bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–08–02
forty-five papers selected by
Anna Vainshtein, Craft Science Inc.
  1. The Impact of Ageing on Skeletal Muscle: Roles of Mitochondrial Dysregulation, Systemic Communication, and Exercise.
  2. Reduced Synaptophysin-like 2 (MG29/SYPL2) Levels Mimic Age-Related Alterations in Skeletal Muscle Calcium Homeostasis and Lipid Signaling.
  3. Timing the strain: skeletal muscle clock as regulator of physical activity.
  4. Putting the brakes on muscle growth: Myostatin as regulator of disuse atrophy.
  5. Mechanisms of Impaired Skeletal Muscle Regeneration and Therapeutic Approaches in Aging and Chronic Disease.
  6. TRF2 couples muscle stem cell identity to regenerative repair.
  7. Chemotherapy induces tissue NAD + loss, and downregulation of NAD + biosynthetic enzyme Nrk2 marks muscle wasting.
  8. Imeglimin Attenuates Skeletal Muscle Atrophy in Mouse Models of Obesity and Ageing.
  9. GDF15 modulates mitochondrial content and differentiation-associated metabolic remodeling in skeletal muscle cells.
  10. YAP1-Driven Pathogenic Fibro-Adipogenic Progenitors Secrete IL-6 and FGF21 to Mediate Muscle-Bone Crosstalk and Promote Bone Loss.
  11. CXCL14 Enhances Myocyte Fusion and Activates the FAK-ERK5 Signaling Pathway in Skeletal Muscle Stem Cells and Myoblasts.
  12. Co-culture of bone marrow-derived macrophages with aged primary myoblasts.
  13. Piezo1 Regulates the Skeletal Muscle Length-Tension Relationship Through Channel-Independent Mechanotransduction.
  14. Myostatin Orchestrates miR-124-Mediated Epigenetic Silencing of ITGB1 to Suppress Skeletal Muscle Growth.
  15. Transcriptomic Signatures of Exercise-Modality Responses in Aged Human Skeletal Muscle.
  16. Fractionated proteomics identifies a protein network mitigating resistance exercise-induced damage in human skeletal muscle.
  17. Non-apoptotic role of caspase enzymes in satellite cells from human skeletal muscle.
  18. Murine pancreatic tumors induce pathological remodeling of muscles critical to chewing and swallowing.
  19. Biomarkers and Early Mechanisms of Sarcopenia: Central Roles of Mitochondrial Dysfunction, Inflammaging, Cellular Senescence, and Neuromuscular Degeneration.
  20. Fiber type specific tibialis anterior muscle atrophy and oxidative capacity reduction is contemporaneous with death of larger lumbar motor neurons in old rats.
  21. Niclosamide reprograms macrophages and improves muscle integrity in Duchenne muscular dystrophy models.
  22. Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking.
  23. Satellite Cell Isolation, Culture, and Infection After Retroviral Preparation.
  24. The titin N2A-MARP signalosome constrains muscle longitudinal hypertrophy in response to stretch.
  25. Chrono-Exercise Medicine: Why Biological Timing Matters for Human Health.
  26. Skeletal muscle reprogramming of metabolic, ribosomal and developmental pathways contributes to Roux-en-Y gastric bypass-induced adaptation in women.
  27. MICAL1 Contributes to Myogenic Differentiation by Modulating Actin Remodeling and YAP1 Nuclear Localization in C2C12 Myoblasts.
  28. eIF6 links histone acetylation with translational control of HDAC in skeletal muscle.
  29. β-Hydroxy-β-methylbutyrate (HMB) Counteracts Atrophy and Restores Circadian Rhythms in Myotubes.
  30. Impact of total creatine and accessible phosphate pool on endurance exercise: implications for muscle fibers bioenergetic specificity and creatine supplementation.
  31. Protocol for transcriptional profiling of fiber type and regeneration markers in mouse Tibialis Anterior muscle.
  32. Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
  33. Exercise rejuvenates the "muscle-heart" crosstalk: skeletal muscle-derived exosomal miRNAs in cardiac aging.
  34. Cytoskeleton-Membrane Uncoupling in Duchenne Muscular Dystrophy: Implications for Newborn Screening and Early Protection.
  35. Nanotechnological Strategies to Promote Skeletal Muscle Regeneration in Aging.
  36. Primary Culture of Myogenic Progenitor Cells Derived from Embryologically Diverse Post-Mortem Human Skeletal Muscles.
  37. Evodiamine alleviates cancer cachexia-induced muscle atrophy by inhibiting STAT3 signaling pathway.
  38. Sustained loss of Pptc7 triggers variable skeletal muscle dysfunction and diminished body mass through dysregulation of BNIP3.
  39. Tissue nanotransfection-mediated induction of neurogenic programs promotes myoprotective responses in denervated skeletal muscle.
  40. Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies.
  41. Identification of Potential Biomarkers Associated with Impaired Fatty Acid Oxidation in Aged Skeletal Muscle Using Bioinformatics and Machine Learning Approaches.
  42. Neuregulin attenuates diaphragm muscle protein degradation via an intricate signaling network.
  43. A Multi-Institution Biobanking Pipeline for Primary Human Satellite Cells and Fibro-Adipogenic Progenitors.
  44. Favorable outcome of engraftment of custom designed RADA16-I based hydrogels functionalized with SDF1 or IL4 mimicking peptides to injured or dystrophic muscles.
  45. Diosgenin Alleviates Age-Related Sarcopenia by Promoting Satellite Cell Proliferation and Myogenic Differentiation via Activation of the SIRT1/PGC-1α Signaling Pathway.
  1. J Cell Physiol. 2026 Aug;241(8): e70212
    The Impact of Ageing on Skeletal Muscle: Roles of Mitochondrial Dysregulation, Systemic Communication, and Exercise.
    Juan Diego Hernández-Camacho, Marielle Saclier.
      Ageing is a major risk factor for degenerative diseases, including sarcopenia, which is characterized by a progressive loss of skeletal muscle mass and function, frailty, and is associated with increased mortality. Skeletal muscle regeneration relies on muscle stem cells and efficient communication with cellular microenvironment. With ageing, skeletal muscle regenerative capacity declines, and sarcopenia results from complex, multitissue dysregulation involving mitochondrial dysfunction, immune ageing, chronic inflammation, senescence, extracellular matrix modification, disruption of neuromuscular junctions and muscle-specific vulnerability. This review summarizes current knowledge contributing to sarcopenia and inefficient muscle repair during ageing from cell-autonomous metabolic dysregulation to age-associated changes in the local and systemic cellular environment. We also explore recent insights into important role of exercise on muscle tissue health. Overall, emerging technologies, including human muscle atlases and spatial transcriptomics, together with exercise-based interventions, will help to identify of novel biomarkers and therapeutic targets to better prevent and treat sarcopenia.
    Keywords:  ageing; cellular communication; exercise; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1002/jcp.70212
  2. Biomolecules. 2026 Jul 04. pii: 988. [Epub ahead of print]16(7):
    Reduced Synaptophysin-like 2 (MG29/SYPL2) Levels Mimic Age-Related Alterations in Skeletal Muscle Calcium Homeostasis and Lipid Signaling.
    Kamal Awad, Jian Huang, Marian N Aziz, Zhiying Wang, Leticia Brotto, Kyung Eun Lee, Jongsoo Kim, Rajendiran Karthikraj, Liubov V Gushchina, Noah Weisleder, Marco Brotto.
      Sarcopenia is characterized by progressive loss of skeletal muscle mass and function and is a major contributor to frailty, disability, and mortality in older adults. Store-operated calcium entry (SOCE) is a crucial regulator of skeletal muscle calcium homeostasis, and impaired SOCE has been linked to age-related muscle weakness. Here, we identify the synaptophysin family member synaptophysin-like protein 2, also known as mitsugumin 29 (MG29; encoded by the human gene SYPL2 and the mouse ortholog Mg29), as a key organizer of triad membrane cholesterol and lipid signaling required for normal SOCE during aging. Using Mg29-/- mice as a model of accelerated sarcopenia, together with RNA interference against Mg29 in adult muscle and primary myotubes, we quantified changes in muscle morphology, contractile function, SOCE activity, and targeted lipidomic profiles. Reduced MG29 expression led to decreased muscle fiber cross-sectional area, reduced specific force, blunted SOCE, and marked alterations in membrane cholesterol content and fatty acid-derived lipid mediators. Cholesterol depletion by methyl-β-cyclodextrin in wild-type myotubes produced SOCE defects similar to those observed in aged wild-type and young Mg29-/- muscles, indicating that MG29-dependent maintenance of membrane cholesterol is required for normal SOCE. Acute Mg29 knockdown also altered myogenic differentiation, the expression of calcium-handling and stress-response genes, and the release and consumption of specific polyunsaturated fatty acid-derived lipid mediators. Together, these findings identify MG29 as a critical regulator of SOCE and lipid signaling in skeletal muscle and suggest that its age-related decline contributes to sarcopenia by disrupting triad membrane organization and excitation-contraction coupling.
    Keywords:  MG29; SOCE; calcium homeostasis; lipid signaling; mitsugumin 29; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/biom16070988
  3. NPJ Metab Health Dis. 2026 Jul 29. pii: 29. [Epub ahead of print]4(1):
    Timing the strain: skeletal muscle clock as regulator of physical activity.
    Ippei Kawano, Gad Asher.
      Skeletal muscle harbors cell-autonomous circadian clock that is implicated in muscle as well as systemic metabolic and physiological functions. Emerging evidence highlights how the muscle clock integrates time-signals to regulate physical activity. Physical activity imposes recurrent and temporally structured physiological and metabolic perturbations. Here we discuss the literature and propose that the muscle clock is well-positioned to execute anticipatory regulation by engaging metabolic programs in advance of predictable muscle demands.
    DOI:  https://doi.org/10.1038/s44324-026-00121-5
  4. Exp Physiol. 2026 Jul 26.
    Putting the brakes on muscle growth: Myostatin as regulator of disuse atrophy.
    Derk H C Nieuwenhuijsen, Moritz Eggelbusch, Rob C I Wüst.
      Skeletal muscle is a highly plastic tissue that rapidly adapts to changes in mechanical loading and metabolic activity. Periods of inactivity, including bed rest, limb immobilization or microgravity, induce a pronounced loss of muscle mass and function. This review examines the mechanistic role of myostatin (growth differentiation factor-8; GDF-8), a member of the transforming growth factor-β superfamily, in mediating inactivity-induced skeletal muscle atrophy. Accumulating evidence from human and rodent studies demonstrates that physical inactivity upregulates myostatin expression and signalling, shifting muscle protein turnover toward net protein degradation. Mechanistically, myostatin binds to the activin type IIB receptor (ActRIIB) and activates Smad2/3 signalling, which suppresses Akt phosphorylation and downstream mTOR activity, resulting in reduced protein translation. Diminished Akt signalling activates FoxO transcription factors, promoting ubiquitin-proteasome-mediated proteolysis. In parallel, myostatin maintains satellite cells in a quiescent state, impairing MyoD-driven activation and limiting myogenesis, thereby reducing regenerative capacity during and after physical inactivity. We provide a narrative mini-review on the time course of gene expression of myostatin during inactivity. Finally, these mechanistic insights have stimulated therapeutic strategies targeting the myostatin-ActRIIB axis, notably bimagrumab, a monoclonal antibody against ActRIIB and inhibitor of downstream myostatin signalling. Evidence from human and rodent studies suggests that myostatin inhibition may represent a promising strategy to counteract skeletal muscle disuse atrophy caused by inactivity. Collectively, the current evidence highlights myostatin as a central molecular integrator of mechanical unloading-induced muscle atrophy.
