bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–03–22
38 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Cellular Senescence in Skeletal Muscle Aging.
  2. ECSIT facilitates exercise-induced amelioration of skeletal muscle atrophy by maintaining mitochondrial quality control in Middle-aged mice.
  3. Exerkine-loaded exosomes in muscle aging: a nexus of exercise, regeneration, and crosstalk.
  4. Molecular and Cellular Mechanisms of Sarcopenia: Integrating Fiber-Type Remodeling, Contractile Protein Dynamics, and Systemic Regulatory Pathways.
  5. Treating age-related loss of muscle mass and function: Where should we be focusing?
  6. Viscoelastic properties of dystrophin-deficient mouse skeletal muscles are resilient to isometric fatiguing exercise.
  7. Skeletal muscle adaptation to muscle activity and hypoxia: Differential structural and metabolic remodelling.
  8. Deficient Cardiolipin Remodelling Alters Muscle Fibre Composition and Neuromuscular Connectivity in Barth Syndrome.
  9. SIK1 drives lipid-induced insulin resistance in skeletal muscle by linking TGFβ1-Smad2/3 activation to PDE4-cAMP dysregulation.
  10. Acute metabolic and molecular responses to sprint interval versus moderate-intensity continuous exercise in healthy young men.
  11. Interaction of Sepsis, Disuse, and Aging on Skeletal Muscle Function and Remodeling in Male and Female Mice.
  12. Phospholipid Glutathione Peroxidase Overexpression Mitigates Cancer Cachexia by Protecting Muscle Mass and Lowering Inflammation.
  13. Impact of C4BPA on Muscle progenitor cell differentiation: insights for Duchenne muscular dystrophy treatment.
  14. Inhibition of N-Terminal Acetyltransferase C Mitigates Endoplasmic Reticulum Stress-Mediated Muscle Atrophy in Cancer Cachexia.
  15. Cisplatin-associated transcriptional changes in ER stress-related genes in skeletal muscle and C2C12 myotubes.
  16. Skeletal muscle metabolism in health and disease: Mechanisms, interventions, and clinical perspectives.
  17. PIEZO1 Channels Modulate the Small Extracellular Vesicle Release in C2C12 Cells.
  18. Blood Biochemical Responses to Acute Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).
  19. Mechanisms underlying age-related changes in the human skeletal muscle bioenergetic system.
  20. Laminin-α2 is required for the maintenance of the myotendinous junction in vivo.
  21. Myofibrillar protein accumulation but reduced protein synthesis in PDCD4-depleted myotubes.
  22. Skeletal muscle reprogramming in peripheral nerve injury: mechanisms, therapeutic roles, and complication management.
  23. Picalm Coordinates Clathrin-Mediated Endocytosis And Actin Remodeling During Myogenesis.
  24. Exercise modality-dependent non-hypertrophic anabolic adaptations in skeletal muscle of rats with type 2 diabetes.
  25. Sepsis, Disuse, Aging, and Sex: A Toxic Quartet Crippling Muscle Recovery.
  26. Isolation of Skeletal Muscle Satellite Cells for In Vitro Myogenesis Studies.
  27. IL-15 Links Muscle-Kidney Crosstalk to Preserving Podocyte Mitochondrial Fusion and Attenuating Diabetic Nephropathy.
  28. Myosin binding protein-C limits strain induced cross-bridge detachment in response to rapid stretch in cardiac and skeletal muscle.
  29. CTLA4-Ig reduces proliferation and inflammatory gene expression in muscle fibroblasts, corresponding to less fibrosis and inflammation in mdx muscular dystrophy.
  30. Mitochondrial Adaptations in Skeletal Muscle Following Incretin-Based Therapies: In Vitro.
  31. Tumor-muscle communication in cancer-associated cachexia (Review).
  32. Transcriptomic insights into aerobic exercise-mediated attenuation of high-fat diet-induced muscle wasting.
  33. Progranulin Regulates Protein Synthesis in Myocytes Through an Ephrin Type A Receptor 2-Dependent Pathway.
  34. Glucagon-Like Peptide-1 Receptor Agonism and Muscle Health: Vascular and Myocellular Effects on Glucose and Protein Metabolism.
