bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–05–10
forty-one papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Polyamines and autophagy as a dynamic regulatory network in skeletal muscle regeneration and aging.
  2. Cellular senescence in skeletal muscle regeneration.
  3. Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
  4. Exercise-induced microRNAs: molecular pathways and adaptive remodeling of skeletal muscle.
  5. DNM2 lipid binding drives centronuclear myopathy and represents a potential therapeutic target.
  6. Ageing-Associated Dysregulation of Myogenic Differentiation in Inclusion Body Myositis.
  7. The central role of macrophages in skeletal muscle regeneration: Phenotypic Polarization, metabolic reprogramming, and therapeutic prospects.
  8. Fibro-adipogenic progenitors enhance functional and structural properties of human 3D tissue engineered skeletal muscles.
  9. Protein and Skeletal Muscle Metabolism.
  10. iPSC-derived skeletal muscle spheroids for Duchenne Muscular Dystrophy modeling.
  11. Direct aldosterone stimulation of skeletal muscle fibroblasts changes gene expression and differentially affects fibroblast functions from normal and diseased muscles.
  12. Mitochondrial dynamics and oxidative metabolism: an emerging role for Septin7 in skeletal muscle.
  13. Caloric restriction reprograms skeletal muscle molecular pathways in non-human primates: potential relevance to human aging biology.
  14. Chondrolectin regulates the sublaminar localization and regenerative function of muscle satellite cells in mice.
  15. FURIN Stimulates NOTCH2 and NOTCH3 Pathways, Leading to Return of Function in Aged Cells.
  16. Time-of-day, satellite cells, and velocity collectively influence ex vivo isovelocity force production in mouse extensor digitorum longus muscle.
  17. PGC-1α pathway dysregulation disrupts myofiber specification in a mouse model of SBMA.
  18. Periodontitis induces skeletal muscle atrophy by increasing circulating levels of activin A.
  19. Scaffold Protein PDLIM5 Regulates TRPC1 Calcium Channel Mediated Store-Operated Calcium Entry in Mouse Myoblasts.
  20. High and moderate intensity exercise training differentially impact microvascular function in skeletal muscle of mice lacking adiponectin.
  21. Pathogenic human huntingtin expression causes prolific intramuscular aggregation, leading to nuclear, metabolic, and physiological dysregulation in striated muscle.
  22. Circadian biology and exercise: the time to move.
  23. Repeated evolutionary turnover of vertebrate skeletal muscle myosins.
  24. C26 and CT26 colorectal cancer models exhibit divergent cachexia phenotypes, intramuscular inflammation, and protein turnover signaling.
  25. Mechanosensitive Ion Channels: Molecular Hubs Integrating Skeletal Muscle Adaptation and Systemic Homeostasis.
  26. Skeletal Fiber Type in Muscle Pain and Dysfunction.
  27. Niacin accelerates skeletal muscle regeneration and enhances C2C12 differentiation by activating the PI3K/Akt signaling pathway.
  28. Identifying Quiescent Satellite Cells: A Scoping Review of Transcriptomic Markers and Limitations.
  29. RAGE Re-Expressed at Myofibre Level Drives Muscle Wasting in Cancer Conditions.
  30. Mitochondrial Network Dynamics in Aging: Cellular Mechanisms, Intercellular Communication, and Their Impact on Tissue Adaptability.
  31. MG53, a Regenerative Myokine Linking Skeletal Muscle to Cardiac Repair.
  32. Skeletal muscle as a dynamic immunological niche for vaccination.
  33. Innovations in skeletal muscle regeneration: from physiology to bioengineering approaches for repair and restoration.
  34. PACS2 Alleviates Sepsis-Induced Myopathy by Activating ERK-MAPK Signalling Pathway to Suppress ER-Phagy.
  35. Muscle-derived Mimecan regulates hypothalamus-brown adipose tissue communication and promotes health and lifespan in mice.
  36. Garlic-derived metabolite activates LKB1, promotes adipose eNAMPT secretion, and improves age-related muscle function via hypothalamic signaling.
  37. Single-cell transcriptional landscape of muscle-derived stem/progenitor cells reveals hallmarks of aging and rejuvenation.
  38. mRNA-Based Vaccines and Immunomodulatory Strategies for Muscle Regeneration and Recovery: A Comprehensive Review.
  39. ANXA11 suppression restores muscular function in the mdx mouse model of Duchenne muscular dystrophy (DMD).
  40. Advantages of Skeletal Muscle Preservation in Settings of Weight Loss.
  41. Skeletal muscle mitochondrial bioenergetics in pregnancy: a comparison of in vivo and in vitro outcomes.
  1. Mech Ageing Dev. 2026 May 03. pii: S0047-6374(26)00040-0. [Epub ahead of print]231 112188
    Polyamines and autophagy as a dynamic regulatory network in skeletal muscle regeneration and aging.
    Lavinia Attili, Marianna Nicoletta Rossi, Rachele Di Santo, Guglielmo Duranti, Roberta Ceci, Manuela Cervelli.
      Autophagy is a core cellular mechanism that preserves tissue homeostasis by removing damaged proteins and organelles. In skeletal muscle, proper regulation of autophagic flux is essential for maintaining metabolic and structural integrity, whereas its disruption contributes to muscle atrophy, metabolic dysfunction, and age-related functional decline. Increasing evidence identifies polyamines, particularly spermidine (Spd), as important modulators of autophagy and cellular resilience, with beneficial effects on stress responses, metabolic regulation, and lifespan extension. Physical exercise likewise acts as a physiological inducer of autophagy, promoting muscle remodelling, mitochondrial quality control, and adaptive responses to stress. Within this framework, spermine oxidase (SMOX) has emerged as a relevant regulator of muscle homeostasis. SMOX expression is maintained in healthy muscle but declines in atrophic conditions. By converting spermine into spermidine, SMOX may help sustain autophagy-related pathways and support muscle mass under physiological conditions. This review explores the interplay between exercise, spermidine, and SMOX, highlighting autophagy as a unifying regulatory axis. We summarize current evidence on their individual and combined roles in preserving muscle function and discuss their potential relevance for promoting healthy muscle aging and counteracting sarcopenia.
    Keywords:  Atrophy; Autophagy; Polyamine metabolism; Skeletal muscle; Spermidine
    DOI:  https://doi.org/10.1016/j.mad.2026.112188
  2. Cell Regen. 2026 May 07. pii: 15. [Epub ahead of print]15(1):
    Cellular senescence in skeletal muscle regeneration.
    Xingyuan Liu, Huating Wang.
      Skeletal muscle possesses a remarkable capacity for regeneration, driven by the activation and proliferation of Pax7-positive muscle stem cells within a dynamic niche that includes immune cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and neural elements. Cellular senescence, a stress-induced program featuring stable cell-cycle arrest and the senescence-associated secretory phenotype (SASP), has emerged as a critical yet paradoxical regulator of this process. Accumulating evidence indicates that transient senescence, particularly in FAPs, macrophages, and other niche cells during acute muscle injury, plays a beneficial role in supporting muscle regeneration. These senescent cells promote cellular plasticity, enhance myoblast differentiation, facilitate phagocytic clearance of debris, and modulate inflammation and repair via timely SASP factor secretion. However, conflicting findings suggest that senescent cells exert detrimental effects, impairing regeneration by establishing a sustained pro-inflammatory and pro-fibrotic niche, especially when senescence persists in aged or dystrophic muscle. This review synthesizes the complex and contradictory roles of cellular senescence in skeletal muscle regeneration, underscores the distinction between transient pro-regenerative and persistent deleterious senescence, highlights the importance of cell-type-specific contributions, and emphasizes the need for precise characterization of senescent cell dynamics and fate. Resolving these discrepancies will be critical for developing targeted senotherapeutic strategies to enhance muscle regeneration in aging and degenerative diseases.
    Keywords:  Cellular senescence; SASP; Skeletal muscle regeneration
    DOI:  https://doi.org/10.1186/s13619-026-00287-9
  3. Sci Adv. 2026 May 08. 12(19): eaec0795
    Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
    Alice M Ma, Peter H Tran, Nicole L Yang, Jennifer Ngo, Hirotaka Iwasaki, Wenjuan Ren, Simone Livit, Linsey Stiles, Sarah Wang, Trinity Ho, Emma Y Yim, Noelle Morrow, Morgan M Johnson, Caroline Cleary, Kai Zou, Rachelle H Crosbie, Yuwei Jiang, Orian S Shirihai, Jonathan Wanagat, Sushil Mahata, James A Wohlschlegel, Andrea L Hevener, Zhenqi Zhou.
      The maintenance of skeletal muscle mass relies on mitochondrial quality control, including balanced dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a central mediator of mitochondrial fission, is essential for these processes, yet its role in muscle mass regulation remains incompletely defined. Here, we show that acute Drp1 deletion in the skeletal muscle increases Parkin-mediated mitochondrial degradation, reduces mitochondrial DNA (mtDNA) content, and leads to severe muscle atrophy. Although dual deletion of Drp1 and Parkin restores mtDNA content, muscle loss persists. Mechanistically, Drp1 loss impairs mitochondrial respiratory chain activity, suppressing extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and down-regulating the nuclear receptor subfamily 4 group A member 1 (Nur77). Pharmacologic β2-adrenergic receptor activation with clenbuterol reactivated Erk1/2, restored Nur77 expression, and rescued muscle atrophy. These findings define a Drp1-Erk1/2-Nur77 signaling axis linking mitochondrial integrity to skeletal muscle mass and identify a potential therapeutic target for muscle degeneration in mitochondrial and metabolic diseases.
    DOI:  https://doi.org/10.1126/sciadv.aec0795
  4. Pflugers Arch. 2026 May 09. pii: 47. [Epub ahead of print]478(5):
    Exercise-induced microRNAs: molecular pathways and adaptive remodeling of skeletal muscle.
    Kübra Özdemir, Yeliz Demir.