    Keywords:  myostatin; physical inactivity; protein degradation; protein synthesis; satellite cells; skeletal muscle
    DOI:  https://doi.org/10.1113/EP093732
  5. Pharmaceuticals (Basel). 2026 Jul 15. pii: 1091. [Epub ahead of print]19(7):
    Mechanisms of Impaired Skeletal Muscle Regeneration and Therapeutic Approaches in Aging and Chronic Disease.
    Xia Li, Zihao Zhao, Jiawen Yang, Yijie Zhang, Xinlei Yao, Hualin Sun, Yuntian Shen.
      Skeletal muscle regeneration is essential for recovery after injury and for maintaining physical and metabolic function. This capacity declines with aging and is often impaired in chronic diseases, limiting effective repair. This review summarizes the main mechanisms that regulate muscle repair, with a focus on satellite cell activity and its interaction with inflammatory, metabolic, vascular, and fibrotic signals at the molecular and cellular level. We discuss how these processes are disrupted in aging, Duchenne muscular dystrophy, chronic obstructive pulmonary disease, diabetes, chronic kidney disease, and cancer cachexia, leading to delayed repair, reduced myogenic differentiation, and fibrosis. We also review current and emerging strategies to improve muscle regeneration, including exercise, bioactive molecules, physical stimulation, gene-based approaches, engineered biomaterials, and cell or cell-derived therapies. Across these conditions, chronic inflammation, metabolic dysfunction, and fibrotic remodeling appear to be common barriers to effective regeneration. Multi-target therapeutic approaches may offer advantages over single-pathway interventions, although clinical evidence is still limited; initial preclinical results, however, are promising.
    Keywords:  aging; muscle wasting; satellite cells; signaling pathways; skeletal muscle regeneration; therapeutic strategies
    DOI:  https://doi.org/10.3390/ph19071091
  6. Sci Adv. 2026 Jul 31. 12(31): eaei7316
    TRF2 couples muscle stem cell identity to regenerative repair.
    Ji-Hyung Lee, Kiran Kumar Nakka, Ryan P Calhoun, Sarah Hachmer, Adity Gupta, Eric Arreza, Lynn A Megeney, Patrick Seale, Roger A Greenberg, F Jeffrey Dilworth, Foteini Mourkioti.
      Stem cell-mediated regeneration is essential for tissue integrity. In skeletal muscle, tissue repair largely depends on muscle stem cells (MuSCs), which undergo dynamic cell-state transitions through making precise fate decisions during regeneration. However, the molecular regulators of cell-state conversion in MuSCs remain unclear. Here, we identify a previously unrecognized, noncanonical role for TRF2 in MuSC biology. TRF2 is dynamically regulated upon injury and required to preserve stem cell identity, support reparative myogenesis, and sustain self-renewal. MuSC-specific TRF2 disruption exacerbates muscular dystrophy pathology in mice, recapitulating key features of human disease. Mechanistically, TRF2 associates with regulatory regions enriched for DNA G-quadruplex-forming sequences at lineage-specific genes, sustaining their expression. These findings establish TRF2 as a pivotal regulator of adult stem cell function and tissue-specific regenerative responses.
    DOI:  https://doi.org/10.1126/sciadv.aei7316
  7. bioRxiv. 2026 Jul 13. pii: 2026.07.11.736679. [Epub ahead of print]
    Chemotherapy induces tissue NAD + loss, and downregulation of NAD + biosynthetic enzyme Nrk2 marks muscle wasting.
    Noora Pöllänen, Caleb J Gammon, Fabrizio Pin, Joshua R Huot, Roberta Sartori, Fabio Penna, Juha Hulmi, Andrea Bonetto, Eija Pirinen.
       Background: Aberrant NAD + metabolism has been implicated in the pathogenesis of cancer cachexia, highlighting this pathway as a potential therapeutic target to mitigate skeletal muscle wasting. However, it remains unclear whether chemotherapeutic agents contribute to the onset of cachexia by disrupting NAD + metabolism. Here, we investigated the effects of commonly used chemotherapy regimens on NAD + metabolism in skeletal muscle and liver of healthy mice.
    Methods: Healthy mice were treated with either 2-week regimens of folfiri or cisplatin, or 5-week regimens of folfiri or folfox, with vehicle-treated mice serving as controls. Cachexia-related outcomes were assessed, while skeletal muscle and liver tissues were analyzed for NAD metabolites and markers of NAD + metabolism. Given the consistent downregulation of the NAD + biosynthetic enzyme Nrk2 in cachectic chemotherapy-treated mice, we examined skeletal muscle Nrk2 / NRK2 expression across published murine and human cachexia datasets, and in additional models of muscle wasting and hypertrophy.
    Results: NAD + loss was observed in atrophic muscle following administration of cisplatin (2-week treatment; -14% vs controls, p=0.047) and folfiri (5-week treatment; -18%, p=0.069). In contrast, muscle NAD + levels were preserved in non-atrophic groups (2-week folfiri and 5-week folfox). Muscle Nrk2 was the most responsive NAD + biosynthetic enzyme, showing consistent downregulation across chemotherapy models with ongoing or developing muscle loss: cisplatin (-93%, p<0.001), folfiri (-84%, p<0.001) and folfox (-92%, p<0.001). In the liver, NAD + levels declined after prolonged 5-week folfiri (-20%, p=0.013) and folfox (-15%, p=0.043) treatments. These changes were accompanied by distinct alterations in NAD + biosynthesis pathways, indicating treatment-specific reorganization of hepatic NAD + metabolism. Cross-study analyses revealed early and consistent skeletal muscle Nrk2 downregulation across multiple murine cachexia models and human inactivity studies, whereas cachexia-targeted interventions in rodents and resistance training in humans increased its expression.
    Conclusions: These findings demonstrate that chemotherapy distrupts tissue NAD + metabolism, with skeletal muscle NAD + loss accompanying muscle atrophy and hepatic NAD + levels declining after prolonged treatment. The early and robust responsiveness of muscle Nrk2 expression to changes in muscle mass underscores its potential as a dynamic indicator for predicting treatment-induced changes in muscle mass. Together, these results provide new molecular insight into the metabolic basis of chemotherapy-induced muscle wasting and support further investigation of NAD + -targeted strategies in this context.
    DOI:  https://doi.org/10.64898/2026.07.11.736679
  8. J Cachexia Sarcopenia Muscle. 2026 Aug;17(4): e70354
    Imeglimin Attenuates Skeletal Muscle Atrophy in Mouse Models of Obesity and Ageing.
    Yangli Ye, Diandian Qian, Ikumi Nomura, Naoki Kobayashi, Yukiko Shimizu, Tadashi Okamura, Motoharu Awazawa, Kohjiro Ueki.
       BACKGROUND: Sarcopenia is a major contributor to frailty and mortality in ageing and obesity and is tightly linked to metabolic dysfunction. Imeglimin is a first-in-class oral hypoglycaemic agent targeting mitochondrial function; however, despite the central role of mitochondria in skeletal muscle homeostasis, its effects on skeletal muscle under sarcopenia-relevant conditions remain unclear.
    METHODS: Imeglimin was administered to male C57BL/6 mice with high-fat diet (HFD)-induced obesity for 6 weeks and to naturally aged (18 months old) male mice for 12 weeks. Skeletal muscle fibre morphology and transcriptomic profiles were analysed in fast- and slow-twitch muscles. In parallel, C2C12 myotubes were exposed to palmitate with or without imeglimin, and inflammatory gene expression and reactive oxygen species (ROS) generation were assessed.
    RESULTS: Imeglimin significantly increased the cross-sectional area (CSA) of Type II fibres in the extensor digitorum longus (EDL) muscle of HFD-fed mice (+66%, p < 0.01 vs. controls). Transcriptomic analyses revealed suppression of conserved molecular signatures of muscle atrophy, including activation of immediate-early genes and inflammatory pathways (-62% to -79%, p < 0.05 vs. HFD-fed mice). In palmitate-treated C2C12 myotubes, imeglimin attenuated lipotoxicity-induced inflammatory gene expression (-28% to -72%, p < 0.05 vs. controls) with reduced ROS generation, consistent with its cell-autonomous effect on myocytes. Notably, in naturally aged mice, 12-week imeglimin treatment preserved EDL muscle fibre size (+14%, p < 0.05 vs. controls) without altering systemic glucose tolerance, accompanied by transcriptomic changes overlapping with those observed in the HFD model (-27% to -82%, p < 0.05 vs. aged controls).
    CONCLUSIONS: Imeglimin attenuates skeletal muscle atrophy in obesity and ageing, accompanied by coordinated suppression of stress- and inflammation-associated transcriptional programmes. These findings indicate that pharmacological regulation of mitochondrial stress responses influences skeletal muscle vulnerability under chronic metabolic stress and identify skeletal muscle as a previously underappreciated target of imeglimin action.
    Keywords:  ageing; imeglimin; muscle atrophy; obesity; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.70354
  9. Am J Physiol Endocrinol Metab. 2026 Jul 30.
    GDF15 modulates mitochondrial content and differentiation-associated metabolic remodeling in skeletal muscle cells.
    Bianca Cristine Favero-Santos, Carolina Martins Lazaro, Jung Tae Kim, Dimitrius Santiago P S F Guimarães, Ninon M Flores Barrios, Letícia Basso Gomes, Priscila R Raimundo, Francisco Breno S Teofilo, Michelle Gomes da Silva, Thais Amanda Reia, André Gustavo de Oliveira, Marieli Mariano Gonçalves Dias, André Schwambach Vieira, Ana Carolina Migliorini Figueira, Minho Shong, Leonardo R Silveira.
      Growth differentiation factor 15 (GDF15) is a distant member of the transforming growth factor-β (TGF-β) superfamily increasingly implicated in metabolic regulation. Evidence points to GDF15 as a myokine that regulates systemic energy homeostasis, yet its role in skeletal muscle remains unclear. Here, we investigated whether GDF15 modulates mitochondrial phenotype during myogenesis using mouse C2C12 myoblasts and complementary models. Bioinformatic analyses of GDF15 interaction networks and gene ontology terms revealed enrichment for pathways related to cell differentiation and metabolic regulation. During myogenic differentiation, GDF15 expression increased at both mRNA and protein levels, with cytoplasmic localization and secretion into the extracellular medium, paralleling enhanced mitochondrial content, mitochondrial DNA copy number, and oxygen consumption. Knockdown of GDF15 reduced mitochondrial markers, increased lactate production, and promoted apoptosis, whereas GDF15 overexpression produced opposite effects. Mechanistically, GDF15 overexpression enhanced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) transactivation and peroxisome proliferator-activated receptor (PPAR) response element activity, effects that were abolished by silencing PPARδ or estrogen-related receptor alpha (ERRα), suggesting a PGC1α-dependent mechanism. Transcriptomic profiling further supported enrichment of nuclear receptor-related pathways, including PPAR and cAMP response element-binding protein (CREB1) signaling. Finally, exercise training in male C57BL/6 mice elevated GDF15 levels in soleus muscle and improved aerobic performance. Together, these findings demonstrate that GDF15 promotes an oxidative phenotype in skeletal muscle cells through PGC1α-dependent activation of PPAR and ERRα, identifying GDF15 as an autocrine regulator of mitochondrial metabolism and muscle adaptation.
    Keywords:  Growth differentiation factor 15; Mitochondrial Biogenesis; Myotubes; Skeletal muscle; Transcriptional activation
    DOI:  https://doi.org/10.1152/ajpendo.00438.2025
  10. Adv Sci (Weinh). 2026 Jul 27. e76788
    YAP1-Driven Pathogenic Fibro-Adipogenic Progenitors Secrete IL-6 and FGF21 to Mediate Muscle-Bone Crosstalk and Promote Bone Loss.