  35. Baculovirus-mediated gene transfer enables functional expression of the PIEZO1 ion channel in isolated muscle satellite cells.
  36. American College of Sports Medicine Position Stand. Resistance Training Prescription for Muscle Function, Hypertrophy, and Physical Performance in Healthy Adults: An Overview of Reviews.
  37. Increasing protein intake without increased physical activity is unlikely to improve muscle health: the new U.S. dietary guidelines.
  38. Hot melt extruded Kyungohkgo attenuates skeletal muscle atrophy by downregulating the FOXO3a/MuRF-1/atrogin-1 axis.
  1. Endocrinol Metab (Seoul). 2026 Mar 13.
    Cellular Senescence in Skeletal Muscle Aging.
    Yang Li, Huating Wang.
      Cellular senescence is increasingly recognized as a pivotal mechanism driving skeletal muscle aging and the development of sarcopenia, a condition characterized by the progressive loss of muscle mass, strength, and function. This review synthesizes recent evidence detailing the accumulation of senescent cells in aged skeletal muscle, including muscle stem cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, endothelial cells, and even post-mitotic myofibers. Senescence in these cell types impairs regenerative signaling, disrupts niche homeostasis, and propagates chronic inflammation. Emerging therapeutic strategies, termed senotherapeutics, aim to counteract these effects through senolytics (which eliminate senescent cells) and senomorphics (which modulate the senescence-associated secretory phenotype), as promising interventions to restore muscle function and delay sarcopenia. We will also discuss the remaining challenges and future directions for studying senescence in skeletal muscle.
    Keywords:  Aging; Cellular senescence; Senotherapy; Skeletal muscle
    DOI:  https://doi.org/10.3803/EnM.2025.2816
  2. J Gerontol A Biol Sci Med Sci. 2026 Mar 15. pii: glag065. [Epub ahead of print]
    ECSIT facilitates exercise-induced amelioration of skeletal muscle atrophy by maintaining mitochondrial quality control in Middle-aged mice.
    Jingcheng Fan, Xin Wen, Xuemei Duan, Xue Zhang, Tan Zhang.
      Although exercise is well-established in alleviating aging-associated skeletal muscle atrophy, the underlying mechanism is not fully understood. Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) has been shown to be a crucial adaptor for inflammation and mitochondrial function, however, little is known about the action of ECSIT in skeletal muscle atrophy. Firstly, the young and middle-aged mice were performed with exercise training, skeletal muscle atrophy, mitochondrial quality control, and mitochondrial complex in skeletal muscle were detected. Then, we analyzed the Gene Expression Omnibus (GEO) database and performed in vivo experiments to determine the effect of exercise on ECSIT expression. Furthermore, ECSIT was knockdown in myoblasts to examine its effects on muscle atrophy, mitochondrial quality control and mitochondrial complex. Compared with young mice, middle-aged mice exhibited significant reductions in relative weights of skeletal muscles, grip strength, hang time, and exhaustion exercise performance, while exercise restored these deficits dramatically. Consistently, exercise promoted protein synthesis and inhibited protein degradation in the gastrocnemius of middle-aged mice. Therefore, exercise significantly mitigated skeletal muscle atrophy in middle-aged mice. Concomitantly, exercise alleviated the impaired mitophagy in the gastrocnemius of middle-aged mice. ECSIT expression was elevated in the gastrocnemius of middle-aged mice but was reversed by exercise intervention. Mechanistically, ECSIT knockdown impaired myoblast differentiation, mitochondrial complex and mitochondrial quality control in myoblasts. Collectively, this study reveals, for the first time, that ECSIT is important for myogenesis by maintaining mitochondrial quality control, thereby facilitating exercise-induced amelioration of skeletal muscle atrophy during aging.
    Keywords:  ECSIT; anti-aging; exercise; mitochondria
    DOI:  https://doi.org/10.1093/gerona/glag065
  3. Front Cell Dev Biol. 2026 ;14 1706977
    Exerkine-loaded exosomes in muscle aging: a nexus of exercise, regeneration, and crosstalk.