      Exercise is an effective physiological stimulus that promotes vast structural and functional changes in skeletal muscular tissue. Although transcriptional pathways that control exercise-based plasticity have been studied in depth, recent findings highlight the importance of microRNAs (miRNAs) as an essential post-transcriptional control platform mediating contractile stimuli and molecular and physiologic adaptations. This review provides a synthesis of existing evidence on exercise responsive miRNAs at the systems level, and especially on the topic of skeletal muscle remodeling. The review outlines the effects of different exercise regimens such as endurance, resistance, and high-intensity interval training to dynamic miRNA response to regulate major biological pathways such as mitochondrial biogenesis, protein turnover, angiogenesis, inflammatory signaling, and metabolic regulation. Acute exercise is also typified by temporary changes in miRNAs, which facilitate short-term stress signalling, and chronic training leads to more long-term miRNA re-programming, which facilitates long-term structural and functional remodeling. Also, circulating and exosome-bound miRNAs are also mentioned as potential agents of the muscle-to-organ interaction, thus supporting the idea of skeletal muscle that acts like an endocrine-like organ during exercise. Besides narrative synthesis, the review is based on an exploratory, data-driven re-analysis of publicly available skeletal muscle miRNA sequencing data to define convergent regulatory programs instead of data-specific differentiation. This is observed under integrative pathway and network-level analysis which identifies coordinated miRNA modules linked to mitochondrial regulation, cytoskeletal remodeling, and inflammatory control. Taken together, this framework brings together non-homogenous evidence throughout the literature and highlights the prospect of exercise-sensitive miRNAs as systems-level regulators of skeletal muscle adaptation.
    Keywords:  Exercise adaptation; Exercise-induced signaling; Exosomal communication; Mitochondrial biogenesis; microRNAs
    DOI:  https://doi.org/10.1007/s00424-026-03177-w
  5. JCI Insight. 2026 May 08. pii: e204423. [Epub ahead of print]11(9):
    DNM2 lipid binding drives centronuclear myopathy and represents a potential therapeutic target.
    Raquel Gómez-Oca, Xènia Massana-Muñoz, David Reiss, Juliana De Carvalho Neves, Nadege Diedhiou, Roberto Silva-Rojas, Belinda S Cowling, Marie Goret, Jocelyn Laporte.
      Centronuclear myopathies (CNMs) are rare congenital disorders characterized by muscle weakness, fiber hypotrophy, and organelle mislocalization. Most cases arise from mutations in MTM1 or DNM2, encoding myotubularin and dynamin-2, respectively. DNM2 is a GTPase that binds lipids, oligomerizes around membranes, and mediates fission. We previously showed that DNM2 levels are elevated in MTM1-CNM patients and Mtm1-/y mice, and that normalizing DNM2 rescues disease phenotypes. However, the specific DNM2 functions driving pathology remain unclear. Here, we expressed AAV-delivered WT and DNM2 mutants in WT and Mtm1-/y mouse muscles to disrupt specific DNM2 molecular functions. In WT mice, overexpression of WT DNM2 and most mutants induced CNM-like phenotypes, including reduced force, fiber hypotrophy, and centralized nuclei, consistent with gain-of-function mechanisms. The lipid-binding-defective mutant K562E did not induce disease-like phenotype. In Mtm1-/y mice, K562E mutant markedly improved muscle force, mass, and fiber size, while others failed to rescue. Therefore, we generated Mtm1-/y Dnm2K562E/+ mice, which showed full rescue of survival, motor function, and muscle force, with improved muscle mass, fiber size, and organelle positioning despite persistently elevated DNM2 levels. This study reveals that DNM2 lipid binding, not protein abundance or GTPase activity, drives pathology, and represents the most rational therapeutic target for DNM2 therapy in MTM1-CNM.
    Keywords:  Genetics; Molecular biology; Mouse models; Muscle biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.204423
  6. J Cachexia Sarcopenia Muscle. 2026 ;17(3): e70301
    Ageing-Associated Dysregulation of Myogenic Differentiation in Inclusion Body Myositis.
    Geert M de Vries, Willem De Ridder, Jonathan Baets.
      Skeletal muscle is a postmitotic tissue dependent on a complex and tightly regulated regeneration process involving numerous intracellular and extracellular factors, including myogenic regulatory factors (MRFs), cytokines and myokines. Quiescent satellite cells are activated by physiological stimuli, injury or other traumatic insults for the repair of injuries or growth of the tissue. Activation of satellite cells induces proliferation and expression of MRFs, which in turn activate myogenic differentiation transcription programmes. Transitioning into and committing to terminal differentiation are regulated by myogenin and cell cycle exit markers, notably Rb1 and p21. Differentiation is then complete with the formation of new muscle fibres which incorporate into existing fibres. Upon ageing, the efficiency of differentiation is reduced as a consequence of a loss in the physiological balance between pathways regulating satellite cell quiescence and activation, notably the Notch and Wnt pathways, and increased senescence of the satellite cell pool. Extracellular factors involved in the dysregulation of differentiation upon ageing include low-grade chronic inflammation and remodelling of the extracellular matrix by fibro-adipogenic progenitor cells, thereby negatively affecting the differentiation capacity of satellite cells, resulting in either premature differentiation or senescence. These ageing-associated alterations in muscle homeostasis appear to be amplified in inclusion body myositis (IBM), an idiopathic inflammatory myopathy that almost exclusively manifests in individuals over 45 years of age, making it a prototypical age-related muscle disease. IBM is characterised by chronic inflammation, progressive muscle degeneration and premature ageing of both muscle tissue and the satellite cell niche. Studied with immunohistochemical techniques and multi-omics, muscle biopsy tissue demonstrated increased expression of MRFs as well as increased expression of senescence and genomic stress markers. IBM primary myoblasts demonstrated premature ageing and senescence and increased activity of the Wnt pathway, though differentiation into multinucleated myotubes did not show notable aberrations in signalling pathways or differentiation efficiency. In conclusion, ageing and chronic inflammation lead to dysregulation of key pathways that, in turn, alter the capacity of satellite cells to activate and proliferate, leading to prematurely aged satellite cells that still retain their capacity to differentiate into myofibres. Though in IBM there is an increased abundance of active differentiation markers, reflecting a regenerative response to the massive, sustained muscle atrophy, senescence of the satellite cell niche may impair effective regeneration of the lost muscle tissue.
    Keywords:  inclusion body myositis; muscle regeneration; myogenic differentiation; senescence
    DOI:  https://doi.org/10.1002/jcsm.70301
  7. Biochem Pharmacol. 2026 Apr 30. pii: S0006-2952(26)00358-8. [Epub ahead of print]250(Pt 2): 118025
    The central role of macrophages in skeletal muscle regeneration: Phenotypic Polarization, metabolic reprogramming, and therapeutic prospects.
    Ruiqi Liu, Yuntian Shen, Yutong Wei, Chuli Zhu, Xinlei Yao, Xiaosong Gu, Lei Qi, Hualin Sun.
      Macrophages are central regulators of skeletal muscle regeneration, dynamically transitioning from pro-inflammatory (M1-like) to reparative (M2-like) phenotypes to coordinate debris clearance, inflammation modulation, satellite cell activation, and tissue remodeling. This review details the underlying molecular mechanisms, focusing on metabolic reprogramming, such as the shift to oxidative phosphorylation and key roles of AMPK, lactate, and glutamine metabolism. It further examines the transcriptional networks (e.g., PPARγ, Nfix) and multicellular crosstalk that shape the regenerative niche. We analyze macrophage dysfunction in pathological contexts: aging-related impairments in dynamics and metabolism that hinder repair, and in Duchenne Muscular Dystrophy (DMD), where sustained inflammation and trained immunity drive fibrosis. Current challenges include deciphering macrophage heterogeneity beyond the M1-like/M2-like paradigm and bridging translational gaps between models and human disease. The review outlines therapeutic strategies to reprogram macrophage function, spanning pharmacological agents (AMPK/PPARγ agonists, cytokine/chemokine modulation), nanotechnology, cell therapies (e.g., exosomes), and physical interventions. A key feature is the integration of molecular docking analyses, revealing structural interactions between compounds (e.g., AICAR, Cenicriviroc) and targets like AMPK, PPARγ, CCR2, and CCR5. This provides a structural pharmacology foundation for developing targeted immunometabolic therapies to restore muscle regeneration in injury and degenerative diseases.
    Keywords:  Aging; Duchenne Muscular Dystrophy; Macrophages; Metabolic Reprogramming; Phenotypic Polarization; Skeletal Muscle Regeneration
    DOI:  https://doi.org/10.1016/j.bcp.2026.118025
  8. J Tissue Eng. 2026 Jan-Dec;17:17 20417314261441552
    Fibro-adipogenic progenitors enhance functional and structural properties of human 3D tissue engineered skeletal muscles.
    Roy Augustinus, Lotte A de Ridder, Dongxu Zheng, Marnix Franken, Judit Balog, Patrick J van der Vliet, Alessandro Iuliano, Remko Goossens, Johanna I Hamel, W W M Pim Pijnappel, Jessica C de Greef, Silvère M van der Maarel.
      Human skeletal muscle models often lack important supportive cell types. Here we developed a co-culture three-dimensional tissue engineered skeletal muscle (3D-TESM) model by combining myogenic progenitors (MPs) with genetically-matched immortalized fibro-adipogenic progenitors (iFAPs). FAPs play a crucial physiological role in myogenesis, tissue remodeling and extracellular matrix (ECM) formation. We demonstrate that co-culture 3D-TESMs effectively recapitulate these processes under controlled conditions, thereby enhancing contractile force, muscle tissue integrity and longevity, as well as improving ECM deposition compared to MP-only 3D-TESMs. Moreover, using pro-fibrotic and pro-adipogenic cell culture compositions we were able to mimic pathological features typically observed in muscular dystrophies: excessive ECM production and the formation of fatty infiltrations. This study provides an advanced skeletal muscle model, with enhanced functional and structural properties, capable of recapitulating pathophysiological processes that require FAPs.
    Keywords:  3D tissue engineering; fatty replacement; fibro-adipogenic progenitors; fibrosis; muscle disease; skeletal muscle
    DOI:  https://doi.org/10.1177/20417314261441552
  9. Nutrients. 2026 Apr 13. pii: 1218. [Epub ahead of print]18(8):
    Protein and Skeletal Muscle Metabolism.
    Donny Camera.
      Whole-body skeletal muscle mass is determined by the balance of two concurrent processes-muscle protein synthesis (MPS) and muscle protein breakdown (MPB)-collectively termed muscle protein turnover [...].