    Xiaoyu Cai, Tao Xu, Rui Ma, Weikun Meng, Shutao Gao, Yakefu Abulizi, Alafate Kahaer, Chuanhui Xun, Maierdan Maimaiti, Rui Cao, Weidong Liang, Polati Maimaiti, Qiang Deng, Jun Sheng, Ting Wang, Mingchong Liu, Weibin Sheng.
      Sarcopenia, an age-related degenerative disease of skeletal muscle, is closely associated with osteoporosis and other bone disorders, partly due to dysregulated endocrine function of skeletal muscle. However, the specific cellular sources and molecular mechanisms driving this pathological secretory phenotype remain poorly defined. Using three distinct aging murine models, including sedentary controls, treadmill exercise-trained (TE) mice, and botulinum toxin A (BTXA)-induced muscle atrophy, combined with human cohort analysis, we investigated muscle-bone crosstalk. Fluorescence-activated cell sorting (FACS) was used to isolate fibro-adipogenic progenitors (FAPs). FAP-specific genetic manipulations, including conditional knockout (cKO) mice and adeno-associated virus-mediated knockdown, together with pharmacological inhibition of YAP1, were employed to dissect the mechanistic link between muscle secretory dysfunction and bone metabolism. We demonstrate that pathogenic activation of FAPs serves as a critical cellular source of bone-catabolic myokines during muscle atrophy. In a human cohort of older individuals with sarcopenia, osteoporosis, or osteosarcopenia, FAP numbers were significantly increased and correlated positively with sarcopenia traits and IL-6 and FGF21 levels. In mice, muscle wasting drives FAP accumulation through YAP1-mediated mechanotransduction, characterized by enhanced proliferation, suppressed apoptosis, and acquisition of a profibrotic phenotype concomitant with elevated IL-6 and FGF21 secretion. Using FAP-specific Il6 or Fgf21 knockdown, we showed that genetic ablation of these myokines in FAPs rescued trabecular bone loss despite persistent muscle atrophy. Mechanistically, YAP1 functions as a central regulator of this pathogenic secretory phenotype; FAP-specific Yap1 overexpression may contribute to the myokine dysfunction and bone loss, while FAP-specific Yap1 deletion or pharmacological inhibition diminished bone-loss-related myokine production and ameliorated bone deterioration. FAP-specific Yap1 cKO mice demonstrated that endogenous YAP1 is essential for pathogenic FAP activation and subsequent bone loss. Furthermore, therapeutic targeting of the FAP-YAP1-myokine axis provided robust skeletal protection in ovariectomy-induced postmenopausal osteoporosis. These findings reveal that dysregulated endocrine function of skeletal muscle promotes bone loss through YAP1-driven pathogenic FAPs secreting IL-6 and FGF21, identifying FAP-derived IL-6 and FGF21 as key mediators of muscle-bone crosstalk and establishing the YAP1-FAP-myokine axis as a therapeutic target for preventing bone loss in sarcopenia and osteoporosis.
    Keywords:  FGF21; IL‐6; YAP1; bone metabolism; fibro‐adipogenic progenitors; myokines; sarcopenia; skeletal muscle endocrine function
    DOI:  https://doi.org/10.1002/advs.76788
  11. Int J Stem Cells. 2026 Jul 29.
    CXCL14 Enhances Myocyte Fusion and Activates the FAK-ERK5 Signaling Pathway in Skeletal Muscle Stem Cells and Myoblasts.
    Nurkyz Alymkulova, Younjeong Oh, Jennifer Fransisca, Bagus Sarmito, Yongsung Hwang, Jeong Kyo Yoon.
      Skeletal muscle regeneration is essential for maintaining muscle function throughout life and is regulated by numerous growth factors, cytokines and their associated signaling pathways. In this study, we investigated the role of C-X-C motif chemokine ligand 14 (CXCL14) in myogenic differentiation using skeletal muscle stem cells (MuSC) and the mouse myoblast C2C12 cell line. Notably, CXCL14 significantly enhanced myocyte fusion. To elucidate the underlying regulatory mechanisms, we examined fusion-associated signaling pathways and found that CXCL14 activates the focal adhesion kinase-extracellular regulated protein kinase 5 (FAK-ERK5) signaling pathway. Our findings identify the CXCL14-FAK-ERK5 signaling axis as a positive regulator of myocyte fusion. Furthermore, by establishing fibro-adipogenic progenitors (FAPs) as the primary source of CXCL14 and demonstrating its pro-fusion activity, this study provides new insight into the paracrine regulation from FAPs to MuSCs during muscle regeneration.
    Keywords:  CXCL14; ERK5; FAK; Muscle regeneration; Skeletal muscle satellite cells
    DOI:  https://doi.org/10.15283/ijsc26042
  12. Biol Methods Protoc. 2026 ;11(1): bpag041
    Co-culture of bone marrow-derived macrophages with aged primary myoblasts.
    Ryan Arsenault, Anthony Ziadeh, Alexander Green, Junio Dort.
      Skeletal muscle regeneration depends on the coordinated activity of multiple cell populations within the muscle stem cell niche, most prominently macrophages, which undergo dynamic phenotypic transitions essential to tissue repair. Aging disrupts this process, impairing macrophage signaling and muscle stem cell function in ways that are not yet fully understood. Existing approaches (e.g. conditioned media transfer and indirect transwell co-culture) fail to recapitulate the direct cell-to-cell contact required for continuous, reciprocal regulation throughout the regenerative cascade. Here, we present a protocol for the isolation of bone marrow-derived and tissue-resident macrophages from skeletal muscle, together with a direct co-culture methodology designed to interrogate macrophage-myoblast interactions in an age-relevant context.
    Keywords:  aging; cell isolation; co-culture; macrophages; myoblasts; skeletal muscle
    DOI:  https://doi.org/10.1093/biomethods/bpag041
  13. Biomolecules. 2026 Jun 29. pii: 960. [Epub ahead of print]16(7):
    Piezo1 Regulates the Skeletal Muscle Length-Tension Relationship Through Channel-Independent Mechanotransduction.
    Beatrix Dienes, Áron Gere, Péter Szentesi, László Szabó, Zsigmond Máté Kovács, Zsuzsanna Édua Magyar, Eliza Guti, Tamás Bazsó, Mónika Gönczi, László Csernoch.
      Piezo1 mechanosensitive ion channels convert mechanical stimuli into biochemical signals across diverse tissues, yet their role in the contractile function of adult skeletal muscle remains unclear. Here, we demonstrate that Piezo1 regulates skeletal muscle mechanics through a channel-independent mechanism that tunes the length-tension relationship. We examined the effects of pharmacological modulation using the Piezo1 agonist Yoda1 and antagonist Dooku1 in individual muscle fibers from wild-type mice and from muscles with reduced Piezo1 expression (anti-Piezo1 shRNA) using calcium influx and electrophysiological assays. Ex vivo force measurements were performed on these muscles and compared with the dystrophic mdx model. Piezo1 activation had no effect on force at resting length, whereas its inhibition significantly reduced contractile force at stretched lengths, indicating a selective role in length-dependent force regulation. This effect was independent of extracellular calcium and diminished by Piezo1 knockdown. This reduction was absent in mdx muscle, demonstrating dependence on an intact dystrophin-associated cytoskeleton. These findings identify Piezo1 as a previously unrecognized regulator of muscle mechanical performance that operates independently of ion conduction. Our results uncover a mechanobiological interface between Piezo1 and cytoskeletal integrity, expanding current concepts of muscle mechanoregulation and highlighting Piezo1 as a potential therapeutic target for improving muscle function.
    Keywords:  Piezo1; length-tension relationship; mechanosensation; mechanotransduction; skeletal muscle
    DOI:  https://doi.org/10.3390/biom16070960
  14. Biomolecules. 2026 Jul 10. pii: 1012. [Epub ahead of print]16(7):
    Myostatin Orchestrates miR-124-Mediated Epigenetic Silencing of ITGB1 to Suppress Skeletal Muscle Growth.
    Qi Chen, Xianyu Wen, Mengting Li, Yingfang Niu, Wensai Yu, Yao Yao, Wei Wei, Jie Chen, Lifan Zhang.
      Although myostatin is a well-established inhibitor of myogenesis, its downstream mediators remain poorly characterized. This study identified integrin β1 (ITGB1), an integrin family member, as a novel mediator in myostatin signaling. Our results demonstrated that ITGB1 promoted C2C12 myoblast differentiation. Myostatin treatment significantly downregulated ITGB1 expression and suppressed myogenic differentiation, whereas ITGB1 overexpression reversed the inhibitory effects of myostatin. Bioinformatic prediction and dual-luciferase reporter assay revealed that miR-124 suppressed ITGB1 expression by targeting its 3' untranslated region (UTR). Importantly, miR-124 reduced C2C12 myoblast differentiation by suppressing ITGB1. Furthermore, myostatin treatment markedly enhanced the expression of miR-124 in C2C12 myoblasts, thereby suppressing ITGB1. In vivo, blocking the myostatin/miR-124/ITGB1 pathway significantly promoted skeletal muscle growth in mice. Accordingly, these data revealed that myostatin negatively regulated skeletal muscle growth in mice by promoting the miR-124-mediated epigenetic repression of ITGB1. Our findings provide new insights into the regulation of myogenesis via myostatin signaling.
    Keywords:  ITGB1; miR-124; myostatin; skeletal muscle
    DOI:  https://doi.org/10.3390/biom16071012
  15. Genes (Basel). 2026 Jul 15. pii: 803. [Epub ahead of print]17(7):
    Transcriptomic Signatures of Exercise-Modality Responses in Aged Human Skeletal Muscle.
    Sen Yang, Jian Li.
      Objective: Exercise training helps preserve skeletal muscle health during aging. However, the molecular responses to different exercise modalities in older adults remain unclear. This study reanalyzed human skeletal muscle transcriptomes to compare signatures associated with combined training, resistance training, and high-intensity interval training. Method: We analyzed the older adult subset of GSE97084. This subset included 46 skeletal muscle RNA-seq samples from 23 participants with paired biopsies before and after training. The dataset included seven paired participants in the combined group, eight in the resistance training (RT) group, and eight in the high-intensity interval training (HIIT) group. We performed paired differential expression analysis, GO/KEGG enrichment analysis, GSEA, WGCNA, PPI analysis, regulatory network analysis, and transcriptome-inferred microenvironment signature analysis. Results: The within-modality paired comparisons identified 264 DEGs in the combined group, 297 DEGs in the RT group, and 1098 DEGs in the HIIT group. A total of 62 DEGs were shared across all three modalities. Combined training was mainly linked to extracellular matrix (ECM) organization, vascular regulation, and mitochondrial oxidative metabolism. RT showed prominent collagen, ECM, integrin, focal adhesion, and structural remodeling signatures. HIIT showed the broadest DEG profile under the current threshold. HIIT was characterized by vascular endothelial, angiogenic, ECM/adhesion, oxidative phosphorylation, and immune-related microenvironment signatures. WGCNA and PPI analyses identified candidate hub gene patterns. ECM and basement membrane genes were more prominent after combined training and RT. Vascular endothelial genes were more evident after HIIT. Regulatory network analysis highlighted miR-29 family members as database-supported candidate regulators of ECM-related hub genes. Transcriptome-inferred microenvironment analysis suggested increased endothelial-related signatures across all modalities. This analysis also suggested increased fibroblast/stromal signatures after RT and HIIT and increased macrophage-related signatures after HIIT. Conclusions: Different exercise modalities were associated with partially overlapping but distinct transcriptomic signatures in aged human skeletal muscle. Combined training and RT were mainly related to ECM, stromal, and structural remodeling signatures. HIIT showed broader vascular endothelial and microenvironment-related signatures. These findings should be interpreted as exploratory because this reanalysis used a modest older adult subset from a single public bulk RNA-seq dataset and lacked an independent validation cohort. Larger studies and complementary experimental validation are needed before drawing definitive conclusions about exercise-modality-specific responses in aged human skeletal muscle.