    Yang Li, Qingzhong Wu, Junmin Wang, Jiahao Ding, Jinpeng He.
      This review examines the critical role of extracellular vesicles, specifically exosomes, as mediators of intercellular and inter-organ communication in the context of skeletal muscle aging and regeneration. Skeletal muscle, traditionally viewed as a simple contractile tissue, is now recognized as a potent endocrine organ that secretes a diverse array of signaling molecules, collectively termed "exerkines," in response to physical activity. We integrate contemporary evidence demonstrating how exercise modulates the release and molecular composition of muscle-derived exosomes, which in turn influence key cellular processes. The report details how exosomal cargo, including non-coding RNAs and proteins, regulates muscle stem cell activation and differentiation, counteracts age-related decline (sarcopenia) by modulating protein homeostasis and inflammation, and facilitates systemic metabolic crosstalk with distant tissues such as adipose tissue. We also critically discuss the burgeoning therapeutic potential of engineered exosomes for musculoskeletal health, while highlighting significant and interconnected challenges in the field, including the lack of standardized methodologies and regulatory frameworks. This review provides a nuanced perspective on the "exerkine" hypothesis, underscoring the potential of exercise-modulated exosomes as both diagnostic biomarkers and novel therapeutic agents for maintaining lifelong muscle health.
    Keywords:  exercise; exerkines; exosomes; muscle aging; regeneration
    DOI:  https://doi.org/10.3389/fcell.2026.1706977
  4. Cell Biochem Funct. 2026 Mar;44(3): e70194
    Molecular and Cellular Mechanisms of Sarcopenia: Integrating Fiber-Type Remodeling, Contractile Protein Dynamics, and Systemic Regulatory Pathways.
    Nikam Rutuja Dilesh, Divyansh Khatri, Richa Shrivastava, Sapana Kushwaha.
      Sarcopenia is an age-associated skeletal muscle disorder characterized by progressive declines in muscle mass, strength, and functional performance. A central feature of sarcopenic remodeling is the preferential loss of fast-twitch (Type II) fibers and alterations in contractile protein composition, leading to reduced force generation and impaired muscle quality. Maintenance of skeletal muscle function depends on the integrity of the contractile apparatus, including myosin heavy chain isoforms, titin, actin, troponin, and associated structural proteins, which undergo quantitative and qualitative changes with aging. Multiple aging-related mechanisms including telomere attrition, epigenetic remodeling, mitochondrial dysfunction, ionic dyshomeostasis, hormonal alterations, and chronic low-grade inflammation converge on fiber-type regulation and sarcomeric stability. These upstream processes impair satellite cell renewal, disrupt excitation-contraction coupling, accelerate proteolysis of contractile proteins, and promote maladaptive fiber-type transitions. Ankyrins and muscle ankyrin repeat proteins (MARPs) further modulate sarcomere organization, mechanotransduction, and adaptive stress signaling. Age-related dysregulation of ankyrin-contractile protein interactions compromises structural stability and regenerative capacity, contributing to muscle weakness and frailty. Viewing sarcopenia through the integrated framework of fiber-type plasticity, contractile protein dynamics, and ankyrin-mediated regulation provides a unifying mechanistic perspective that links systemic aging processes to structural muscle decline. This approach highlights potential biomarkers and therapeutic targets for preserving muscle function in aging populations.
    Keywords:  aging; ankyrins; fiber‐type shifts; muscle fiber; muscular dystrophy; myosin heavy chain kinase; sarcopenia
    DOI:  https://doi.org/10.1002/cbf.70194
  5. J Physiol. 2026 Mar 16.
    Treating age-related loss of muscle mass and function: Where should we be focusing?
    Daniel J Ham, Christopher S Fry, Avnika Ashok Ruparelia, Shyuan T Ngo, Séverine Lamon.