    DOI:  https://doi.org/10.3390/nu18081218
  10. Skelet Muscle. 2026 May 02.
    iPSC-derived skeletal muscle spheroids for Duchenne Muscular Dystrophy modeling.
    Joyce Esposito, Felipe de Souza Leite, Igor Neves Barbosa, Thaís Maria da Mata Martins, Giovanna Gonçalves de Oliveira Olberg, Ziad Al Tanoury, Kayque Alves Telles-Silva, Mayana Cristina da Silva Pardo, Tatiana Jazedje, Raul Hernandes Bortolin, Mario Hiroyuki Hirata, Olivier Pourquié, Mayana Zatz.
       BACKGROUND: The progressive skeletal muscle degeneration observed in Duchenne Muscular Dystrophy (DMD) patients requires multiple cycles of satellite cells (SCs) activation to promote tissue regeneration. Dystrophic SCs present intrinsic defects, and the disrupting fibrotic niche hinders appropriate muscle recovery. Traditional 2D culture systems face challenges in modeling the DMD muscle niche and SCs behavior. Our aim was to validate a 3D culture of skeletal muscle spheroids (iSMS) for DMD modeling, as compared to the traditional 2D culture, while investigating the pathophysiological mechanisms of dystrophin deficiency in vitro.
    METHODS: To compare iSMS with traditional 2D myogenic differentiation, we differentiated wild-type (WT), dystrophic (DMD) isogenic induced pluripotent stem cells (iPSCs), as well as iPSCs derived from DMD patients, characterized myogenic markers levels and assessed differences in proliferation and differentiation using RT-qPCR, immunofluorescence, and flow cytometry.
    RESULTS: Our data showed that iSMS improved PAX7 expression in vitro, while MYOD1, MYOG, MYF5, and MYH3 expression were significantly reduced. These findings suggest that, at three weeks of myogenic differentiation, iSMS cultures retained satellite-like cells in a less activated, progenitor-like state. Accordingly, we identified higher expression of canonical Notch signaling genes such as JAG1 and NOTCH1 in iSMS compared to 2D. We also characterized the response of 2D and iSMS to terminal differentiation medium, providing a valuable comparison with muscle fibers derived from human adult myoblasts. Additionally, we showed that DMD iSMS-derived progenitors proliferated at reduced levels compared with WT, a characteristic not observed in progenitors derived from 2D cultures. Finally, we performed iSMS and 2D myogenic differentiation of iPSC lines from three patients with DMD.
    CONCLUSION: Our results highlight important advantages of using the iSMS differentiation platform over 2D for DMD in vitro modeling. Exploring these 3D systems may help to gain a deeper understanding of SCs behavior to advance in novel treatments for DMD, which might be applicable to other forms of muscular disorders.
    Keywords:  Disease Modeling; Duchenne Muscular Dystrophy; Induced pluripotent stem cells; Muscle spheroids; Satellite Cells
    DOI:  https://doi.org/10.1186/s13395-026-00428-3
  11. Front Physiol. 2026 ;17 1760238
    Direct aldosterone stimulation of skeletal muscle fibroblasts changes gene expression and differentially affects fibroblast functions from normal and diseased muscles.
    Chetan K Gomatam, Swathy Krishna, Jeovanna Lowe, Esther Silver, Christoph Lepper, Jill A Rafael-Fortney.
       Introduction: Fibroblasts are critical for stabilizing skeletal muscle and facilitating wound healing after injury but become overactivated and lead to fibrotic replacement of muscle tissue in chronic degenerative diseases such as Duchenne muscular dystrophy (DMD). We have previously shown that the mineralocorticoid receptor (MR) is present in skeletal muscle and MR antagonist drugs reduce fibrosis and chronic inflammation in dystrophic mouse models. Indirect MR signaling from other cell types in the muscle microenvironment affects fibroblast gene expression and function. However, the direct effects of MR activation of skeletal muscle fibroblasts are unknown.
    Methods: To determine whether direct stimulation with the endogenous MR agonist aldosterone changes gene expression in skeletal muscle fibroblasts, we performed RNA sequencing comparing fibroblasts isolated from neonatal wild-type skeletal muscles treated with aldosterone or vehicle. To further investigate the effects of aldosterone treatment of fibroblasts in skeletal muscle health and disease, we then performed in vitro proliferation and migration assays on fibroblasts isolated from neonatal and adult wild-type and dystrophic muscles.
    Results: Treatment with aldosterone leads to differential expression of 492 genes in fibroblasts isolated from neonatal wild-type mouse muscles. Protein levels of differentially expressed genes Fkbp5, p57 and c-Fos were also increased by direct aldosterone stimulation of fibroblasts from both wild-type and dystrophic muscles. Surprisingly, cultured fibroblasts from both neonatal wild-type and dystrophic muscles retain a higher proliferation rate compared to adult muscle fibroblasts. Direct aldosterone treatment represses proliferation and slows scratch-wound closure kinetics only in fibroblasts isolated from adult dystrophic skeletal muscle.
    Discussion: This study shows that aldosterone treatment of skeletal muscle fibroblasts alters gene expression. However, fibroblasts from adult dystrophic muscle appear most sensitive to gene expression changes after short-term aldosterone treatment. These data suggest that MR signaling in the skeletal muscle microenvironment may differentially affect fibroblasts in wound healing and in chronic fibrotic diseases such as muscular dystrophies.
    Keywords:  Duchenne muscular dystrophy; fibroblasts; fibrosis; mdx; mineralocorticoid receptor
    DOI:  https://doi.org/10.3389/fphys.2026.1760238
  12. J Physiol. 2026 May 07.
    Mitochondrial dynamics and oxidative metabolism: an emerging role for Septin7 in skeletal muscle.
    Márcio Augusto Campos-Ribeiro, Rudá Prestes E Albuquerque, Thiago N Menezes, Vanessa Morais Lima.
      
    Keywords:  cytoskeleton; mitochondrial dynamics; mitochondrial function; skeletal muscle metabolism
    DOI:  https://doi.org/10.1113/JP291379
  13. Skelet Muscle. 2026 May 08.
    Caloric restriction reprograms skeletal muscle molecular pathways in non-human primates: potential relevance to human aging biology.
    Jayanta Kumar Das, Nirad Banskota, Stefano Donega, Nader Shehadeh, Yulan Piao, Nathan Price, Julie A Mattison, Julián Candia, Rafael de Cabo, Luigi Ferrucci.
       BACKGROUND: Caloric restriction (CR), achieved by reducing energy intake without malnutrition, has been shown to preserve muscle function and delay age-related declines in strength and mobility by modulating key metabolic and molecular pathways involved in muscle maintenance. While most initial research on CR was done in rodents, non-human primates (NHPs) offer a higher translatable animal model for understanding CR effects due to their close genetic, physiological and cognitive similarities to humans.
    METHODS: In this cross-sectional study, we investigated skeletal muscle gene expression changes induced by 30% CR in skeletal muscle in rhesus monkeys (n = 18 CR, n = 18 control). We performed high-depth RNA sequencing to profile gene expression and alternative splicing variants and identify pathways linked to aging, regeneration/degeneration, and energy metabolism.
    RESULTS: Transcriptomic profiling revealed widespread gene expression differences between CR animals compared to controls. Genes that were overexpressed were mainly involved in pathways related to energy metabolism, mitochondrial function, signaling, and oxidative stress response. Conversely, underexpressed genes were connected to immune response, extracellular matrix organization, apoptosis, and ribosomal RNA processing. Further, we identify alternative splicing as a major mechanism by which CR modulates genes involved in muscle function, metabolism, and aging.
    CONCLUSIONS: Caloric restriction preserves skeletal muscle by enhancing metabolism, limiting degeneration and inflammation, and engaging conserved mechanisms across species.
    Keywords:  Caloric restriction; Gene expression; Muscle; Non-human primates; RNA; Splicing
    DOI:  https://doi.org/10.1186/s13395-026-00422-9
  14. iScience. 2026 May 15. 29(5): 115703
    Chondrolectin regulates the sublaminar localization and regenerative function of muscle satellite cells in mice.
    Lijie Gu, Kun Ho Kim, Xiyue Chen, Stephanie N Oprescu, Yufen Li, Junxiao Ren, Shihuan Kuang, Feng Yue.
      Skeletal muscle satellite cells (SCs) reside between the myofiber sarcolemma and basal lamina, where extracellular matrix (ECM) interactions maintain stemness and regenerative function. Here, we identify chondrolectin (CHODL), a type I transmembrane protein with a C-type lectin domain, as a critical regulator of SC biology. Single-cell RNA-seq analysis reveals that Chodl is highly enriched in quiescent SCs but downregulated in proliferating myoblasts. The conditional deletion of Chodl in embryonic myoblasts (Chodl MKO ) or adult SCs (Chodl PKO ) leaves muscle development intact yet delays injury-induced regeneration in young and aged mice. Chodl-deficient SCs exhibit reduced self-renewal and diminished proliferation, leading to defective myofiber repair. In silico network perturbation further predicts disrupted ECM-ligand interactions and Notch signaling, consistent with SC mislocalization outside the basal lamina and precocious activation in Chodl PKO muscle. Together, these findings establish CHODL as a determinant of SC niche localization and function, linking ECM interactions to muscle stem cell maintenance and repair.
    Keywords:  Cell biology; Molecular biology; Organizational aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115703
  15. Life (Basel). 2026 Apr 01. pii: 588. [Epub ahead of print]16(4):
    FURIN Stimulates NOTCH2 and NOTCH3 Pathways, Leading to Return of Function in Aged Cells.
    Peter L Elkin, Jiaxing Liu, Jisaiah T Wheeler, Thomas M Suchyna, Wilma A Hofmann.
       BACKGROUND: Aging is accompanied by a progressive decline in skeletal muscle regeneration, largely due to impaired myogenic differentiation. The proprotein convertase FURIN is a key protease responsible for activating several signaling molecules, including precursors of NOTCH receptors, which regulate cell fate and differentiation. In this study, we investigated whether age-associated downregulation of FURIN contributes to impaired NOTCH2/3 signaling and myogenic function.