    Keywords:  aging; exercise training; high-intensity interval training; resistance training; skeletal muscle; transcriptomics
    DOI:  https://doi.org/10.3390/genes17070803
  16. Nat Commun. 2026 Jul 28. pii: 7110. [Epub ahead of print]17(1):
    Fractionated proteomics identifies a protein network mitigating resistance exercise-induced damage in human skeletal muscle.
    Maithreyan Kuppusamy, Daniel Jacko, Yamini Gupta, Sandro Sieger, Kirill Schaaf, Martin Matijass, Käthe Bersiner, Jonas Zacher, Sara Bonini, Miguel Cosenza-Contreras, Peter van der Ven, Wilhelm Bloch, Dieter O Fürst, Dominic Winter, Jörg Höhfeld, Pitter F Huesgen, Sebastian Gehlert.
      Resistance exercise (RE) improves strength and muscle mass, with multiple benefits for human health. However, intense RE also induces acute myofibrillar damage. The molecular mechanisms that preserve, mark, degrade, and restore damaged proteins to keep skeletal muscle working under RE are incompletely understood. Based on repeated sampling of human skeletal muscle, we show here that acute, repeated and interrupted RE induce dynamic changes of the protein landscape associated with the sarcomeric cytoskeleton. These changes correlate with changes in phosphorylation indicative of adaptation and deadaptation signaling footprints. Regulation mainly affects the protein network linked to the muscle maintenance protein BAG3, which includes mechanosensory proteins, small heat shock proteins, and a lipid droplet associated protein. All network components exhibit altered phosphorylation and increased cytoskeletal association after damaging RE. Moreover, network components cooperate to recognize strained skeletal muscle structures and mediate their degradation through chaperone-assisted selective autophagy (CASA). Our study thus identifies key regulators of skeletal muscle homeostasis in humans.
    DOI:  https://doi.org/10.1038/s41467-026-75501-y
  17. Biogerontology. 2026 Jul 25. pii: 131. [Epub ahead of print]27(4):
    Non-apoptotic role of caspase enzymes in satellite cells from human skeletal muscle.
    Roberta Di Pietro, Rosa Mancinelli, Gianna Impicciatore, Gianmarco Stati, Stefania Fulle, Silvia Sancilio.
      Satellite cells (SCs) are essential for skeletal muscle regeneration, but their function declines with aging, often associated with increased pro-apoptotic signaling. This study investigated the impact of in vitro serum starvation-as a model of acute microenvironmental and nutrient stress-on the apoptosis and differentiation potential of human SCs from young and aged donors. SCs were isolated from the Vastus Lateralis of young and aged subjects and cultured in serum-free medium for up to 72 h. We assessed apoptosis through Annexin V/PI staining, TUNEL assays, and caspase activity measurements, while transcriptional profiles were analyzed via RT-PCR. Aged SCs displayed a significantly higher susceptibility to stress-induced apoptosis compared to young controls, marked by the early upregulation of CASP9 and FOXO1. While typical nucleosomal DNA fragmentation was absent, we observed the activation of caspase-3 after 72 h of starvation. In aged cells, activated caspase-3 co-localized with myogenin and extranuclear DNA at sites of nuclear remodeling. Notably, treatment with a pan-caspase inhibitor (z-VAD-fmk) prevented the formation of micronuclei and myotubes, further highlighting a non-apoptotic role for these enzymes. Aged SCs also showed a distinct cell cycle profile characterized by an enlarged G0/G1 phase and altered expression of CDK and CCNB1 genes. Our findings suggest that in human aged SCs, caspase enzymes serve a dual role: mediating a heightened stress response and facilitating the nuclear remodeling necessary for myogenic differentiation. These results clarify how intrinsic aging shapes the response of muscle stem cells under severe environmental and metabolic resource deprivation.
    Keywords:  Aging; Apoptosis; Differentiation; Muscle stem cells; Stress conditions
    DOI:  https://doi.org/10.1007/s10522-026-10478-1
  18. Am J Physiol Cell Physiol. 2026 Jul 29.
    Murine pancreatic tumors induce pathological remodeling of muscles critical to chewing and swallowing.
    Sarah M Duckett, Jeremy B Ducharme, Martin M Schonk, Daria Neyroud, Sarah M Judge, Andrew R Judge.
      Cancer cachexia is a debilitating syndrome defined by involuntary weight loss due to loss of muscle mass, with or without loss of fat mass. Cachexia is particularly prevalent in pancreatic cancer, affecting up to 70% of patients at diagnosis, and is associated with reduced physical function, impaired treatment tolerance, and worsened survival. Skeletal muscle, including muscles involved in respiration and locomotion, exhibit extensive pathological remodeling in cachexia, including myofiber atrophy and transcriptional reprogramming. Whether muscles that are critical to chewing and swallowing respond similarly remains unknown. To address this gap, we collected masseter (chewing) and digastric (swallowing) muscles from cachectic mice bearing orthotopic KPC pancreatic tumors (n=8) and cancer-free Sham controls (n=8). Hematoxylin and eosin staining revealed increased mononuclear cell content, centralized nuclei, and expanded interstitial spaces in both muscles of KPC mice. Myofiber cross-sectional area was reduced by 42% in the masseter and 23% in the digastric. RNA sequencing revealed distinct transcriptional responses between these muscles. The masseter muscle showed enrichment of catabolic signaling pathways, including proteolytic and stress-response programs, alongside downregulation of extracellular matrix and growth-related programs. In contrast, the digastric muscle exhibited robust upregulation of immune and inflammatory pathways, including innate and adaptive immune signaling, with minimal overlap between muscles. Collectively, these findings demonstrate that pancreatic cancer drives pathological remodeling and atrophy in muscles central to chewing and swallowing while eliciting distinct, muscle-specific transcriptional responses, changes that could negatively affect food and nutrient intake and thereby contribute to cachexia progression.
    Keywords:  cancer cachexia; digastric; masseter; muscle atrophy; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00390.2026
  19. Int J Mol Sci. 2026 Jul 16. pii: 6332. [Epub ahead of print]27(14):
    Biomarkers and Early Mechanisms of Sarcopenia: Central Roles of Mitochondrial Dysfunction, Inflammaging, Cellular Senescence, and Neuromuscular Degeneration.
    Hechmi Toumi, Ahmad Almhdie-Imjabbar, Nada Ibrahim, Eric Lespessailles.
      Sarcopenia is a progressive age-related skeletal muscle disorder characterized by the loss of muscle mass, strength, and physical performance, leading to frailty, disability, and increased mortality. Although its clinical consequences are well recognized, the underlying biological mechanisms remain incompletely understood, limiting the development of early diagnostic strategies and targeted therapies. Increasing evidence indicates that sarcopenia results from complex interactions among mitochondrial dysfunction, chronic low-grade inflammation (inflammaging), cellular senescence, neuromuscular junction degeneration, and anabolic resistance. The present review critically summarizes the current evidence on the principal circulating and molecular biomarkers associated with these interconnected mechanisms. Mitochondrial dysfunction appears to represent an early upstream event that promotes excessive reactive oxygen species production, defective mitophagy, inflammatory activation, and cellular senescence. Chronic inflammation, mediated primarily through IL-6 and TNF-α, further accelerates muscle catabolism and regenerative failure, whereas senescence-associated pathways impair satellite cell function and muscle repair. Neuromuscular degeneration and anabolic resistance further contribute to progressive muscle atrophy and functional decline. Among the candidate biomarkers, GDF-15, FGF-21, IL-6, TNF-α, CAF22, p16INK4a, p21/CDKN1A, IGF-1, and myostatin appear particularly promising for characterizing the biological heterogeneity of sarcopenia. However, no single biomarker currently demonstrates sufficient diagnostic accuracy for routine clinical use. Instead, integrated multi-biomarker approaches combining mitochondrial, inflammatory, senescence-associated, neuromuscular, and anabolic markers may improve early diagnosis, risk stratification, and personalized therapeutic strategies. Future prospective longitudinal studies are required to validate these biomarkers and facilitate their translation into clinical practice.
    Keywords:  CAF22; GDF-15; IGF-1; SASP; biomarkers; cellular senescence; denervation; inflammaging; mitochondrial dysfunction; myostatin; neuromuscular junction; sarcopenia
    DOI:  https://doi.org/10.3390/ijms27146332
  20. Physiol Rep. 2026 Jul;14(14): e71035
    Fiber type specific tibialis anterior muscle atrophy and oxidative capacity reduction is contemporaneous with death of larger lumbar motor neurons in old rats.
    Kathryn D Rooker, Genesis A Hernandez-Vizcarrondo, Sang Won Cheung, Sanjana Mahadev Bhat, Alyssa D Brown, Gary C Sieck, Matthew J Fogarty.
      Age-associated muscle weakness and atrophy of limb muscles, termed sarcopenia, is a major factor in the morbidity of the elderly. It is becoming increasingly recognized that a substantial contribution to the sarcopenic phenotype arises from motor neuron (MN) death in old age and subsequent muscle denervation. In human and rodent models, mitochondrial dysfunction is a leading culprit in both muscle and MN deterioration with age. In other motor pools within the Fischer 344 (F344) aging rat model, we showed that sarcopenia is selective to type IIx/b muscle fibers. We also showed a loss of larger MNs and denervation of the IIx/b fibers, which together comprise more fatigable fast (type FF) motor units. This selective vulnerability of larger MNs and type IIx/b muscle fibers to sarcopenia is further reflected by reductions in oxidative capacity of IIx/b fibers, as assayed by determining the maximum velocity of the succinate dehydrogenase reaction (SDHmax). Here, we hypothesize similar changes will occur in F344 tibialis anterior (TA) muscle from young (6-months) and old (24-months) groups. We also predict lumbar MN death in young and old F344 rats. We found selective atrophy of type IIx/b fibers in the TA from old rats. In old age, SDHmax was reduced but only in IIx/b TA fibers. These muscle observations were concomitant with the death of larger lumbar MNs in old age. This study indicates the remarkable selectivity of type FF TA motor units to age-associated perturbations and sarcopenia.
    Keywords:  motor unit; oxygen consumption; sarcopenia; succinate dehydrogenase
    DOI:  https://doi.org/10.14814/phy2.71035
  21. Biochem Pharmacol. 2026 Jul 28. pii: S0006-2952(26)00635-0. [Epub ahead of print] 118296
    Niclosamide reprograms macrophages and improves muscle integrity in Duchenne muscular dystrophy models.
    Martina Milani, Ilaria Della Valle, Alessio Torcinaro, Nicoletta Parente, Silvia Tortoriello, Chiara Santucci, Giorgia Sperandio, Alessandro Panci, Gerald Pfister, Alessia Chiavaro, Simona Rossi, Mauro Cozzolino, Lylia Mekzine, Vincent Mouly, Francesca De Santa, Nadia D'Ambrosi, Savina Apolloni.
      Duchenne Muscular Dystrophy (DMD) is a severe X-linked disorder characterized by progressive degeneration of skeletal and cardiac muscles caused by mutations in the DMD gene encoding dystrophin, a protein essential for cytoskeletal integrity and muscle function. A truncated dystrophin leads to increased muscle susceptibility to contraction-induced damage, driving chronic inflammation and fibrosis. Although corticosteroids remain the standard of care, novel therapeutic strategies are urgently needed. Niclosamide, a long-established anthelmintic drug, has recently been repurposed in inflammatory and fibrotic conditions, including neuromuscular diseases. We investigated the effects of niclosamide in vitro using primary macrophages from mdx mice, human DMD myoblasts, and murine C2C12 myoblast cultures, and in vivo in a proof-of-concept study in mdx mice. In primary mdx macrophages, niclosamide reduced inflammation and reactive oxygen species production, while promoting an anti-inflammatory/pro-regenerative phenotype. In parallel, niclosamide enhanced the differentiation of human DMD myoblasts, and conditioned medium from niclosamide-treated macrophages significantly improved C2C12 myoblast differentiation. In treated mdx mice, niclosamide improved muscle resistance and reduced muscle damage, as indicated by decreased plasma creatine kinase levels and lower immunoglobulin infiltration. These effects were accompanied by modulation of key markers involved in muscle proliferation and differentiation, supporting a beneficial role of niclosamide in promoting muscle repair in dystrophic muscle. Overall, these findings indicate that niclosamide promotes an anti-inflammatory and pro-regenerative environment, enhancing myoblast differentiation and limiting muscle degeneration, supporting its potential role as a promising therapeutic candidate for Duchenne muscular dystrophy.