      Increased life expectancy across developed countries has highlighted the personal and societal value of healthy ageing. A well-functioning neuromuscular system is fundamental to quality of life and functional independence. The systemic deterioration of tissue and organ function during ageing is reflected in the diverse cellular and molecular mechanisms implicated in the age-related loss of muscle mass and strength and its extreme form, termed sarcopenia. Proposed contributors include neurodegeneration, impaired proteostasis, deficient regeneration, systemic hormonal decline, chronic inflammation, and dysregulation of muscle-resident cell populations such as muscle stem cells, fibro-adipogenic progenitors and immune cells. Recent efforts have added granularity to our understanding of the molecular response of muscle to ageing and started to unravel the cellular origins of these signals. Advancements in cell-targeting strategies (e.g. AAV capsids and antibody-targeted therapeutics) are opening new avenues for targeted interventions. Nonetheless, this raises the salient question - what should treatments for age-related muscle wasting target? While anabolic and catabolic signalling within muscle fibres has been the primary target of strategies to counteract age-related muscle loss, these efforts may be futile if impairment in other cell types such as muscle stem cells and motor neurons drive the wasting process. Furthermore, individual differences in activity, nutrition, sex, comorbidities and genetics are likely to influence the predominant mechanisms driving age-related muscle wasting. This multifactorial condition may therefore require a multifactorial solution, with scientists focusing on diverse causal mechanisms to identify and develop effective interventions.
    Keywords:  ageing; muscle fibre; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP289838
  6. Physiol Rep. 2026 Mar;14(6): e70841
    Viscoelastic properties of dystrophin-deficient mouse skeletal muscles are resilient to isometric fatiguing exercise.
    Deirdre L Merry, Pavithran Devananthan, Natalia Kabaliuk, Angus Lindsay.
      Exercise prescription for Duchenne muscular dystrophy (DMD) is complicated by the susceptibility of unstable skeletal muscle to contraction-induced damage. Although evidence suggests that isometric contractions can confer molecular and physiological benefits to DMD muscle, their impact on viscoelastic properties has not been assessed in vivo. Given that DMD is characterized by muscular instability due to the absence of dystrophin, we employed "myomechanical profiling"-a custom apparatus compatible with an MCR702e rheometer-to evaluate stiffness, compressibility, and elasticity of the tibialis anterior muscle of male mice following a bout of submaximal isometric fatiguing exercise. Fatigue was standardized to a 50% reduction in strength. Immediately after exercise, both dystrophin-positive (wildtype) and dystrophin-deficient (mdx) muscles exhibited reduced compressibility. Storage and loss moduli, reflecting stiffness and energy dissipation during rotational deformation, increased markedly in fatigued wildtype muscle but remained unchanged in mdx muscle. Conversely, elasticity was unaffected in wildtype muscle but shifted mdx muscle toward a more viscous state. These findings indicate that compressibility, stiffness, and energy storage capacity are not disproportionately affected in dystrophin-deficient muscle compared to wildtype muscle following fatiguing contractions. Thus, metabolically fatiguing, non-lengthening contractions appear not to compromise viscoelastic properties in dystrophin-deficient muscle, supporting their potential clinical use without exacerbating muscle instability.
    Keywords:  Duchenne muscular dystrophy; exercise; muscle stiffness; rheology; viscoelasticity
    DOI:  https://doi.org/10.14814/phy2.70841
  7. J Physiol. 2026 Mar 18.
    Skeletal muscle adaptation to muscle activity and hypoxia: Differential structural and metabolic remodelling.
    David Hauton, Roger W P Kissane, James McCullagh, Stuart Egginton.