    METHODS: An initial bioinformatics analysis of public scRNA-seq data from Genotype-Tissue Expression (GTEx) project indicated age-related expression of genes in the NOTCH signaling pathway. In vitro verification used early- and late-passage C2C12 myoblasts as a model of muscle cell aging to compare the expression of these genes. Late-passage C2C12 cells were transiently transfected with FURIN plasmid to assess restoration of differentiation potential, quantified by the fusion index, myogenic marker expression, and morphology.
    RESULTS: Expression of FURIN, NOTCH2 and NOTCH3 was negatively correlated with age, whereas GZMB increased with age in GTEx dataset. Late-passage myoblasts exhibited impaired myotube formation, reflecting age-associated loss of myogenic capacity. Restoration of FURIN expression in aged myoblasts was associated with reduced GZMB levels, increased expression of embryonic myosin heavy chain IGF1, and partial recovery of myogenic differentiation and myotube formation.
    CONCLUSIONS: These findings suggest that age-associated loss of FURIN contributes to impaired NOTCH2/3 pathways and myogenic dysfunction. Overexpression of FURIN partially rescues the myogenic phenotype and increases expression of early myogenic markers in aged cells, identifying FURIN as a potential regulator of muscle regenerative capacity during aging. We suggest FURIN as a promising candidate target for further investigation into the mechanisms driving aging or age-related decline.
    Keywords:  FURIN; GTEx; NOTCH signaling; aging; myogenesis; skeletal muscle regeneration
    DOI:  https://doi.org/10.3390/life16040588
  16. Physiol Rep. 2026 May;14(9): e70902
    Time-of-day, satellite cells, and velocity collectively influence ex vivo isovelocity force production in mouse extensor digitorum longus muscle.
    Ryan E Kahn, Sudarshan Dayanidhi, Richard L Lieber.
      Skeletal muscles are exquisitely designed to produce force that facilitate movement. Circadian "molecular clocks" residing in muscle play a role in regulating force production with muscle stem cell (satellite cells, SC) molecular clocks modulating isometric and eccentric force according to time-of-day. However, many tasks of daily living and exercise (i.e., walking/running) involve force and power produced during muscle shortening. Thus, the purpose of this study was to determine whether isovelocity forces and power are also modulated by SCs according to time-of-day. Using previously published samples (a mouse model capable of SC ablation), we evaluated isovelocity forces across a range of velocities (1-11 Lf/s) at two different times of day ZT1, ZT9 in the presence and absence of SCs. The main finding of this investigation was that isovelocity force production is regulated by a third-order interaction effect between time-of-day × SCs × velocity (p < 0.001). Additionally, a significant effect of time-of-day was observed for isovelocity force and power when comparing ZT1 vs. ZT9 SC+ mice whereas this effect was absent in SC- animals. These results suggest SCs harbor a time-of-day and velocity dependent effect on isovelocity force production and power. Further work is required to elucidate the underlying mechanisms of this phenomenon.
    Keywords:  force production; force‐velocity; muscle mechanics; satellite cells; time‐of‐day
    DOI:  https://doi.org/10.14814/phy2.70902
  17. JCI Insight. 2026 May 07. pii: e203215. [Epub ahead of print]
    PGC-1α pathway dysregulation disrupts myofiber specification in a mouse model of SBMA.
    Curtis J Kuo, Laura B Chopp, Zhigang Yu, Luhan Ni, Hien T Zhao, Janghoo Lim, Andrew P Lieberman.
      Skeletal muscle pathology is a critical but poorly understood contributor to neuromuscular degeneration in spinal and bulbar muscular atrophy (SBMA), a CAG/polyglutamine (polyQ) expansion disorder caused by mutation in the androgen receptor (AR). Using a gene-targeted SBMA mouse model, we applied single-nucleus RNA sequencing to identify a disease-specific population of skeletal muscle myonuclei that replaced normal myonuclear subtypes. This transition was associated with dysregulation of the pathway governed by PGC-1α, a central regulator of myofiber specification and metabolic identity. PGC-1α dysfunction in SBMA muscle was age-, hormone-, and polyQ length-dependent and was partially rescued by subcutaneous delivery of AR-targeted antisense oligonucleotides. Integrated ChIP-seq and RNA-seq analyses revealed that aberrant PGC-1α activity promoted the expression of a distinct set of myofiber specification genes while downregulating those that define healthy Type IIb and Type IIx myonuclei. We propose a model in which this dysfunction arose downstream of polyQ-mediated sequestration of PGC-1α cofactors MEF2, CREB, and CBP, leading to transcriptional reprogramming and cellular dysfunction. These findings implicated PGC-1α dysregulation as a key event linking AR polyQ expansion to skeletal muscle degeneration and suggested a shared mechanism for polyQ-mediated muscle pathology across related neurodegenerative diseases.
    Keywords:  Genetic diseases; Muscle biology; Neurodegeneration; Neuromuscular disease; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.203215
  18. Nat Commun. 2026 05 06. pii: 4063. [Epub ahead of print]17(1):
    Periodontitis induces skeletal muscle atrophy by increasing circulating levels of activin A.
    Wonn Shim, Joonho Suh, Ha Kyeong Kim, Na-Kyung Kim, Yongbaek Kim, Yong Taek Jeong, Min-Sung Kim, Se-Jin Lee, Yun-Sil Lee.
      Periodontitis is linked to various systemic conditions, but its impact on skeletal muscle remains unclear. Here, we utilized a ligature-induced periodontitis model in male mice and showed that periodontitis significantly reduces muscle and bone mass without affecting fat mass or food intake. Interestingly, activin A, well-documented inducer of muscle atrophy, is highly expressed in periodontitis-affected gingiva. The activin A gene (Inhba) is predominantly expressed in gingival fibroblasts and epithelial cells, which undergo significant proliferation as periodontitis progresses, as well as in myeloid cells infiltrating inflamed periodontal tissues and myeloid cell-derived osteoclasts. A similar upregulation pattern of INHBA was also confirmed in periodontitis-affected human tissues by scRNA-seq analysis. Furthermore, we demonstrated that serum activin A levels are increased in periodontitis-affected mice and patients. Gingival overexpression of activin A via AAV-Inhba transduction activates canonical activin signaling in skeletal muscle, as evidenced by increased pSMAD3 and MuRF1 expression, leading to significant muscle loss. Notably, intra-gingival injection of siInhba significantly reduced serum activin A levels and restored muscle mass and myofiber size. Our findings indicate that activin A is a mediator of muscle atrophy in periodontitis and suggest that local injection of siInhba may prevent periodontitis-induced muscle atrophy without apparent systemic adverse effects.
    DOI:  https://doi.org/10.1038/s41467-026-72766-1
  19. J Cell Physiol. 2026 May;241(5): e70173
    Scaffold Protein PDLIM5 Regulates TRPC1 Calcium Channel Mediated Store-Operated Calcium Entry in Mouse Myoblasts.
    Mingyi Dong, Tomoaki Niimi, Andrés Daniel Maturana.
      Intracellular calcium (Ca2+) signaling controls myoblast proliferation, fusion, and myofiber formation. In myoblasts, Transient Receptor Potential Canonical (TRPC) channels, with TRPC1 as a predominant isoform, mediate store-operated Ca²⁺ entry (SOCE) and are essential for myogenesis. PDLIM5 (ENH1), a PDZ-LIM scaffold protein, organizes signaling events, including ion channel regulation and transcriptional control in muscles. This study aims to test the hypothesis that PDLIM5 regulates TRPC1-mediated Ca2+ entry in myoblasts. Thapsigargin-induced SOCE was suppressed by the SOCE inhibitors Gd3+ and 2-APB, as well as by TRPC1 siRNA, supporting the involvement of TRPC1 in SOCE in C2C12 myoblasts. Additionally, SOCE inhibition decreased the number of nuclei per myotube and reduced the size of myotubes. ENH1 siRNA knockdown significantly downregulated TRPC1 and STIM1 mRNA expression, increased basal cytosolic Ca2+ level, and impaired SOCE response and myotube maturation. Overexpression of ENH4, a skeletal muscle-specific short splice variant of ENH1, similarly repressed TRPC1-mediated SOCE and myotube formation. Conversely, ENH1 overexpression enhanced SOCE without altering the mRNA levels of TRPC1, Orai1, or STIM1. Immunoprecipitation showed a physical interaction between ENH1/ENH4 and TRPC1. In differentiated myotubes, TRPC1 also contributed to thapsigargin-induced SOCE, as evidenced by the reduced Ca2+ entry following TRPC1 knockdown. ENH1 knockdown and ENH4 overexpression significantly attenuated SOCE in myotubes; notably, ENH1 knockdown also increased basal cytosolic Ca2+ level. In contrast to myoblasts, ENH1 overexpression did not enhance SOCE in myotubes, concomitant with the absence of a detectable interaction between ENH1 and TRPC1, whereas ENH4 retained its association with TRPC1. These findings suggest that ENH1 and ENH4 differentially modulate TRPC1-dependent Ca2+ entry in C2C12 cells, thereby regulating myogenic differentiation and contributing to skeletal muscle formation and development.
    Keywords:  PDLIM5; TRPC1; myogenesis; skeletal muscle; store operated calcium entry
    DOI:  https://doi.org/10.1002/jcp.70173
  20. J Appl Physiol (1985). 2026 May 06.
    High and moderate intensity exercise training differentially impact microvascular function in skeletal muscle of mice lacking adiponectin.
    Steven Medarev, Xiangyu Zheng, Vito Evola, Maxwell Parr, Ashton Foster, Arjith Rathakrishnan, Hyerim Park, Josh Maraj, Payal Ghosh, Daniel Machin, Judy Muller-Delp.