    Keywords:  Duchenne muscular dystrophy; Inflammation; Macrophages; Niclosamide; Skeletal muscles; mdx
    DOI:  https://doi.org/10.1016/j.bcp.2026.118296
  22. Biomolecules. 2026 Jun 30. pii: 966. [Epub ahead of print]16(7):
    Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking.
    Stephen H Holland, Ricardo Carmona-Martinez, Andreas Hentschel, Alexa Derksen, Kaela O'Connor, Daniel O'Neil, Kelly Ho, Stephen D Baird, Andreas Roos, Sally Spendiff, Hanns Lochmüller.
      Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), provides the UDP-N-acetylglucosamine (UDP-GlcNAc) required for protein glycosylation. Biallelic mutations in GFPT1 cause congenital myasthenic syndromes (GFPT1-CMS), yet the molecular mechanisms linking impaired glycosylation to skeletal muscle dysfunction remain incompletely understood. Here, we combine cellular models of inducible Gfpt1 knockdown and a skeletal muscle-specific Gfpt1 knockout mouse (Gfpt1Tm1d/Tm1d) with whole-cell proteomics, immunoblot studies and secretomics to define glycosylation-dependent defects in intracellular trafficking, ER stress signaling and autophagy. Global proteomic profiling of Gfpt1-deficient myoblasts revealed marked downregulation of protein trafficking pathways and impaired secretion of key muscle cargo proteins, including serglycin (Srgn). Loss of GFPT1 reduced both high-molecular-weight glycosylated serglycin and its core protein, accompanied by intracellular retention and decreased secretion. These trafficking defects coincide with robust activation of the unfolded protein response (UPR), evidenced by increased Xbp1 expression and accumulation of spliced Xbp1s across pharmacologic, cellular, and mouse models of GFPT1 deficiency. Converging evidence from proteomics, immunoblotting, and immunofluorescence demonstrated impaired autophagy, including increased LC3-II accumulation, elevated p62/Sqstm1 levels, and enhanced p62-positive puncta in both Gfpt1-deficient C2C12 myoblasts and skeletal muscle. Soluble/insoluble fractionation further confirmed p62 accumulation, indicating defective autophagic flux and buildup of aggregated cargo. Together, these findings identify a glycosylation-dependent failure in protein trafficking that triggers ER stress, UPR activation, and autophagy impairment in Gfpt1-deficient skeletal muscle. This mechanistic cascade provides a unifying explanation for muscle pathology in GFPT1-CMS and suggests that restoring glycosylation or improving proteostasis may represent viable therapeutic approaches.
    Keywords:  GFPT1; autophagy; congenital myasthenic syndrome; glycosylation; trafficking
    DOI:  https://doi.org/10.3390/biom16070966
  23. Bio Protoc. 2026 Jul 20. 16(14): e5751
    Satellite Cell Isolation, Culture, and Infection After Retroviral Preparation.
    Chuanli Zhou, Yue Lu, Elizabeth H Chen.
      Satellite cells are adult skeletal muscle stem cells that play essential roles in muscle regeneration. Understanding their behavior is critical for elucidating the mechanisms of muscle repair and advancing muscle regenerative therapies. This requires efficient methods for genetic manipulation in these cells. Retroviral-mediated gene delivery is commonly used for stable transgene expression in immortalized cell lines. However, existing approaches are not optimized for primary satellite cells, often resulting in variable efficiency and inconsistent outcomes. Here, we describe an optimized protocol for satellite cell isolation and culture, as well as retroviral production and infection of primary satellite cells that achieves high transduction efficiency. The satellite cell isolation procedure enriches for myofiber fragments prior to satellite cell release, thereby reducing contamination by non-myogenic cells and improving cell purity. Another key feature of this protocol is the concentration of retroviral particles and their resuspension in satellite cell growth medium prior to infection, which minimizes satellite cell exposure to packaging cell-conditioned medium. Compared to standard approaches, this protocol improves both infection efficiency and reproducibility. It is readily adaptable to a wide range of downstream applications, including microscopies, biochemical assays, and molecular biology analyses. Key features • Optimization of culture conditions for satellite cells, ensuring high retroviral transduction efficiency. • Efficient production and concentration of retroviral particles for reliable infection of satellite cells. • Compatibility with multiple downstream applications for studying satellite cell biology, including microscopies, biochemical assays, and molecular biology analyses.
    Keywords:  Cell culture; Genetic manipulation; Retroviral transduction; Satellite cell; Skeletal muscle
    DOI:  https://doi.org/10.21769/BioProtoc.5751
  24. Elife. 2026 Jul 30. pii: RP107597. [Epub ahead of print]14
    The titin N2A-MARP signalosome constrains muscle longitudinal hypertrophy in response to stretch.
    Robbert van der Pijl, Jochen Gohlke, Joshua Strom, Eva Peters, Shengyi Shen, Stefan Conijn, Zaynab Hourani, Stephan Lange, Ju Chen, Paul Langlais, Siegfried Labeit, Henk L Granzier, Coen Ottenheijm.
      Titin-based mechanosensing is a key driver of trophic signaling in muscle, yet the downstream pathways linking titin sensing to muscle remodeling remain poorly understood. To investigate these signaling mechanisms, we utilized unilateral diaphragm denervation (UDD), an in vivo model that induces titin-stiffness-dependent hypertrophy via mechanical stretch. Using UDD in rats and mice, we characterized the longitudinal hypertrophic response and distinguished stretch-induced signaling from denervation effects by performing global transcriptomic and proteomic analyses following UDD and bilateral diaphragm denervation (BDD) in rats. Our findings identified upregulation of titin-associated muscle ankyrin repeat proteins (MARPs). Subsequent phosphorylation enrichment mass spectrometry in mouse diaphragm highlighted the involvement of the N2A-element. UDD in MARP knockout (KO) mice resulted in enhanced longitudinal hypertrophy, with Western blot analysis revealing activation of the mTOR pathway. Furthermore, pharmacological inhibition of mTORC1 with rapamycin suppressed longitudinal hypertrophy, demonstrating that mTOR signaling regulates titin-mediated hypertrophic growth in a MARP-dependent manner. These findings establish MARPs as key modulators of titin-based mechanotransduction and highlight mTORC1 as a central regulator of longitudinal muscle hypertrophy.
    Keywords:  MARP; cell biology; hypertrophy; mechanosensing; mouse; muscle; physics of living systems; rat; signaling; titin
    DOI:  https://doi.org/10.7554/eLife.107597
  25. Biomedicines. 2026 Jul 17. pii: 1601. [Epub ahead of print]14(7):
    Chrono-Exercise Medicine: Why Biological Timing Matters for Human Health.
    Stuart J Hesketh.
      Exercise medicine has traditionally focused on defining the optimal mode, intensity, duration, and frequency of physical activity required to improve health and performance. However, increasing evidence suggests that biological timing represents an additional and often overlooked determinant of exercise responsiveness. Circadian rhythms regulate numerous physiological processes relevant to exercise adaptation, including metabolism, mitochondrial function, protein turnover, and skeletal muscle function, while exercise itself is increasingly recognised as a potent non-photic zeitgeber capable of influencing circadian organisation. Rather than advocating a universally optimal time-of-day for exercise, this Perspective proposes "chrono-exercise medicine", as a conceptual framework through which biological timing can be integrated into personalised exercise prescription. It discusses the emerging role of circadian phenotyping, skeletal muscle molecular clocks, and temporal multi-omic approaches for understanding interindividual variability in exercise responses. Together, with key methodological, translational, and clinical challenges that must be addressed to enable biologically informed exercise prescription. It is proposed that the future of precision medicine will depend not only on how exercise is prescribed, but also on when it is prescribed and to whom.
    Keywords:  chronotype; circadian phenotyping; exercise prescription; exercise timing; healthy ageing; skeletal muscle clock; zeitgeber
    DOI:  https://doi.org/10.3390/biomedicines14071601
  26. EBioMedicine. 2026 Jul 31. pii: S2352-3964(26)00294-X. [Epub ahead of print]130 106410
    Skeletal muscle reprogramming of metabolic, ribosomal and developmental pathways contributes to Roux-en-Y gastric bypass-induced adaptation in women.
    Chantal A Pileggi, Dhanuddara Mohottalage, Luke S Kennedy, Majid Nikpay, Lauren M K Hamilton, Martín Roffe, Michel N Kanaan, Amer Jarrar, Nicole Kolozsvari, Dongdong Wang, Miroslava Cuperlovic-Culf, Tommy Alain, Gregory R Steinberg, Ruth McPherson, Robert Dent, Mary-Ellen Harper.
       BACKGROUND: Understanding how skeletal muscle responds to weight loss is crucial for developing targeted strategies to manage obesity and promote sustained improvement in metabolic health. Here, we investigated the molecular mechanisms underlying skeletal muscle reprogramming of gene expression and metabolic activity following Roux-en-Y gastric bypass (RYGB).
    METHODS: Forty-one women were studied before and one year after RYGB surgery. We leveraged multi-omics (DNA methylomics and transcriptomics) and machine learning approaches to complement muscle metabolic analyses and clinical data to identify mechanisms underlying RYGB-induced muscle metabolic reprogramming.
    FINDINGS: RYGB markedly decreased body weight and fat mass and improved metabolic health. Integrative analysis of vastus lateralis muscle identified 8233 genes with differentially methylated regions and 2173 differentially expressed genes post-RYGB surgery, of which 1197 genes were both differentially methylated and differentially expressed. Promoter hypomethylation was associated with the enhanced expression of transcription factors involved in skeletal muscle development and ribosomal subunits. In contrast, expression of genes encoding mitochondrial proteins decreased despite increases in mitochondrial content and enhanced mitochondrial function in skeletal muscle post-RYGB. Pre-operative muscle OXPHOS capacity, and expression of skeletal muscle hypertrophy and differentiation genes MYOC and EHMT2 were associated with weight loss success.
    INTERPRETATION: RYGB improves systemic metabolic health and induces sustained skeletal muscle bioenergetic reprogramming characterised by enhanced expression of genes involved in myogenesis and protein translation, but decreased expression of genes involved in mitochondrial metabolism, which may reflect improved mitochondrial quality and function. These findings advance our understanding of skeletal muscle metabolic responses to weight loss and of individual variability in metabolic phenotypes.
    FUNDING: Canadian Institutes of Health Research (CIHR PJT183651-M-EH, 201709FDN-CEBA-116200-GRS), Diabetes Canada Investigator Award grant OG-3-22-5645-GS (GRS), J. Bruce Duncan Endowed Chair in Metabolic Diseases (GRS), Tier 1 Canada Research Chair in Mitochondrial Bioenergetics and Metabolic Health (M-EH), Tier 1 Canada Research Chair in Metabolic Diseases (GRS).