      Delivery and utilisation of oxygen are critical determinants of skeletal muscle function, and therefore aerobic performance. Angiogenesis, the process of microvascular bed expansion, may be initiated by several tissue-level stimuli (e.g. of haemodynamic, myogenic or metabolic origin), which are typically present during dynamic exercise. Understanding the relative contribution of these distinct physiological stimuli to skeletal muscle remodelling is needed to develop effective therapeutic strategies to alleviate impaired tissue oxygen supply. In the present study, we uncoupled the predominantly mechanotransductive (i.e. elevated vascular shear stress and cyclical muscle activation) and predominantly chemotransductive (i.e. local tissue hypoxia) stimuli present during exercise by exposing C57b6 mice to either indirect muscle stimulation (10 Hz; ST) or systemic hypoxia (10% oxygen; H), for 7 days, respectively. Furthermore, we combined these stimuli (H+ST) to determine whether the effects were additive. After 7 days of intervention, the tibialis anterior muscle was sampled for histological quantification of microvascular supply and metabolomics analysis. We showed that ST promoted a significant angiogenic response within the muscle whereas H did not. Interestingly, the combined H+ST group had a blunted angiogenic response. Branch-chain amino acid levels were significantly decreased following ST, H and H+ST, consistent with an increased metabolic requirement for ATP, which represents an energy deficit. Proximate metabolites of the glycolytic pathway were significantly reduced following hypoxia, but not stimulation. Together, these observations are commensurate with mechanotransduction triggering structural remodelling of muscle that preserves the metabolome of muscle tissue, whereas chemotransduction inhibits the angiogenic response induced by ST, possibly as a consequence of altered glycolytic metabolism. KEY POINTS: Angiogenesis, the process of microvascular bed expansion, may be initiated by several tissue-level stimuli (e.g. haemodynamic, myogenic or metabolic in origin), which are typically present during dynamic exercise. There has been controversy about the structural (capillary) response of skeletal muscle to altered O2 status, involving decreased supply (hypoxia) or increased demand (activity). Here, we demonstrate that 7 days of activation of skeletal muscle by indirect electrical stimulation led to significant expansion of the capillary bed. However, a similar adaptive structural response was not observed following hypoxia. When combining indirect stimulation and hypoxia, hypoxia appears to blunt structural remodelling. Proximate metabolites of the glycolytic pathway were significantly reduced following hypoxia, but not stimulation. Together, these observations suggest that mechanotransduction (via indirect stimulation) triggers structural remodelling of muscle that preserves the metabolome of muscle tissue, whereas chemotransduction (via hypoxia) inhibits the angiogenic response induced by stimulation, possibly because of altered glycolytic metabolism.
    Keywords:  angiogenesis; exercise; hypoxia; metabolomics
    DOI:  https://doi.org/10.1113/JP290009
  8. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70246
    Deficient Cardiolipin Remodelling Alters Muscle Fibre Composition and Neuromuscular Connectivity in Barth Syndrome.
    Catalina Matias, Paige L Snider, Elizabeth A Sierra Potchanant, Joshua R Huot, Rahul Raghav, Michael T Chin, Simon J Conway, Jeffrey J Brault.
       BACKGROUND: Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by mutations in the TAFAZZIN gene, which disrupts cardiolipin (CL) remodelling and mitochondrial function. While cardiac manifestations of BTHS are well characterized in male patients, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood.
    METHODS: We investigated neuromuscular and mitochondrial alterations in a novel murine model (TazPM) carrying a patient-derived D75H point mutation knocked into the Tafazzin locus. This mutation preserves protein abundance but abolishes enzymatic activity. Skeletal muscle function was assessed via weightlifting and hanging tests. Muscle fibre composition and neuromuscular junction (NMJ) integrity were evaluated using immunofluorescence, western blotting and in vivo electrophysiology. Mitochondrial morphology was examined by transmission electron microscopy, and bioenergetics were quantified using ultra-performance liquid chromatography. Stress signalling was assessed by western blotting.
    RESULTS: Male TazPM mice exhibited seven-fold elevated total monolysocardiolipin and five-fold reduced mature CL levels, confirming deficient transacylase activity. These mice exhibited lower muscle strength and endurance, 32% smaller muscle fibres of all types and a shift towards fast-twitch type 2B fibres, which are more susceptible to fatigue. Electrophysiological analysis revealed a 60% reduction in motor unit number and an increase in average single motor unit potential, indicating motor neuron remodelling. NMJ protein analysis showed decreased MUSK and DOK7 and increased CHRNA1, suggesting impaired NMJ integrity. Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins (NDUFB8, MCU, TMEM65), resting ATP, phosphocreatine and adenine nucleotide ratios were unchanged in both glycolytic and oxidative muscles. However, stress signalling pathways were markedly activated, including phosphorylation of eIF2α, increased CHOP, DELE1, p53 expression and altered Wnt/β-catenin signalling components.