      We tested the hypothesis that the absence of circulating adiponectin, associated with reduced aerobic exercise, contributes to impaired microvascular function and oxidative capacity in the skeletal muscle of adult mice. Adiponectin knockout (AdipoKO) and wild-type (WT) mice were assigned to either a moderate or high intensity exercise (EX) training protocol or remained sedentary (SED) for an 8-10 week period. At the end of this period, in vivo microvascular dynamics were measured, followed by ex vivo assessment of arteriolar vasoreactivity. Oxidative capacity and capillary density in skeletal muscle were evaluated using citrate synthase activity assays and immunohistochemical staining for lectin, respectively. Our results showed that moderate intensity exercise training increased oxidative capacity in the soleus muscle of WT mice, whereas AdipoKO mice did not show similar improvements. Moderate intensity exercise training also increased capillary-to-fiber ratio in WT mice, however, these exercise training-associated vascular adaptations were absent in AdipoKO mice. Moderate intensity exercise training increased vasorelaxation to acetylcholine in arterioles from AdipoKO mice as compared to those from WT mice. In contrast, high intensity exercise training augmented flow-mediated vasodilation in arterioles from WT mice, but not in arterioles from AdipoKO mice. These findings suggest that adiponectin is important for exercise training-induced improvements in skeletal muscle oxidative capacity and microvascular function. The lack of adiponectin disrupts these beneficial adaptations, suggesting that adiponectin plays an important role in mediating vascular health responses to aerobic exercise training in skeletal muscle.
    Keywords:  aerobic exercise; capillarity; endothelium; flow-mediated dilation; microcirculation
    DOI:  https://doi.org/10.1152/japplphysiol.00918.2025
  21. bioRxiv. 2026 Apr 22. pii: 2026.04.20.719674. [Epub ahead of print]
    Pathogenic human huntingtin expression causes prolific intramuscular aggregation, leading to nuclear, metabolic, and physiological dysregulation in striated muscle.
    Tadros A Hana, Kiel G Ormerod.
      Huntington's disease is caused by expansion of a CAG repeat in the human HTT gene, producing a mutant huntingtin protein that misfolds and forms intracellular aggregates. Although Huntington's disease is primarily characterized as a neurodegenerative disorder, mutant huntingtin is ubiquitously expressed, and peripheral tissues such as skeletal muscle exhibit pathological abnormalities. To define the muscle-intrinsic consequences of pathogenic huntingtin expression, we expressed caspase-6 truncated pathogenic human huntingtin in body wall muscle of Drosophila melanogaster larvae and performed quantitative structural and functional analyses. Aggregate analysis revealed that fluorescence intensity increased with aggregate size while aggregate morphology became more irregular. Delaying transgene expression until later stages of larval development dramatically reduced aggregate number, demonstrating a strong temporal dependence of aggregate formation. Myonuclei were enlarged, misshapen, and exhibited significantly reduced fluorescence intensity, consistent with altered chromatin organization. Notably, huntingtin aggregates were observed within the nucleus, indicating that nuclear proteostasis is directly perturbed by pathogenic huntingtin in muscle cells. Despite these intracellular defects, muscle fiber shape and sarcomere organization were preserved, suggesting that contractile apparatus assembly is not overtly disrupted. In contrast, mitochondrial organization was severely affected, with extensive mitochondrial aggregation throughout muscle fibers, consistent with altered organelle homeostasis. Functional analyses demonstrated that pathogenic huntingtin expression significantly impaired neuromuscular performance. Larvae exhibited reduced excitatory junctional potentials and diminished muscle contractile force, indicating compromised synaptic transmission and muscle function. Together, these findings demonstrate that pathogenic human huntingtin expression in skeletal muscle is sufficient to drive widespread protein aggregation, nuclear and mitochondrial abnormalities, and functional deficits despite the absence of overt structural changes. Our results highlight the importance of muscle-intrinsic pathogenic mechanisms and provide a quantitative framework for understanding how mutant huntingtin disrupts cellular organization and physiology outside the nervous system.
    DOI:  https://doi.org/10.64898/2026.04.20.719674
  22. Life Metab. 2026 Jun;5(3): loag009
    Circadian biology and exercise: the time to move.
    Zhihui Zhang, John A Hawley, Min-Dian Li.
      Exercise performance in endurance- and power-based events is time-of-day dependent in both humans and rodents. Accordingly, there has been growing interest in determining whether there is an optimal time of day for physical activity that can amplify the well-known benefits of exercise on metabolic health in humans. Here, we discuss critical features of circadian biology that underpin many of the physiological responses to the timing of exercise. Recent studies indicate that the circadian clock regulates exercise capacity through the coordination of tissue-specific physiological responses, including fuel metabolism and mitochondrial biogenesis. Synchronized actions between circadian clocks and clock-output pathways residing in the skeletal muscle and other tissues are likely to explain how external time-of-day cues influence exercise performance and physiological responses to exercise. Understanding the circadian biology of exercise will provide the foundation on which future individualized exercise protocols are prescribed to improve metabolic health outcomes at both individual and population levels.
    Keywords:  circadian clock; circadian rhythm; exercise; exercise training; metabolic health; skeletal muscle
    DOI:  https://doi.org/10.1093/lifemeta/loag009
  23. Proc Biol Sci. 2026 May 06. pii: 20260254. [Epub ahead of print]293(2070):
    Repeated evolutionary turnover of vertebrate skeletal muscle myosins.
    Christina M Harvey, Eric R Schuppe, Michael S Brainard, Matthew J Fuxjager, James B Pease.
      Myosin heavy chain proteins are essential for muscle contraction and nearly every physiological function in animals, but their diversity and evolution outside mammals are largely unknown. We comprehensively model the evolutionary history of 1201 heavy-chain myosins from across Chordata. We find that skeletal muscle myosins are located in a conserved tandem gene array in all vertebrate species, but repeated gene duplication-loss turnover has surprisingly led to an independently evolved set of core skeletal muscle myosins in each major vertebrate group. Despite these separate derivations of these myosin subfamilies, each major vertebrate group exhibits tissue-specific patterns of subfamily expression and specialized myosin subfamily expression in extreme muscles. Our results show that muscle evolution across vertebrates is not based on conserved one-to-one orthologous motor myosins, as might be expected for such a core structural protein family. Instead, we find that skeletal muscle myosins have evolved as a shifting cluster of genes that is constantly changing and diversifying to balance maintainance of core physiological processes and innovation of new physiological possibilities.
    Keywords:  RNA-seq; evolution; gene family evolution; genomics; molecular evolution; myosin; protein structure; skeletal muscle; vertebrates
    DOI:  https://doi.org/10.1098/rspb.2026.0254
  24. bioRxiv. 2026 Apr 24. pii: 2026.04.21.719997. [Epub ahead of print]
    C26 and CT26 colorectal cancer models exhibit divergent cachexia phenotypes, intramuscular inflammation, and protein turnover signaling.
    Xinyue Lu, Hanan Tlais, Hamood Rehman, Ashtyn N Martens, Abigail L Hartz, Vandre C Figueiredo, James F Markworth.
      Colorectal cancer (CRC) cachexia induces skeletal muscle dysfunction, impeding quality of life and worsening cancer prognosis. Multiple preclinical models, including the widely used mouse model of subcutaneous inoculation with the C26 colorectal carcinoma cell line, have been developed to study the biological mechanisms of CRC cachexia and elucidate potential new treatments. It has been proposed that a distinct cell line of the same origin, namely CT26, is relatively non-cachexic. However, studies evaluating the relative potential of C26 and CT26 cells to induce cancer cachexia in parallel have been limited. The differences in the biological mechanisms by which C26 and CT26 impact skeletal muscle mass and function have also not been fully elucidated. In the current study, we investigated the differential capacity of C26 and CT26 to induce cancer cachexia using both an in vitro cancer-muscle cell co-culture and an in vivo syngeneic mouse model. Our results show that both C26 and CT26 cells induced significant atrophy of murine C2C12 skeletal myotubes. In the mouse model, while C26 and CT26 both reduced skeletal muscle mass and fat mass, only C26 tumors led to loss of body weight and impaired skeletal muscle force output. We further show that C26 tumor-bearing mice exhibit greater muscle inflammation than CT26 tumor-bearing mice. In addition, mice bearing C26 and CT26 tumors showed differential regulation of the innate immune responses and muscle protein turnover. Overall, our data suggests that although both C26 and CT26 cells do exhibit cachexic effects, C26 cells induce greater loss in body weight, fat mass, skeletal muscle mass, and physical function via promoting chronic inflammation and deregulating protein balance of skeletal muscle.
    DOI:  https://doi.org/10.64898/2026.04.21.719997
  25. Int J Biol Sci. 2026 ;22(8): 4225-4242
    Mechanosensitive Ion Channels: Molecular Hubs Integrating Skeletal Muscle Adaptation and Systemic Homeostasis.
    Chong Zhao, Jinying Zhang, Xu Wang, Hongzhen Li, Jie Huang, Jiacheng Wang, Jianhao Wang, Haoran Zhang, Yan Zeng, Haiying Liu, Shuai Xu.
      Skeletal muscle's ability to perceive and adapt to physical force is fundamental to tissue homeostasis and systemic health. At the core of this process, mechanosensitive ion channels (MSCs)-notably the Piezo and TRP families-function as primary transducers. This review synthesizes how these channels convert diverse mechanical stimuli into biochemical signals. We delineate how their activation, primarily through Ca2+ influx, engages downstream signaling hubs, including the Hippo-YAP/TAZ, MAPK, and PI3K-Akt-mTOR pathways. These cascades subsequently orchestrate muscle growth, regeneration, and metabolic remodeling. We then bridge these molecular mechanisms to clinical relevance, analyzing how physical therapies like low-intensity pulsed ultrasound and electrical stimulation precisely target these networks to enhance muscle repair. Furthermore, we explore the role of MSCs in driving skeletal muscle's function as an endocrine organ. Mechanical activation triggers myokine release, mediating critical inter-organ communication with bone, adipose, and immune systems. Collectively, this review establishes MSCs as pivotal molecular hubs that integrate external physical energy with local tissue repair and systemic physiological regulation.
    Keywords:  Piezo; TRP; calcium signaling; mechanotransduction; muscle regeneration; myokines; skeletal muscle
    DOI:  https://doi.org/10.7150/ijbs.127875
  26. Biomedicines. 2026 Mar 31. pii: 794. [Epub ahead of print]14(4):
    Skeletal Fiber Type in Muscle Pain and Dysfunction.
    Maria Lopes Cardia, Bruno Daniel Carneiro, Isaura Tavares, Daniel Humberto Pozza.