    Keywords:  Bariatric surgery; DNA methylation; Epigenetics; Metabolism; Mitochondria; Obesity; Ribosome; Transcriptomics; Type 2 diabetes; Weight loss
    DOI:  https://doi.org/10.1016/j.ebiom.2026.106410
  27. Int J Mol Sci. 2026 Jul 22. pii: 6505. [Epub ahead of print]27(14):
    MICAL1 Contributes to Myogenic Differentiation by Modulating Actin Remodeling and YAP1 Nuclear Localization in C2C12 Myoblasts.
    Thanh Huu Phan Ngo, Quoc Kiet Ly, Wan Lee.
      Molecule Interacting with CasL 1 (MICAL1) is a flavoprotein monooxygenase that promotes filamentous actin (F-actin) depolymerization. Transcriptomic studies have linked MICAL1 downregulation to skeletal muscle atrophy and muscular dystrophy, yet its functional contribution to myogenesis remains unexplored. We found that MICAL1 protein increased progressively during myogenic differentiation of C2C12 cells, reaching a maximum on day 5 in parallel with myosin heavy chain (MyHC). siRNA-mediated MICAL1 silencing produced an ~1.7-fold accumulation of F-actin, while total β-actin protein remained unchanged, indicating a shift in the G-/F-actin equilibrium toward polymerization rather than altered actin expression. The accumulated F-actin reduced YAP1 phosphorylation, promoted its nuclear translocation, and increased the expression of the YAP1 target gene CTGF. MICAL1 depletion also enhanced myoblast proliferation: EdU incorporation and cell viability increased, and PCNA, CCNB1, and CCND1 protein expression was upregulated, while the cell cycle distribution shifted toward the G2/M phase, with a reciprocal loss in G0/G1. Concurrently, MICAL1 knockdown suppressed MyoD, Myogenin, and MyHC throughout differentiation and severely impaired myotube formation, with reductions in the fusion index, myotube area, and length. We conclude that MICAL1 is required for the proliferation-to-differentiation switch in myoblasts and that its activity restrains F-actin-driven YAP1 signaling to permit timely myogenic commitment. MICAL1 may therefore represent a candidate for further investigation in muscle-wasting diseases.
    Keywords:  MICAL1; YAP1; actin remodeling; cell cycle; flavoprotein monooxygenase; mechanotransduction; myogenic differentiation
    DOI:  https://doi.org/10.3390/ijms27146505
  28. Mol Cell Biochem. 2026 Jul 29.
    eIF6 links histone acetylation with translational control of HDAC in skeletal muscle.
    Alessandra Scagliola, Annarita Miluzio, Ivan Ferrari, Daniel Brina, Sara Ricciardi, Stefano Biffo.
      Skeletal muscle is crucial for glucose regulation and amino acid storage, significantly influencing overall metabolic balance. Its function is tightly regulated by complex mechanisms, with histone acetylation as a key epigenetic control point. Our previous work identified eIF6 as a key regulator of muscle energy homeostasis and demonstrated its role in modulating histone acetylation in the liver. However, whether similar epigenetic mechanisms underpin eIF6's effects in muscle remains undetermined. To investigate this, we measured H3K9 acetylation levels and HDAC activity both in vivo, using eIF6+/- mice, and in vitro, following eIF6 depletion. Our findings demonstrate that eIF6 downregulation in C2C12 myoblasts drives an increase in histone acetylation, a pattern also evident in heterozygous eIF6 primary satellite cells, both in their undifferentiated state and following differentiation. In vivo, eIF6+/- mice show pronounced histone hyperacetylation, especially in younger animals, which correlates with a specific decrease in class II HDACs, particularly HDAC4 and HDAC5. This trend is further supported by in vitro data and findings from Drosophila eIF6+/- mutants, both of which exhibit decreased HDAC activity. Importantly, the reduction in HDAC4 and HDAC5 activity appears to result from decreased protein levels, driven by eIF6-dependent translational regulation of their mRNAs. All together, these findings establish a link between mRNA translation and histone acetylation in muscle, underpinning translational control as a master regulator of histone acetylation.
    Keywords:  Histone acetylation; Protein synthesis regulation; RiboSeq; Skeletal muscle; eIF6
    DOI:  https://doi.org/10.1007/s11010-026-05637-4
  29. Int J Mol Sci. 2026 Jul 10. pii: 6189. [Epub ahead of print]27(14):
    β-Hydroxy-β-methylbutyrate (HMB) Counteracts Atrophy and Restores Circadian Rhythms in Myotubes.
    Meytal Cohen-Or, Nava Chapnik, Natalie Avital-Cohen, Oren Froy.
      β-hydroxy-β-methylbutyrate (HMB), a bioactive metabolite of leucine, is widely recognized for its anabolic and anti-catabolic effects in skeletal muscle. However, the molecular mechanisms underlying these effects, particularly in relation to circadian regulation, remain incompletely understood. Here, we investigated the impact of HMB on dexamethasone-induced muscle atrophy in C2C12 myotubes, with a focus on anabolic signaling and circadian clock regulation. C2C12 myotubes were treated with HMB or HMB after dexamethasone-induced atrophy. HMB treatment significantly improved cell viability, surface area and fiber diameter by reducing expression of CBL-B, MuRF1 and Atrogin1, key mediators of muscle proteolysis, and increasing myogenin expression compared with atrophic conditions. While HMB did not activate AKT or mTOR, it robustly increased phosphorylation of P70S6K and S6 through a phospholipase D (PLD)-dependent mechanism. HMB restored disrupted circadian clock gene expression induced by dexamethasone, including normalization of expression patterns. HMB also enhanced circadian rhythmic amplitude and advanced phase timing, indicating improved clock robustness. These findings identify circadian regulation as a novel target of HMB action and demonstrate that HMB preserves muscle homeostasis through coordinated modulation of anabolic signaling and intrinsic circadian machinery. This study provides mechanistic insight into how HMB protects against muscle atrophy and highlights circadian regulation as an important contributor to skeletal muscle health.
    Keywords:  HMB; P70S6K; atrophy; circadian; clock; mTOR; metabolism; muscle
    DOI:  https://doi.org/10.3390/ijms27146189
  30. Eur J Appl Physiol. 2026 Jul 27.
    Impact of total creatine and accessible phosphate pool on endurance exercise: implications for muscle fibers bioenergetic specificity and creatine supplementation.
    Bernard Korzeniewski.
       PURPOSE: To determine the effect of the total creatine (tCr) and accessible phosphate (aP) pool (tCaP) on the kinetic variables (maximal muscle oxygen consumption, V̇O2max, transition time of the muscle V̇O2 on-kinetics, t0.63, time to exhaustion, tlim, critical power, CP and work over CP in the power-duration relationship, W') of intense moderate-term endurance exercise.
    METHODS: A dynamic computer model of the skeletal muscle bioenergetic system, involving the each-step-activation mechanism of system stimulation during work transitions and Pi-double-threshold mechanism of muscle fatigue is used.
    RESULTS: A decrease in tCaP significantly increases V̇O2max, tlim and CP, moderately increases W' and shortens t0.63. Significantly enough decrease in tCaP moves the system (at a determined power output) from the severe to heavy (and further to moderate) exercise intensity domain. An increase in tCr alone has an insignificant effect on the system.
    CONCLUSIONS: A decrease in tCaP, especially in aP, increases fatigue resistance of muscle during endurance exercise through attenuation of Pi increase during exercise. An increase in tCr alone has little impact on fatigue resistance. In the sequence of muscle cell types: glycolytic fast-twitch type II skeletal muscle fibers → oxidative slow-twitch type I skeletal muscle fibers → heart muscle fibers the tCaP, especially aP, pool size decreases, which can contribute to the increasing fatigue-resistance in this sequence. While Cr supplementation, elevating tCr, increases the strength and force of acute maximal-intensity very-short-term exercise, it has no significant effect on endurance exercise, at least through the creatine kinase system.
    Keywords:  Accessible phosphate pool; Bioenergetic system; Computer model; Endurance exercise; Fatigue resistance; Heart muscle; Skeletal muscle; Total creatine pool
    DOI:  https://doi.org/10.1007/s00421-026-06365-9
  31. STAR Protoc. 2026 Jul 29. pii: S2666-1667(26)00387-4. [Epub ahead of print]7(3): 104734
    Protocol for transcriptional profiling of fiber type and regeneration markers in mouse Tibialis Anterior muscle.
    Zuleyha Yildirim, Aurélia Noll, Jean-Christophe Amé, Françoise Dantzer.
      Skeletal muscle integrity and function depend on fiber-type composition and regenerative capacity. Evaluating both components in normal and injured tissues provides valuable insights into subtle declines in muscle function and recovery. We describe a protocol for the transcriptional analysis of the major fast-twitch type II myofibers and regeneration-related genes in normal and local-injured mouse Tibialis Anterior skeletal muscles. We describe steps for integrating freeze-induced injury, sample collection, tissue dissociation, RNA extraction, and gene expression analysis by quantitative reverse-transcription PCR (RT-qPCR).
    Keywords:  Cell Biology; Molecular Biology; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.xpro.2026.104734
  32. Sci Adv. 2026 Jul 31. 12(31): eaef0140
    Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
    Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.
      Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.
    DOI:  https://doi.org/10.1126/sciadv.aef0140
  33. Front Cardiovasc Med. 2026 ;13 1863985
    Exercise rejuvenates the "muscle-heart" crosstalk: skeletal muscle-derived exosomal miRNAs in cardiac aging.
    Ruibin Jing, Xue Pang, Xiaona Zhu, Sibao Huang, Xing Gao.
      The deleterious intersection of sarcopenia and age-related heart failure represents a profound global health challenge. While skeletal muscle is increasingly recognized as a major endocrine hub, cannot fully account for the persistent epigenetic changes in the aged myocardium. This points to a key mechanistic gap in the "muscle-heart" inter-organ crosstalk. Following PRISMA guidelines, this systematic review (incorporating 51 rigorous in vivo and clinical studies) maps the bimodal skeletal muscle-derived extracellular vesicle (SkM-EV) and microRNA (miRNA) axis in cardiac aging. We delineate a pathological baseline where aging and sarcopenia trigger the release of senescence-associated extracellular vesicles (EVs). These toxic vesicular payloads actively propagate myocardial inflammaging, structural remodeling, and apoptosis. Conversely, regular exercise rejuvenates by this network via an epigenetic mechanism. Mechanical loading stimulates the systemic release of "exerkines"-exercise-conditioned EVs enriched with potent cardioprotective myomiRs (e.g., miR-1, miR-133a, miR-342-5p). By systematically categorizing these findings from single-molecule downstream targets (anti-apoptosis, anti-fibrosis) to macroscopic poly-pathway synergy (antioxidant and metabolic reprogramming), we construct a comprehensive molecular roadmap of EV-mediated myocardial rejuvenation. Ultimately, deciphering this vesicular signaling network will elucidate the fundamental epigenetic mechanisms underlying "exercise as medicine," and paves the way for novel translational horizons. We propose that targeting the bimodal SkM-EV axis will accelerate the development of EV-based liquid biopsies for sarcopenic cardiomyopathy and pioneer cell-free "exercise mimetics" for frail, exercise-intolerant aging populations.
    Keywords:  cardiac aging; exercise mimetics; exerkines; extracellular vesicles (Exosomes); microRNAs (myomiRs); sarcopenia; skeletal muscle-Heart crosstalk
    DOI:  https://doi.org/10.3389/fcvm.2026.1863985
  34. Cytoskeleton (Hoboken). 2026 Jul 29. e70175
    Cytoskeleton-Membrane Uncoupling in Duchenne Muscular Dystrophy: Implications for Newborn Screening and Early Protection.
    Houda Cohen, Nora Hosny, Brian R Thompson, Joseph M Metzger.
