a drug that hinders lysosomal acidification by blocking vATPase-mediated proton pumping, in myoblasts and myotubes. Myotubes were subjected to chronic contractile activity (CCA) to mimic "exercise" to evaluate any therapeutic potential and reversal of pathophysiology. Induced lysosomal dysfunction was evident from impaired processing of the protease cathepsin B, enhanced lysosomal accumulation and increased autophagic markers Lamp1, p62, and the LC3II/I ratio. BAF attenuated lysosomal protease degradation measured using the substrate DQ-BSA in both myoblasts and myotubes. Many of the adverse effects generated by BAF in myotubes were reversed by CCA, manifested by a decrease in immature cathepsin B, a down-regulation of Lamp1, p62, LC3II/I and partial restoration of lysosomal protein degradation enzymatic capacity. To investigate further improvements in lysosomal function in a healthy cellular model, we treated myotubes with C1, a curcumin analogue. C1 decreased Lamp1, p62 and the LC3II/I ratio, all of which indicate improved lysosomal function and autophagosome clearance with a greater lysosomal ability to degrade substrates. Additionally, C1 was able to mimic the improved mitochondrial content induced by CCA. Thus, contractile activity and curcumin analogues may provide useful therapeutic potential to resuscitate lysosomal function, improve muscle health and ameliorate lysosome-mediated diseases. NEW AND NOTEWORTHY: This study explores the potential of chronic contractile activity (CCA) in reversing the compromised lysosomes caused by the disruption of lysosomal acidification in myotubes. Remarkably, CCA mitigated the effects of Bafilomycin A1-induced lysosomal dysfunction, enhancing protease activity and increased mitochondrial content. Treatment of myotubes with the curcumin analogue C1 reduced lysosomal accumulation and enhanced mitochondrial content suggesting that contractile activity-based interventions and small-molecule modulators of lysosomal pathways may represent promising complementary strategies for treating lysosome-related diseases and enhancing muscle health.
    Keywords:  autophagy; bafilomycin A; exercise; lysosomes; mitochondria
    DOI:  https://doi.org/10.1002/jcp.70231
  44. Int J Mol Sci. 2026 Sep 10. pii: 8057. [Epub ahead of print]27(18):
    Skeletal Muscle Effects of GLP 1 Receptor Agonists: Molecular Mechanisms and Comparative Insights on Semaglutide and Tirzepatide, a Narrative Review.
    Domenico Cautela, Valeria Incarbona, Angela Lombardi, Bruna Laratta, Curzio Massimo Castaldo, Maria Luisa Balestrieri, Edoardo Mocini, Silvia Migliaccio, Daniela Tardito.
      GLP-1 receptor agonists (GLP-1RAs), dual GLP-1/GIP agonists, and the more recent triple GLP-1/GIP/glucagon agonists have transformed the treatment of type 2 diabetes mellitus (T2DM) and obesity, resulting in significant weight reduction. However, a substantial proportion (20-40%) of this weight loss is attributable to a decrease in lean mass, thereby raising concerns regarding potential sarcopenia-related risk. However, decreased lean mass is not sufficient to determine sarcopenia, which is now defined by the combined presence of decreased muscle mass, diminished strength, and impaired physical function, particularly in older or frail individuals. Thus, a further clarification of the potential mechanisms through which these molecules affect skeletal muscle is needed to optimize their use. The objective of this study is to synthesize preclinical, metabolomic, and clinical evidence on the effects of GLP-1RAs and dual/triple agonists on skeletal muscle, with a specific comparison between semaglutide and tirzepatide. This narrative review was based on a comprehensive literature search of PubMed/MEDLINE, Scopus, and Google Scholar, encompassing articles published through June 2026. This search was supplemented by manual citation tracking, which identified additional studies including preclinical and metabolomic investigations, randomized controlled trials, observational studies, and meta-analyses. Preclinical data suggest that GLP-1R/GIPR activation can positively modulate anabolic pathways, mitochondrial biogenesis, and muscle inflammation. Metabolomic evidence reveals lipid and amino acid remodeling compatible with improved mitochondrial function. Clinically, lean mass loss proportional to weight reduction is consistently observed, generally without meaningful declines in strength or performance; data for tirzepatide are more limited. Lean mass, however, is not synonymous with skeletal muscle. A paradox emerges between the presence of protective molecular signals and the clinical evidence of lean-mass loss. This phenomenon may be explained by a systemic energy/protein deficit rather than a direct catabolic effect of the drugs, although current evidence does not fully distinguish these mechanisms. The effectiveness of weight reduction should be considered a pivotal metric in clinical practice, particularly in populations susceptible to sarcopenia.
    Keywords:  GLP-1 receptor agonists; dual GLP-1/GIP agonists; lean mass; metabolomics; sarcopenia; semaglutide; skeletal muscle; tirzepatide
    DOI:  https://doi.org/10.3390/ijms27188057
  45. J Sports Sci. 2026 Sep 22. 1-17
    Skeletal muscle function does not differ between menstrual cycle phases: A prospective cohort study across three cycles.
    Christine Heinrich, Katharina Herzog, Kevin Happ, Lilli Venth, Daniel Niederer, Michael Behringer.
      Fluctuations in ovarian hormones across the menstrual cycle have been proposed to influence skeletal muscle function, yet current evidence remains inconsistent. This study investigated associations between menstrual cycle phases and multidimensional outcomes of skeletal muscle function across three menstrual cycles. In this prospective cohort study repeated within-subjects measurements were performed during the early follicular, ovulatory and mid-luteal phases in physically active eumenorrheic females. Cycle phases were verified using luteinizing hormone detection and salivary hormone analysis. Outcomes included concentric and eccentric isokinetic peak torque of leg extension, muscular fatigue resistance and jump performance. Contractility was quantified by tensiomyography, and muscle stiffness was evaluated using shear wave elastography. Thirty-two participants were enrolled, and 14 completed all measurements. No significant effect of phase occurred for functional parameters or muscle stiffness. Significant effects of cycle were observed for eccentric peak torque, total work, drop jump height, reactive strength index and relaxed muscle stiffness with varying directions of change; however, no phase-dependent pattern emerged. Estradiol concentrations did not vary significantly, whereas progesterone concentrations increased significantly during the mid-luteal phase. We concluded that skeletal muscle function appeared to be largely unaffected by menstrual cycle phases. Potential phase-related effects are likely minimal under real-life conditions.
    Keywords:  Menstrual cycle; muscle contractility; muscle function; muscle stiffness; muscle strength
    DOI:  https://doi.org/10.1080/02640414.2026.2735713
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