      Different types of skeletal muscle fibers display marked heterogeneity in metabolic, mechanical, and regenerative properties. However, their role in chronic musculoskeletal pain remains insufficiently integrated into clinical models. Chronic pain is associated with altered neuromuscular control, prolonged low-level activation, and reduced recruitment of high-threshold motor units. These factors may promote fiber type-specific remodeling. This narrative review critically synthesizes current evidence on the relationship between musculoskeletal pain and muscle fiber types. The focus was on metabolic vulnerability, mechanical susceptibility, and regenerative capacity. A structured literature search was conducted in PubMed, Scopus, and Web of Science, focused on human studies and key translational models. Chronic musculoskeletal pain is characterized by acquired fiber type-specific adaptations rather than a fixed unfavorable profile. In chronic pain scenarios, Type I fibers present features of chronic overload, including hypertrophy with insufficient capillarization and increased satellite cell activity. Type II fibers exhibit relative disuse, atrophy, and reduced satellite cell content, resembling accelerated muscle aging. Symptom duration, neuromuscular control strategies, and task-specific loading patterns modulate these adaptations, with interindividual variation. Muscle dysfunction in chronic pain reflects maladaptive but potentially reversible neuromuscular and histological plasticity. These findings indicate that rehabilitation strategies should be individualized, involving context-specific exercise strategies to restore muscle structure, function, and regenerative potential in chronic musculoskeletal conditions.
    Keywords:  chronic pain; delayed onset muscle soreness; fast-twitch; muscle fibers; muscle regeneration; musculoskeletal pain; satellite cells; skeletal; skeletal muscle; slow-twitch
    DOI:  https://doi.org/10.3390/biomedicines14040794
  27. Biochem Pharmacol. 2026 May 02. pii: S0006-2952(26)00349-7. [Epub ahead of print]250(Pt 2): 118016
    Niacin accelerates skeletal muscle regeneration and enhances C2C12 differentiation by activating the PI3K/Akt signaling pathway.
    Lizhi Dai, Jingxuan Wang, Zheyuan Cao, Tong Yu, Jia Liu, Youchong Li, Yuhao Zhang, Jianhua Xiao.
      Skeletal muscle injury is prevalent in clinical practice and sports medicine, and efficient regeneration is crucial for restoring motor function. Niacin (vitamin B3, NIA), a water-soluble essential nutrient and key precursor of nicotinamide adenine dinucleotide (NAD + ), regulates muscle metabolism and mitochondrial function, but its role and underlying mechanisms in skeletal muscle injury repair remain unclear. In this study, a mouse model of acute skeletal muscle injury was established via intramuscular injection of bupivacaine hydrochloride, and C2C12 myoblasts were used as an in vitro model to explore NIA's effects on muscle regeneration and myogenic differentiation. In vivo experiments showed that oral NIA supplementation (73 m g/kg/day for 8 weeks) significantly promoted repair of the injured tibialis anterior (TA) muscle: compared with the NC group, NIA-treated mice had increased TA muscle mass, larger myofiber cross-sectional area, a higher proportion of centrally nucleated fibers, and improved muscle function. Western blot analysis revealed that NIA upregulated the expression of myogenic regulatory factors (MRFs) including Pax7, MyoD, and MyoG in injured tissues. In vitro assays demonstrated that NIA promoted C2C12 myoblast differentiation dose-dependently, with 1 mM as the optimal concentration, confirmed by increased MyoD and MyoG expression and a higher myotube fusion index. Bioinformatics analyses predicted the PI3K/Akt signaling pathway as a potential downstream target. Mechanistically, NIA increased Akt phosphorylation (p-Akt) in C2C12 cells, while PI3K inhibition by LY294002 eliminated NIA-induced p-Akt upregulation, MRFs expression, and myotube fusion. In conclusion, NIA accelerates skeletal muscle regeneration and enhances C2C12 myoblast differentiation by activating the PI3K/Akt signaling pathway. This study clarifies NIA's molecular mechanism in muscle regeneration and provides a theoretical basis for its clinical application in treating skeletal muscle injury.
    Keywords:  C2C12; MRFs; Muscle injury repair; Muscle regeneration; Niacin; PI3K/Akt
    DOI:  https://doi.org/10.1016/j.bcp.2026.118016
  28. Am J Physiol Cell Physiol. 2026 May 06.
    Identifying Quiescent Satellite Cells: A Scoping Review of Transcriptomic Markers and Limitations.
    Anika L Syroid, Alexandra P Steele, Kevin A Murach, Thomas J Hawke.
      Skeletal muscle regeneration relies on the resident stem cell population, termed satellite cells. Mechanistically, understanding the quiescence and activation dynamics of muscle satellite cells are essential for regenerative therapies and emerging applications such as cellular agriculture. Quiescent satellite cells (QSCs) are typically identified by expression of PAX7 and functional characteristics including a lack of proliferation. However, with the rapidly growing body of transcriptomic data, there is a lack of consensus regarding what markers can be used to identify quiescent satellite cells across transcriptomic studies. The purpose of this review was to evaluate the transcripts currently used to identify QSCs using transcriptomics and to establish an evidence-based foundation that could be used for future analyses. After surveying published single-cell transcriptomic studies, we identified Pax7 and/or Myf5 as the most used markers of general satellite cell identity, while Spry1, Cd34, and Calcr, together with the absence of Myod1, Mki67, and Cdk1 were most commonly used to identify QSC clusters in murine studies. In contrast, there is currently insufficient literature to make a confident conclusion on quiescence markers in larger mammals, including humans, pigs, and cattle. We also highlight the conceptual and technical challenges associated with transcriptomic analysis of satellite cell subpopulations, including continuum-based cell states, isolation induced transcriptional changes, and inconsistent terminology. As a field, greater consistency in language, standardized analyses, and cross-species validation will be required to progress the study of satellite cell quiescence and its translational utility.
    Keywords:  Quiescence; Satellite cell; Single-cell/nuclei RNA sequencing; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00101.2026
  29. J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70302
    RAGE Re-Expressed at Myofibre Level Drives Muscle Wasting in Cancer Conditions.
    Sara Chiappalupi, Giulia Gentili, Laura Salvadori, Martina Paiella, Marcello Manfredi, Vittoria Federica Borrini, Kaamashri Mangar, Ann Marie Schmidt, Maurizio Muscaritoli, Francesca Riuzzi, Guglielmo Sorci.
       BACKGROUND: Cancer cachexia (CC) is a highly debilitating syndrome characterized by loss of body and muscle weight affecting most advanced cancer patients. The receptor for advanced glycation end-products (RAGE) is expressed by several cell types and sustains the inflammatory response in acute and chronic diseases. Total ablation of RAGE (Ager-/- mice) translates into restrained CC and increased survival in tumour-bearing mice. RAGE, which is not expressed in adult healthy myofibres, is re-expressed in atrophying myofibres in cancer conditions. However, the specific contribution of muscular RAGE to CC was unknown.
    METHODS: Using an HSA/Cre-loxP system, we generated a tamoxifen-inducible conditional AgermKO mouse model in which RAGE is selectively ablated in myofibres. Tamoxifen-treated AgermKO, Agerflox and Ager-/- mice were subcutaneously injected with Lewis lung carcinoma (LLC) cells, and body changes and survival were monitored until 25 dpi, when histological, molecular and proteomic analyses were performed in tumour-bearing and control mice. Muscle samples of pre-cachectic and cachectic pancreatic cancer patients were analysed to validate the results.
    RESULTS: Compared with LLC-Agerflox mice, LLC-AgermKO mice showed reduced (7.5% [p = 0.004] vs. 15.1% [p < 0.0001]) body weight loss, no significant reduction of hind-limb muscle mass and strength and myofibre cross-sectional areas, increased survival (69.2% vs. 42.9% mice alive at 25 dpi) and restrained muscle and serum pro-inflammatory factors. Mechanistically, AgermKO muscles resist cancer-induced atrophy by maintaining an active Akt-GSK-3β-PGC-1α pathway, and increasing the synthesis of myosin heavy chain (MyHC)-I and -IIa (71.8% [p = 0.008] and 73.9% [p = 0.002] increase, respectively) along with a 76.3% (p = 0.008) increase in hybrid MyHC-I/IIa myofibres. Distinct proteomic signatures characterize muscles of tumour-bearing mice in dependence on RAGE expression, supporting a protective effect of RAGE ablation in muscles. LLC/AgermKO muscles showed increased amounts of several enzymes involved in glycolysis and glucose catabolism, typical of Warburg metabolism. Noteworthy, muscles of pre-cachectic and cachectic cancer patients showed ~3-fold increase (p < 0.05) in RAGE amounts and reduced Akt-GSK-3β-PGC-1α pathway, compared with healthy control subjects.
    CONCLUSIONS: Our data provide evidence that RAGE engagement at myofibre level drives loss of body and muscle weights and inflammation in cancer conditions. RAGE ablation in muscles confers resistance to CC through myofibre remodeling and glycolytic reprogramming. On the clinical side, the overexpression of RAGE is an early event in muscles of cancer patients, suggesting a role for RAGE in the onset of the cachectic syndrome. Thus, the molecular targeting of RAGE might be useful to counteract cachexia and prolong survival in cancer patients.
    Keywords:  RAGE; animal models; cancer cachexia; muscle wasting; myofibre remodeling
    DOI:  https://doi.org/10.1002/jcsm.70302
  30. Int J Mol Sci. 2026 Apr 16. pii: 3557. [Epub ahead of print]27(8):
    Mitochondrial Network Dynamics in Aging: Cellular Mechanisms, Intercellular Communication, and Their Impact on Tissue Adaptability.
    Luminita Labusca, Teodor Stefan Gheorghevici, Bogdan Puha.
      Beyond their classical role as "cellular powerhouses", mitochondria are increasingly recognized as dynamic and interconnected networks whose architecture, quality control, and intercellular communication influence cellular and organismal homeostasis. Mitochondrial dynamics-including fusion-fission balance, mitophagy-biogenesis coupling, intracellular organization, and intercellular transfer via tunneling nanotubes, extracellular vesicles, or transient cell fusion-contribute to tissue adaptation and functional decline during aging. Focusing on cardiac muscle, skeletal muscle, and the nervous system, this narrative review synthesizes current evidence describing how aging disrupts mitochondrial network integrity through altered dynamics, impaired organelle positioning and transport, reduced mitophagy, mtDNA instability, and compromised metabolic coupling between cells. These alterations propagate across tissues, limiting energetic flexibility, stress resilience, and regenerative capacity. Building on these mechanisms, we discuss a systems-level perspective in which aging is associated with progressive loss of mitochondrial network coherence rather than solely cumulative molecular damage. Within this framework, mitochondrial connectivity functions as an integrative descriptor of cellular resilience: well-organized networks counteract metabolic perturbations, whereas functionally decoupled networks amplify stress and promote maladaptive aging trajectories. Emerging evidence indicates that physiological and pharmacological interventions, including endurance exercise, caloric restriction or mimetics, fusion-supporting pathways, and mitophagy-enhancing strategies, can partially restore network organization even later in life. Molecular, cellular, and tissue-level insights are integrated to highlight mitochondrial network dynamics as both a mechanistic contributor to aging and a potentially modifiable target for future preventive and therapeutic interventions.