      The cytoskeleton of striated muscle integrates force transmission, mechanotransduction, and sarcolemmal stability through coordinated networks of sarcomeres, costameres, and intermediate filaments. Together, these systems establish mechanical continuity between the contractile apparatus, the sarcolemma, and the extracellular matrix. In Duchenne muscular dystrophy (DMD), loss of dystrophin disrupts cytoskeleton-membrane coupling, resulting in early mechanical instability, abnormal calcium influx, and progressive myofiber injury. Although the genetic defect is present from birth, clinical diagnosis is typically made only after substantial tissue remodeling has already occurred, highlighting a critical gap between disease onset and clinical recognition. Newborn screening now enables detection during a pre-symptomatic phase in which muscle architecture remains relatively preserved, reframing DMD as a disorder initiated by early mechanical instability within a dynamically developing tissue environment. Current therapeutic strategies, including corticosteroids, exon-skipping approaches, gene replacement therapies, and epigenetic modulation, primarily target established pathology rather than early disease mechanisms. In contrast, earlier intervention may offer the opportunity to preserve cytoskeletal integrity and stabilize the sarcolemma, thereby limiting downstream degenerative cascades. Together, these considerations support a revised framework in which cytoskeleton-membrane uncoupling represents an early and potentially actionable event in DMD pathogenesis.
    Keywords:  Duchenne muscular dystrophy; cardiac muscle; costamere; cytoskeleton; dystrophin; membrane instability; muscle regeneration; newborn screening; sarcolemma; skeletal muscle
    DOI:  https://doi.org/10.1002/cm.70175
  35. Int J Mol Sci. 2026 Jul 10. pii: 6167. [Epub ahead of print]27(14):
    Nanotechnological Strategies to Promote Skeletal Muscle Regeneration in Aging.
    Flavia Carton, Manuela Malatesta.
      During aging, skeletal muscle undergoes a decline in mass and strength. This condition, known as sarcopenia, involves many physiological and metabolic impairments, thus representing a healthcare, social, and economic burden. Various pharmacological and non-pharmacological approaches have been explored to counteract sarcopenia; however, no definite treatment has so far been found. The present narrative review summarizes nanotechnology-based strategies designed to promote muscle preservation and functional recovery in aging. Synthetic organic or inorganic nanoconstructs and natural extracellular vesicles have been used as nanocarriers for drug delivery, have been active as intrinsic therapeutic agents, have been employed to build biomimetic nanoscaffolds to sustain muscle regeneration, or have been combined to form hybrid nanosystems with multiple therapeutic functions. These nanotools demonstrated promising results in vitro and in animal models, being able to counteract major factors responsible for sarcopenia, such as oxidative stress, inflammation, mitochondrial dysfunction, increased proteolysis, and impaired stem cell function. However, nanotools have mostly been tested on biological models far from the physiologically aged human muscle. Moreover, limitations still remain to be solved to make these nanotools suitable for regenerative medicine; in particular, the systemic administration requires nanoconstruct functionalization for skeletal muscle targeting, and proper clearance should be ensured to avoid toxicity and immunogenicity related to long-term use.
    Keywords:  aging; exosomes; extracellular vesicles; muscle atrophy; nanoparticles; nanostructured hydrogels; regenerative medicine; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms27146167
  36. Ann Anat. 2026 Jul 29. pii: S0940-9602(26)00569-8. [Epub ahead of print] 153348
    Primary Culture of Myogenic Progenitor Cells Derived from Embryologically Diverse Post-Mortem Human Skeletal Muscles.
    Florian J Jaklin, Liz Keller, Andreas Spittler, Lukas Reissig, Oskar C Aszmann.
       BACKGROUND: Primary human satellite cells (SCs) are essential for skeletal muscle regeneration research, but access to tissue is constrained by the need for invasive biopsies. Post-mortem muscle represents a potential alternative, yet data on establishing expandable myogenic cultures from multiple human muscle groups are sparse.
    OBJECTIVE: To develop a workflow for isolating, expanding, and morphologically assessing myogenic progenitor cells from embryologically distinct muscles of human body donors.
    METHODS: Eighteen biopsies from six muscles (erector spinae, vastus lateralis, brachioradialis, masseter, extraocular muscles, diaphragm) were collected from three body donors (age 79-85 years; post-mortem intervals 13-30hours). Cells were isolated by enzymatic dissociation, enriched by fluorescence-activated cell sorting (CD31⁻/CD45⁻/CD56⁺), and cultured for six weeks. Differentiation was assessed by phase-contrast microscopy.
    RESULTS: Viable cells were isolated from all donors (median viability 10.3%). Cultures were established from one of three donors; the remaining two failed due to insufficient biopsy size (procedural) and low viability despite the shortest post-mortem interval (biological), respectively. In the successful donor, five of six muscles including somitic and non-somitic origins gave rise to adherent cultures forming structures morphologically consistent with myotubes. Culture viability increased from 11.6% to 36.7% over six weeks.
    CONCLUSION: Post-mortem skeletal muscle from anatomical body donors can yield cells capable of in vitro expansion and morphological myogenic differentiation across embryologically diverse muscle groups. Inter-donor variability limits consistent success. This pilot study provides a practical workflow and documents both successful and unsuccessful outcomes to inform future optimization.
    Keywords:  body donors; embryological origin; fluorescence-activated cell sorting; myogenic progenitor cells; post-mortem skeletal muscle; primary cell culture; satellite cells
    DOI:  https://doi.org/10.1016/j.aanat.2026.153348
  37. Eur J Pharmacol. 2026 Jul 27. pii: S0014-2999(26)00661-8. [Epub ahead of print]1031 179179
    Evodiamine alleviates cancer cachexia-induced muscle atrophy by inhibiting STAT3 signaling pathway.
    Changwei Pang, Linlin Zhang, Dong Fang, Yan Qi.
      Cancer-associated cachexia (CAC) is a multifactorial syndrome characterized by progressive skeletal muscle and adipose tissue wasting, for which effective therapies remain limited. Here, we report that evodiamine (EVO), a bioactive alkaloid derived from Evodia rutaecarpa, markedly alleviates bladder cancer-associated cachexia in both in vivo and in vitro models. In T24 tumor-bearing mice, EVO significantly attenuated body weight loss and preserved skeletal muscle and fat mass without affecting primary tumor growth. In C2C12 myotubes exposed to tumor-conditioned medium, EVO dose-dependently prevented myotube atrophy and suppressed the expression of the muscle-specific ubiquitin ligases MuRF1 and Atrogin-1. Transcriptomic analysis identified the JAK-STAT pathway as a key target of EVO. Mechanistically, EVO selectively inhibited STAT3 phosphorylation at Tyr705 in cachectic muscle, accompanied by reduced expression of atrophy-related markers including Trim63 (MuRF1) and Atrogin-1, and restoration of Myosin Heavy Chain expression. Pharmacological reactivation of STAT3 by the agonist Colivelin abrogated the protective effects of EVO, confirming a STAT3-dependent mechanism. Collectively, these findings identify EVO as a potential therapeutic agent for the treatment of cancer-associated cachexia through targeted inhibition of STAT3 signaling.
    Keywords:  Bladder cancer; Cancer-associated cachexia; Evodiamine; STAT3 signaling; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179179
  38. bioRxiv. 2026 Jul 18. pii: 2026.07.13.738264. [Epub ahead of print]
    Sustained loss of Pptc7 triggers variable skeletal muscle dysfunction and diminished body mass through dysregulation of BNIP3.
    Tessa M Lochetto, Thiago N Menezes, Kevin Cho, Srikar Vegesna, Michaela M Morhaus, Jeremie L A Ferey, Merima Forny, Leah P Shriver, Gretchen A Meyer, Gary J Patti, Natalie M Niemi.
      The mitochondrial phosphatase PPTC7 is required to sustain mammalian metabolism, as its global knockout (KO) triggers hypoketotic hypoglycemia and perinatal lethality in mice. However, the extent to which the loss of Pptc7 manifests pathology beyond the perinatal transition is unknown. Furthermore, PPTC7 was recently identified as dual functional, regulating mitochondrial protein phosphorylation and receptor mediated mitophagy, rendering it unclear which function(s) may influence in vivo physiology. Here, we find that sustained, inducible Pptc7 KO decreased lean mass, compromised whole body oxygen consumption, and altered circulating metabolites in adult male mice. We hypothesized that these phenotypes stemmed from skeletal muscle dysfunction and found lower mass and fiber cross-sectional area with shifts in fiber type distribution in select muscles of the hindlimb in Pptc7 KO animals. Loss of PPTC7 increased BNIP3 protein levels and decreased mitochondrial content in skeletal muscle, suggesting elevated mitophagy may drive pathology. Consistently, KO of Bnip3 rescued the lower body weight and lean mass seen in inducible Pptc7 KO adult animals and partially rescued perinatal lethality in global Pptc7 KO mice. These data demonstrate that loss of PPTC7 incites surprisingly variable dysfunction across physiological contexts that at least partially stems from dysregulated BNIP3.
    DOI:  https://doi.org/10.64898/2026.07.13.738264
  39. bioRxiv. 2026 Jul 13. pii: 2026.07.10.737742. [Epub ahead of print]
    Tissue nanotransfection-mediated induction of neurogenic programs promotes myoprotective responses in denervated skeletal muscle.
    Ana I Salazar-Puerta, Sara Kheirkhah, Jordan T Moore, Carlos A Vasquez-Martinez, Carolina Velasquez-Quintero, Hallie Harris, Manami Fukuda, Megumi E Fukuda, Jonathan P Stranan, Fangli Zhao, Kavya Dathathreya, Jared Albert, Prameela Bobbili, Charles D Wendt, Jonathan Winograd, Ian L Valerio, Candice Askwith, Amy M Moore, W David Arnold, Daniel Gallego Perez.
      Peripheral nerve injuries often result in prolonged skeletal muscle denervation, leading to progressive atrophy, fibrosis, neuromuscular instability, and loss of regenerative capacity before axons can reinnervate distal targets. Here, we developed a non-viral strategy using tissue nanotransfection (TNT) to deliver the neurogenic transcription factor cocktail Ascl1 , Brn2 , and Myt1l ( ABM ) directly to denervated skeletal muscle. In vitro , ABM -transfected myoblasts sustained expression of the reprogramming factors, acquired neuron-like morphologies, upregulated neuronal markers including Tuj1, Map2, and Syp, and exhibited electrophysiological properties consistent with membrane excitability. RNA sequencing confirmed broad activation of neurogenic transcriptional programs, with enrichment of pathways associated with neuronal fate commitment, neuron differentiation, axon guidance, synaptogenesis, and developmental signaling. In a mouse model of sciatic nerve transection, TNT enabled localized ABM expression in denervated gastrocnemius muscle. ABM -TNT treatment accelerated resolution of denervation-associated fibrillation potentials and showed trends toward improved twitch and tetanic torque, compound muscle action potential amplitudes, and muscle mass preservation. Transcriptomic profiling of treated muscles 5 weeks after injury revealed distinct gene expression programs enriched for muscle regeneration, neuromuscular organization, trophic support, extracellular matrix remodeling, angiogenesis, myogenesis, and metabolic adaptation. Network analyses further identified activation of neurogenic regulators, neurotrophic signaling, and vascular-support pathways. These findings establish TNT-mediated ABM delivery as a non-viral platform for inducing neurogenic and myoprotective programs in denervated muscle, suggesting a potential strategy to preserve muscle viability during the prolonged interval required for peripheral nerve regeneration.
    DOI:  https://doi.org/10.64898/2026.07.10.737742
  40. Int J Mol Sci. 2026 Jul 16. pii: 6338. [Epub ahead of print]27(14):
    Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies.
    Tyler G B Soule, Mikhaela B Slavin, Carly S Pontifex, Mohamed Z Dabaja, Arthur Melnyk, Antoine Dufour, Nicolas A Dumont, Timothy E Shutt, Gerald Pfeffer.
      There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery-Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target.