    Keywords:  aging; intercellular mitochondrial communication; mitochondria; mitophagy; myocardial aging; neurodegeneration; skeletal muscle aging
    DOI:  https://doi.org/10.3390/ijms27083557
  31. Biomolecules. 2026 Apr 01. pii: 524. [Epub ahead of print]16(4):
    MG53, a Regenerative Myokine Linking Skeletal Muscle to Cardiac Repair.
    Yuchen Chen, Kyung Eun Lee, Jongsoo Kim, Jae-Kyun Ko, Ki Ho Park.
      Mitsugumin 53 (MG53, also TRIM72) is a muscle-enriched tripartite motif protein with a well-established role in acute membrane repair and cytoprotection in striated muscle and other stressed tissues. MG53 is a core component of cellular repair machinery, rapidly sensing membrane disruption and coordinating membrane resealing, mitochondrial preservation, and anti-inflammatory modulation. In contrast to its high expression in skeletal muscle, endogenous MG53 expression in the adult human heart is minimal, raising the question of how MG53 exerts cardioprotective effects in the human heart. Recent studies help address this by identifying MG53 as a circulating regenerative myokine. MG53 is secreted from skeletal muscle into the bloodstream and can reach distal organs, including the heart. These findings support a muscle-to-heart endocrine model in which MG53 mediates tissue crosstalk and helps provide repair capacity to the myocardium when intrinsic cardiac MG53 is low. Here, we summarize recent advances in MG53 biology, emphasizing molecular mechanisms and inter-organ communication underlying cardioprotection. We further highlight translational strategies leveraging recombinant MG53- and MG53-based therapeutics and discuss challenges that must be addressed for future clinical applications. Collectively, these insights support MG53 as an endocrine repair factor linking skeletal muscle to cardiac repair and a potential regenerative cardiovascular target.
    Keywords:  MG53; TRIM72; cardioprotection; inter-organ communication; membrane repair; mitochondrial protection; muscle-derived myokine; regenerative medicine
    DOI:  https://doi.org/10.3390/biom16040524
  32. Front Immunol. 2026 ;17 1808541
    Skeletal muscle as a dynamic immunological niche for vaccination.
    Moataz Noureddine, Michael Schotsaert.
      Intramuscular vaccination has long been a cornerstone of preventive medicine and has substantially reduced global mortality from infectious disease. As vaccine development has expanded to address increasingly complex targets, including chronic infections and cancer, it has become clear that vaccine efficacy depends not only on antigen design but also on the inflammatory and cellular cues present at the site of delivery. Despite this, the skeletal muscle-the most common site of vaccine administration-has received comparatively little attention as an immunological environment. Skeletal muscle is a highly dynamic, regenerative tissue whose immune composition is actively remodeled by injury, aging, and disease. How these context-dependent immune states shape vaccine uptake and downstream immune responses remains poorly understood. In this review, we examine the immune landscape of skeletal muscle in health and disease and discuss how its intrinsic regenerative programs, and their disruption in conditions such as sarcopenia, may influence intramuscular vaccine responses.
    Keywords:  aging; muscle biology; muscle regeneration; sarcopenia; vaccination
    DOI:  https://doi.org/10.3389/fimmu.2026.1808541
  33. Front Physiol. 2026 ;17 1789642
    Innovations in skeletal muscle regeneration: from physiology to bioengineering approaches for repair and restoration.
    Kamal Awad, Julia Aguirre, Misturat Adegbite, Akhilla Sajeev Kumar, Ahmed S Yacoub, Mingxin Xia, Marco Brotto.
      Skeletal muscle is a dynamic tissue essential for voluntary movement, metabolism, and thermoregulation. Yet, its intrinsic regenerative capacity is overwhelmed in volumetric muscle loss (VML), where damage exceeds the native repair threshold. Conventional treatments such as muscle flaps and grafts provide only partial structural and functional recovery, underscoring the need for regenerative strategies that more precisely recapitulate the molecular and cellular physiology of muscle healing. This review first outlines the physiology of injury and muscle regeneration, with emphasis on key molecular pathways that govern inflammation, fibrosis, and myogenesis in VML. Building on this biological framework, we then examine hydrogels as soft material platforms for skeletal muscle tissue engineering, including: (i) acellular hydrogels and nanoparticle-loaded hydrogels designed to modulate the biochemical and biophysical microenvironment; (ii) cell-loaded hydrogels that deliver myogenic or stem/progenitor cell populations; and (iii) drug-loaded hydrogels for localized, sustained release of growth factors, cytokines, nucleic acids, or small molecules. Finally, we discuss emerging directions, including nanoparticle-integrated systems, dynamically stiffening or softening hydrogels, and advanced biofabrication approaches, and consider how these cellularized and acellular drug-, cell-, or nanoparticle-loaded hydrogels can be strategically leveraged to treat complex skeletal muscle injuries.
    Keywords:  engineering innovation; hydrogels; muscle grafts; myogenesis; physiology; regeneration; skeletal muscle; volumetric muscle loss (VML)
    DOI:  https://doi.org/10.3389/fphys.2026.1789642
  34. J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70308
    PACS2 Alleviates Sepsis-Induced Myopathy by Activating ERK-MAPK Signalling Pathway to Suppress ER-Phagy.
    Xuexin Li, Zu-An Shi, Fei He, Guo Mu, Feixiang Wang, Bowen Sun, Xiaobin Wang, Li Liu.
       BACKGROUND: Sepsis-induced myopathy (SIM) is a common and life-threatening complication, but its underlying mechanisms remain poorly understood. PACS2, a key resident protein at mitochondria-associated endoplasmic reticulum membranes (MAMs), regulates ER homeostasis under various pathological conditions. However, whether sepsis disrupts PACS2-dependent MAM integrity, thereby triggering ER dysfunction and muscle wasting, remains unexplored.
    METHODS: We established a sepsis mouse model via cecal ligation and puncture (CLP) and assessed muscle function using compound muscle action potential (CMAP) recording and grip strength measurements. Muscle atrophy was evaluated by H&E staining and Western blotting. PACS2 expression was determined by Western blotting, immunohistochemistry and qRT-PCR. MAM integrity was assessed by immunofluorescence co-localization of IP3R and VDAC1, and ER-phagy (reticulophagy) activation was evaluated by transmission electron microscopy, Western blotting and fluorescence microscopy. To investigate the functional role of PACS2, adeno-associated virus (AAV)-mediated PACS2 overexpression was performed in mouse tibialis anterior muscle and gastrocnemius muscles, followed by RNA-sequencing analysis. The MAPK pathway proteins p-ERK, p-P38 and p-JNK levels were assessed by Western blotting, and the involvement of ERK-MAPK signalling was tested pharmacologically via intraperitoneal injection of the ERK inhibitor SCH772984.
    RESULTS: Septic mice developed progressive skeletal muscle atrophy (p < 0.001) and dysfunction (p < 0.01), accompanied by 56% reduction in PACS2 expression at 96 h post-CLP (p < 0.01), 25% decrease in MAM integrity (p < 0.05) and subsequent activation of FAM134B-mediated ER-phagy (p < 0.01). AAV-mediated PACS2 overexpression significantly alleviated muscle atrophy by restoring MAM integrity by 28% (p < 0.01), reducing FAM134B expression by 43% (p < 0.01) and attenuating ER-phagy (p < 0.01). Co-immunoprecipitation revealed no detectable direct protein-protein interaction between PACS2 and FAM134B. Transcriptome sequencing and Western blotting analysis demonstrated that PACS2 overexpression specifically activated the ERK-MAPK signalling pathway (55% increase in p-ERK, p < 0.01) without affecting p-P38 or p-JNK levels (p>0.05), which suppressed FAM134B-mediated ER-phagy (p < 0.05) and ameliorated muscle atrophy (p < 0.05) by inhibiting nuclear translocation of TFEB (p < 0.01). Pharmacological ERK inhibition with SCH772984 abolished the protective effects of PACS2 by promoting TFEB nuclear translocation (p < 0.001) and TFEB-mediated FAM134B expression (p < 0.001).
    CONCLUSIONS: Our findings demonstrate that SIM is closely associated with disrupted MAM integrity. PACS2 plays a critical role in maintaining MAM structural integrity and regulating FAM134B-mediated ER-phagy through the ERK-MAPK-TFEB signalling axis, thereby providing novel mechanistic insights and potential therapeutic targets for SIM.
    Keywords:  ERK–MAPK signalling pathway; FAM134B; MAM; PACS2; sepsis‐induced myopathy
    DOI:  https://doi.org/10.1002/jcsm.70308
  35. Cell Metab. 2026 May 07. pii: S1550-4131(26)00141-5. [Epub ahead of print]
    Muscle-derived Mimecan regulates hypothalamus-brown adipose tissue communication and promotes health and lifespan in mice.
    Kentaro Mori, Shin-Ichiro Imai.
      Inter-organ communication plays a critical role in mammalian aging and longevity control. Here, we identified Mimecan from transcriptomic comparisons between young and aged skeletal muscles. Skeletal muscle-derived Mimecan regulates core body temperature via brown adipose tissue (BAT), which is impaired in aged mice. Skeletal muscle-specific loss- and gain-of-function models demonstrate that Mimecan activates melanocortin 4 receptor (MC4R)-positive neurons in the dorsomedial hypothalamus (DMH) and dorsal hypothalamic area (DHA) via maintaining primary cilia in those neurons, enhancing the sympathetic nervous tone directed to BAT. Furthermore, DMH/DHA-specific Mc4r-knockdown completely abolishes the effect of Mimecan overexpression on BAT function. Lastly, the restoration of Mimecan levels in blood circulation significantly extends lifespan in aged mice, suggesting that Mimecan plays a critical role in counteracting aging and promoting lifespan. Taken together, this study demonstrates the importance of inter-organ communication between the hypothalamus, skeletal muscle, and BAT in the systemic regulation of mammalian aging and longevity.