    Keywords:  adult onset; autophagy; differentiation; mitophagy; myogenesis; myopathy
    DOI:  https://doi.org/10.3390/ijms27146338
  41. Biomolecules. 2026 Jul 14. pii: 1030. [Epub ahead of print]16(7):
    Identification of Potential Biomarkers Associated with Impaired Fatty Acid Oxidation in Aged Skeletal Muscle Using Bioinformatics and Machine Learning Approaches.
    Haoyang Gao, Fangjie Yang, Jiabin Wu, Minghao Ji, Xiaotong Ma, Danlin Zhu, Linlin Zhao, Weihua Xiao.
      Objective: Impaired fatty acid oxidation (FAO) is considered an important metabolic mechanism underlying skeletal muscle aging and sarcopenia; however, the key regulatory molecules involved in this process remain incompletely defined. This study aimed to identify candidate biomarkers associated with impaired FAO in aged skeletal muscle, characterize their potential biological functions and regulatory features through integrated bioinformatics and machine learning analyses, and preliminarily validate their expression patterns in in vivo and in vitro aging models. Methods: Skeletal muscle aging transcriptomic datasets GSE1428 and GSE674 were obtained from the Gene Expression Omnibus database. FAO-related genes were retrieved from GeneCards. Differentially expressed FAO-related genes (DE-FAOGs) were identified through differential expression analysis and were further analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Random forest, Boruta, and protein-protein interaction (PPI) network analyses were used to screen hub genes, and an artificial neural network (ANN) model was constructed. Single-cell RNA sequencing analysis, gene set enrichment analysis, ceRNA network construction, drug prediction, molecular docking, and molecular dynamics simulation were further performed. Hub gene expression was validated by qRT-PCR in naturally aged mice and D-galactose-induced senescent C2C12 cells. Results: A total of 69 DE-FAOGs were identified and were mainly enriched in mitochondrial function, electron transport chain, and energy metabolism-related pathways. Three hub genes, creatine kinase, mitochondrial 2 (CKMT2), actin alpha cardiac muscle 1 (ACTC1), and forkhead box O3 (FOXO3), were identified by random forest, Boruta, and PPI analyses. Receiver operating characteristic (ROC) analysis showed good discriminatory performance for these genes. The three-gene ANN model achieved area under the curve (AUC) values of 0.992 and 0.964 in the training and validation datasets, respectively. Gene set enrichment analysis (GSEA) suggested that the hub genes were closely associated with mitochondrial energy metabolism, lipid metabolism, and stress regulation. qRT-PCR confirmed decreased Ckmt2 expression and increased Actc1 and Foxo3 expression under aging conditions, consistent with the bioinformatics results. Conclusions: CKMT2, ACTC1, and FOXO3 are potential biomarkers associated with impaired FAO in aged skeletal muscle. The ANN model based on these three genes showed good predictive performance and may provide new insights into the metabolic mechanisms and therapeutic targets of sarcopenia.
    Keywords:  aging; artificial neural network; biomarker; fatty acid oxidation; machine learning; sarcopenia
    DOI:  https://doi.org/10.3390/biom16071030
  42. Front Physiol. 2026 ;17 1846390
    Neuregulin attenuates diaphragm muscle protein degradation via an intricate signaling network.
    Nathan J Hellyer, Heather M Gransee, Gary C Sieck, Carlos B Mantilla.
       Introduction: The nerve-derived growth factor neuregulin (NRG) plays a role in the regulation of skeletal muscle mass through Akt and mTOR signaling transduction pathways that regulate both protein synthesis and degradation. We previously reported that NRG increases muscle protein synthesis (~20%) in a PI3 kinase (PI3K)/Akt-dependent manner. However, the effects of NRG on protein degradation are still poorly understood and are needed to elucidate the role of NRG in the maintenance of skeletal muscle protein balance.
    Methods: Neonatal diaphragm muscle ex vivo preparations were pharmacologically treated with NRG and pharmacological inhibitors of PI3K (LY294002, 50 μM), MEK (PD98059, 50 μM) or mTOR (rapamycin, 100 nM). Tyrosine release from muscle was used as a surrogate measure of protein degradation.
    Results: We report that basal protein degradation in the neonatal rat diaphragm muscle is significantly reduced by NRG treatment (19%). Basal protein degradation was increased following treatment with inhibitors of PI3K, MEK or mTOR, with inhibition of each pathway sufficient to increase basal protein degradation greater than 30%. Importantly, NRG treatment in the presence of each of these inhibitors blunts the increase in protein degradation induced by inhibition of PI3K, MEK or mTOR. NRG effects were significantly blunted by rapamycin (p < 0.05 compared to NRG alone), but not by LY294002 or PD98059.
    Discussion: We suggest that both the PI3K/Akt and MAP kinase pathways are important for NRG effects on protein degradation, but that mTOR may be a critical modulator of these effects and thus of protein balance in skeletal muscle.
    Keywords:  epidermal growth factor; heregulin; muscle atrophy; protein balance; skeletal muscle; trophic factor
    DOI:  https://doi.org/10.3389/fphys.2026.1846390
  43. bioRxiv. 2026 Jul 16. pii: 2026.07.15.738758. [Epub ahead of print]
    A Multi-Institution Biobanking Pipeline for Primary Human Satellite Cells and Fibro-Adipogenic Progenitors.
    Frank S Pittman, Adam Rauff, Grace E Privett, Alis Balayan, Severin Ruoss, Robert E Guldberg, Catherine M Robertson, Adam J Engler, Samuel R Ward, Nick J Willett.
      Satellite Cells (SCs) and Fibro-Adipogenic Progenitors (FAPs) are muscle-resident cell populations crucial for maintaining skeletal muscle homeostasis and coordinating regeneration after injuries. However, primary human SCs and FAPs are difficult to co-isolate, and their broad use in translational research has been limited by a lack of standardized biobanking protocols. Recently, we published a protocol for efficient co-isolation of SCs and FAPs from human skeletal muscle. Here, we extend those efforts to establish a comprehensive pipeline for the cryopreservation, cold-chain transport, and independent-site utilization of human SCs and FAPs. Cells taken through this pipeline maintained lineage-specific markers, including Pax7, MyoD and CD56 for SCs, and PDGFRα and TE7 for FAPs, indicating retention of their pre-biobanking phenotype. Furthermore, SCs demonstrate robust myogenic differentiation capacity, and FAPs demonstrate both fibrogenic and adipogenic differentiation capacity post-transport. Finally, previously biobanked SCs were incorporated into in vitro 3D muscle constructs, demonstrating their utility for human-based New Approach Methodologies (NAMs). This framework for multi-site collaboration facilitates broader access to human primary muscle cells, which will improve the scalability and translatability of human-based NAMs for skeletal muscle research.
    Keywords:  Muscle; biobanking; fibro-adipogenic progenitors (FAP); satellite cells (SCs)
    DOI:  https://doi.org/10.64898/2026.07.15.738758
  44. Sci Rep. 2026 Jul 31. pii: 23714. [Epub ahead of print]16(1):
    Favorable outcome of engraftment of custom designed RADA16-I based hydrogels functionalized with SDF1 or IL4 mimicking peptides to injured or dystrophic muscles.
    Anna Ostaszewska, Zuzanna Michalska, Maria Dzierżyńska, Iwona Grabowska, Małgorzata Zimowska, Martyna Fularczyk, Julia Łukaszewicz, Martyna Panasiuk, Gabriela Piórkowska, Anna Kuropka, Piotr Skorupiński, Marta Charzyńska, Alicja Pluta, Monika Bomba, Władysława Stremińska, Katarzyna Jańczyk-Ilach, Sylwia Rodziewicz-Motowidło, Maria A Ciemerych, Edyta Brzoska, Karolina Archacka.
      Although muscle regeneration capacity is remarkable, under some conditions, such as extensive muscle damage or muscular dystrophies, it may be insufficient, leading to impaired muscle repair and deficits in its structure and function. Among the treatments considered for such conditions are those combining the use of biomaterials, cells, and the addition of selected factors. In the current study we for the first time evaluated potential in vivo effects of hydrogels designed by us, based on RADA16-I hydrogel and modified with IL4 or SDF1 mimicking peptides, as well as verified whether such effects depend on the environment of skeletal muscle, i.e. acutely injured or dystrophic, i.e. chronic one. Since induced pluripotent stem cells (iPSCs) and their derivatives are considered for dysfunctional skeletal muscle therapies, we injected muscles with hydrogels only or with hydrogels and myoblasts derived from human iPSCs (hiPSCs). We found that hydrogels functionalized with SDF1 or IL4 mimicking peptides were successfully engrafted in injured muscles, and that peptide presence had a significant, supporting effect on muscle regeneration manifested by improved treadmill outcome, as well as enhanced expression of myogenesis, angiogenesis, and neurogenesis markers. In the acute injury model, these effects were elevated after co-injection of hydrogels and hiPSC-derived DMD myoblasts. An increased expression of markers of myogenesis, neurogenesis, and angiogenesis was also observed in dystrophic muscles, but only after treatment with an SDF1 functionalized hydrogel. In such an environment, transplanted cells were rapidly removed, so their injection had no influence on observed effects. The muscle environment (acute injury versus dystrophic/chronic) was crucial for the final outcome of hydrogel transplantation, injected alone or with hiPSC-derived myoblasts. This outcome was beneficial but significantly different in both models.
    Keywords:  Hydrogels; Interleukin 4; Skeletal muscle; Stromal derived factor 1; Transplantation
    DOI:  https://doi.org/10.1038/s41598-026-49704-8
  45. Aging Cell. 2026 Aug;25(8): e70651
    Diosgenin Alleviates Age-Related Sarcopenia by Promoting Satellite Cell Proliferation and Myogenic Differentiation via Activation of the SIRT1/PGC-1α Signaling Pathway.
    Xin Zeng, Han Ding, Ziye Li, Qian Wang, Peiyao Guan, Tingting Wang, Jiayun Wang, Yansong Fu, Lizhang Chen, Hong Qin.
      Age-related sarcopenia is characterized by a progressive decline in skeletal muscle mass and function, with satellite cell dysfunction representing a central pathogenic mechanism. Diosgenin, a steroidal saponin derived from plants of the Dioscorea genus, has demonstrated potential anti-aging properties; however, its role in sarcopenia remains unclear. In this study, naturally aged C57BL/6J mice and a D-galactose (D-gal)-induced senescent C2C12 cell model were employed to systematically investigate the effects of diosgenin on muscle function, satellite cell dynamics, and the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling pathway. Diosgenin treatment significantly improved forelimb grip strength and exercise endurance, increased the gastrocnemius muscle index, and enlarged muscle fiber cross-sectional area in aged mice. Mechanistically, diosgenin upregulated the expression of myokines meteorin-like protein (METRNL) and insulin-like growth factor 1 (IGF-1) at both mRNA and protein levels, increased the number of proliferative satellite cells positive for paired box 7 (Pax7) and Ki67, and enhanced the expression of myogenic markers, including myogenic factor 5 (Myf5), Pax7, and myosin heavy chain II (MyHC II). These effects were mediated by direct activation of SIRT1, leading to deacetylation of PGC-1α. Notably, pharmacological inhibition of SIRT1 with EX527 markedly abrogated the diosgenin-induced effects. Molecular docking and cellular thermal shift assays further confirmed the direct interaction between diosgenin and SIRT1. Collectively, these findings demonstrate that diosgenin alleviates age-related sarcopenia by activating the SIRT1/PGC-1α signaling pathway to promote satellite cell proliferation and myogenic differentiation, highlighting its potential as a promising therapeutic candidate for sarcopenia.
    Keywords:  SIRT1/PGC‐1α; aging; diosgenin; sarcopenia; satellite cells
    DOI:  https://doi.org/10.1111/acel.70651
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒02 at 3:21.