    Keywords:  MC4R; Mimecan; aging; brown adipose tissue; core body temperature; hypothalamus; longevity; melanocortin 4 receptor; skeletal-muscle-derived factor; sympathetic nervous system
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.003
  36. Cell Metab. 2026 May 07. pii: S1550-4131(26)00144-0. [Epub ahead of print]
    Garlic-derived metabolite activates LKB1, promotes adipose eNAMPT secretion, and improves age-related muscle function via hypothalamic signaling.
    Jun-Ichiro Suzuki, Kiyoshi Yoshioka, Masahiro Kurita, Takumi Sugimoto, Takahiro Eguchi, Naoki Ito, Aoi Kodama, Yasutomi Kamei, Masahiro Ohtani, Toshiaki Matsutomo, Shin-Ichiro Imai.
      Garlic (Allium sativum L.) and its aged extract contain many bioactive compounds that can bring health benefits to humans. Among them, S-1-propenyl-L-cysteine (S1PC) has recently drawn significant attention in the field of nutriceutical research. However, the mechanism of its molecular action has remained poorly understood. Here, we show that S1PC significantly activates liver kinase B1 (LKB1) through enhancing its tertiary complex formation with STRAD and MO25, leading to stimulating the phosphorylation of a mammalian NAD+-dependent protein deacetylase, SIRT1, and promoting the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in white adipose tissue (WAT). Interestingly, eNAMPT secreted from WAT specifically targets the hypothalamus, significantly enhancing skeletal muscle force and improving frailty indices in aged mice. Furthermore, S1PC is also able to increase circulating eNAMPT levels in human individuals who maintain healthy adipose mass. These findings demonstrate that S1PC specifically stimulates the LKB1-SIRT1 pathway and enhances eNAMPT secretion in WAT, counteracting skeletal muscle aging in aged individuals.
    Keywords:  LKB1; S-1-propenyl-L-cysteine; SIRT1; aging; garlic; hypothalamus; liver kinase B1; phosphorylation; skeletal muscle; white adipose tissue
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.006
  37. bioRxiv. 2026 May 01. pii: 2026.04.28.721405. [Epub ahead of print]
    Single-cell transcriptional landscape of muscle-derived stem/progenitor cells reveals hallmarks of aging and rejuvenation.
    Kavitha Mukund, Seth David Thompson, Chelsea L Rugel, Kamil K Gebis, Richard Louis Lieber, Jeffrey N Savas, Shankar Subramaniam, Mitra Lavasani.
      Muscle-derived stem/progenitor cells (MDSPCs) are an adult stem cell population with demonstrated regenerative and rejuvenative potential distinct from other muscle progenitor cells. However, their molecular identity and developmental status remain poorly defined. Using single-cell transcriptomics and proteomics, we comprehensively profiled murine MDSPCs across age groups. We show that MDSPCs exist along a transcriptional continuum of maturation-ranging from metabolically active, proliferative early-stage cells to late-stage, lineage-committed myogenic populations. While lacking canonical pluripotency markers, early-stage MDSPCs express gene programs associated with embryonic progenitor identity, suggesting a non-canonical, multipotent-like state. These features distinguish them from both satellite cells and committed myoblasts. Aging reshapes this continuum by reducing stemness-associated signatures while enhancing differentiation programs and oxidative stress. Our identification of distinct MDSPC states provide critical insights into mechanisms that underly tissue regeneration and aging. These findings offer a blueprint for development of future regenerative therapies to combat age-related functional decline.
    DOI:  https://doi.org/10.64898/2026.04.28.721405
  38. Immunol Invest. 2026 May 07. 1-17
    mRNA-Based Vaccines and Immunomodulatory Strategies for Muscle Regeneration and Recovery: A Comprehensive Review.
    Yunchang Yang, XiangXiang Cao, Yongdong Li, Xinyao Kang, Yuping Huang, Huigen Feng, Changchun Li.
       BACKGROUND: The convergence of vaccinology and immunotherapy with regenerative medicine provides a novel approach to therapeutic strategies for skeletal muscle repair.
    METHODS: This review critically examines the application of mRNA-based platforms and immunomodulatory interventions, systematically bifurcating these strategies into two distinct pathophysiological domains: acute mechanical trauma (sports injuries) and senescence-driven, chronic age-related sarcopenia.
    RESULTS: We detail how engineered mRNA can precisely control the expression of myogenic factors and immune modulators to overcome satellite cell dysfunction and inflammatory dysregulation. Furthermore, we critically evaluate current and emerging therapeutic paradigms - ranging from advanced biomaterial delivery systems to next-generation RNA platforms (e.g. circRNA and saRNA). Finally, we analyze their translational progress, the readiness of diagnostic modalities, and the profound ethical challenges of clinical integration, including the emerging threat of 'gene doping.'
    CONCLUSIONS: This comprehensive reference bridges microscopic molecular insights with macroscopic clinical practice for researchers in immunology, sports medicine, and geriatrics.
    Keywords:  immunotherapy; mRNA vaccine; muscle regeneration; sarcopenia; sports injury
    DOI:  https://doi.org/10.1080/08820139.2026.2667884
  39. Nat Commun. 2026 May 07.
    ANXA11 suppression restores muscular function in the mdx mouse model of Duchenne muscular dystrophy (DMD).
    Wen Tang, Bowen Lin, Ming Jin, Tianzhen Liu, Jingyi Zhou, Yanhong Jin, Yi Chen, Yanan Zhu, Gonglu Liu, Ping Hu, Chengyong Shen, Zhuoxian Meng, Guoping Peng, Liqun Lei, Xingxu Huang, Chenxiao Zhang, Ke Chen, Guiheng Zhang, Xufeng Yang, Xue Lv, Adrien Rousseau, Jian Yang, Zhi-Ying Wu, Ge Bai, Zhen Zhong.
      A critical question in Duchenne muscular dystrophy (DMD) research is whether regulatory mechanisms beyond dystrophin loss contribute to impaired muscle regeneration. Through integrative analysis of proteomics and single-nucleus RNA sequencing database, we identify the upregulation of ANXA11, a gene encoding a Ca²⁺-dependent phospholipid-binding protein, in MYH3⁺ regenerative myofibers from both mdx mice and DMD patients. This upregulation disrupts the maturation of regenerative myofibers, preventing adequate compensation for muscle loss in mdx mice due to dysregulation of the mTOR pathway. Suppression of Anxa11 via genetic knockout or AAV9-mediated knockdown significantly enhanced MYH3⁺ myofiber maturation, accompanied by restored S6 phosphorylation and robust functional muscle recovery in mdx mice. These results establish ANXA11 as a key regulator of muscle regeneration and a potential therapeutic target for DMD.
    DOI:  https://doi.org/10.1038/s41467-026-72824-8
  40. Aging Cell. 2026 May;25(5): e70521
    Advantages of Skeletal Muscle Preservation in Settings of Weight Loss.
    David J Glass.
      There has been a dramatic increase in the use of GLP1R agonists and related "incretins" to treat individuals diagnosed with obesity. However, it has only been recently highlighted that, in addition to the desired loss of adiposity, these medicines also cause a loss of skeletal muscle. It has been debated whether this loss is an issue. Here the consequences of that loss are discussed, and the population most at risk is highlighted. Also, it is pointed out that there are metabolic benefits to maintaining skeletal muscle mass-including a heightened and desirable further loss of adiposity.
    DOI:  https://doi.org/10.1111/acel.70521
  41. J Endocr Soc. 2026 May;10(5): bvag093
    Skeletal muscle mitochondrial bioenergetics in pregnancy: a comparison of in vivo and in vitro outcomes.
    Ericka M Biagioni, Polina M Krassovskaia, Gillian Tiralla, Kelsey H Fisher-Wellman, Chien-Te Lin, Abby D Altazan, R Caitlin Hebert, Sripallavi Yendamuri, Maninder Singh, Owen T Carmichael, P Darrell Neufer, Kristen E Boyle, Leanne M Redman, Nicholas T Broskey.
       Purpose: Exercise-mediated adaptations to mitochondria are well established in nongravid populations; however, the extent to which these adaptations occur during pregnancy remains unclear. Therefore, the objective of this study was to compare skeletal muscle mitochondrial bioenergetics in physically active (n = 10) vs sedentary (n = 9) pregnant women.
    Methods: Groups were matched for age, race, and pregravid body mass index and were studied in the second (T2; weeks 21-25) and third trimester (T3; weeks 31-35). Free-living physical activity was assessed by accelerometry and aerobic fitness by peak oxygen uptake (VO2peak) testing. In vivo mitochondrial capacity was assessed by 31P-magnetic resonance spectroscopy. Primary skeletal muscle myotubes were obtained via muscle biopsy between late T2 and early T3. Mitochondrial in vitro respiration was assessed by high-resolution respirometry, and mitochondrial content was measured by Western blot and enzyme activity.
    Results: Despite a decline in physical activity across gestation, active women maintained a higher VO2peak at T2 (P < .05) and T3 (P < .01) compared with sedentary. There were no differences in phosphocreatine recovery time between groups or timepoints. Myotube mitochondrial respiratory capacity was similar between groups; however, compared with sedentary mothers, active mothers demonstrated increased expression of mitochondrial complexes I, II, and IV proteins (all P < .05). Additionally, myotube mitochondrial efficiency (adenosine triphosphate-to-oxygen consumption ratio) measures were positively correlated with maternal VO2peak at T3 (r = 0.49, P < .05), suggesting a link between fitness and mitochondrial efficiency.
    Conclusion: These findings suggest that late pregnancy may blunt mitochondrial adaptations to aerobic exercise despite a preservation of cardiovascular fitness. Future studies are needed to determine whether increasing activity throughout gestation can enhance mitochondrial respiration.
    Keywords:  exercise; metabolism; mitochondria; myotube; pregnancy
    DOI:  https://doi.org/10.1210/jendso/bvag093
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