    CONCLUSIONS: Whole-body deficiency of tafazzin enzymatic activity, as occurs in BTHS, is sufficient to result in widespread neuromuscular remodelling, including fibre size/type shifts, motor unit loss, NMJ dysregulation and stress pathway activation, without overt energetic failure at rest. These findings suggest that myopathy in BTHS arises not solely from mitochondrial ATP insufficiency but rather from cumulative structural and signalling adaptations.
    Keywords:  ATP; Barth syndrome; adenine nucleotides; cardiolipin; electrophysiology; integrated stress response; mitochondria; neuromuscular junction; skeletal muscle; tafazzin
    DOI:  https://doi.org/10.1002/jcsm.70246
  9. Mol Cell Endocrinol. 2026 Mar 17. pii: S0303-7207(26)00065-1. [Epub ahead of print] 112788
    SIK1 drives lipid-induced insulin resistance in skeletal muscle by linking TGFβ1-Smad2/3 activation to PDE4-cAMP dysregulation.
    Yanli Liu, Yu Shi, Yu Shen, Hui Qu, Li Qin, Suling Huang, Ying Leng.
      Excessive lipid accumulation in skeletal muscle contributes to insulin resistance. Salt-inducible kinase 1 (SIK1) is known to be involved in myogenic differentiation, yet its role in lipid-induced skeletal muscle insulin resistance remains unclear. Here, we identified the functional role of SIK1 in skeletal muscle insulin resistance under lipid overload and delineated the underlying signaling mechanisms. In C2C12 myotubes, palmitate markedly increased SIK1 expression and phosphorylation at Thr182, and further impaired insulin-stimulated Akt phosphorylation and glucose uptake. These effects were blocked by SIK1 knockdown or pharmacological inhibition of SIK. The palmitate-induced upregulation of SIK1 and the associated insulin signaling defects were abolished by inhibition of TGFβ receptor 1 or knockdown of Smad2/3. Moreover, genetic or pharmacological inhibition of SIK1 restored the palmitate-reduced cAMP levels in myotubes, and inhibition of PDE4 similarly rescued cAMP levels and insulin signaling, mimicking the effects of SIK1 suppression. Consistent with these in vitro findings, SIK1 and TGFβ1-Smad2/3 signaling were upregulated while cAMP levels were decreased in skeletal muscle of diet-induced obese (DIO) mice. Either SIK inhibition or blockade of TGFβ1-Smad2/3 signaling restored the impaired insulin-stimulated Akt phosphorylation in isolated skeletal muscle. Together, we demonstrate that SIK1 is upregulated under lipid overload via TGFβ1-Smad2/3 signaling, thereby triggering PDE4-dependent cAMP degradation and consequent insulin resistance in skeletal muscle. These findings establish SIK1 as a critical mediator of lipid overload-induced insulin signaling defects in skeletal muscle.
    Keywords:  Cyclic adenosine monophosphate; Insulin resistance; Salt-inducible kinase 1; Skeletal muscle; Smad; Transforming growth factor β
    DOI:  https://doi.org/10.1016/j.mce.2026.112788
  10. Am J Physiol Endocrinol Metab. 2026 Mar 14.
    Acute metabolic and molecular responses to sprint interval versus moderate-intensity continuous exercise in healthy young men.
    Enda Murphy, Claire Laurens, Laurie Frances, Marie-Adeline Marquès, François Crampes, Isabelle de Glisezinski, Javier Monedero, Helena Kenny, Noel McCaffrey, Francis M Finucane, Cedric Moro, Donal J O'Gorman.
      Background: Exercise intensity is a key determinant of the physiological responses in skeletal muscle that lead to improvements in human health. Whether a bout of brief supramaximal acute exercise has similar effects on muscle physiology and metabolic health to a longer bout of continuous acute exercise remains unclear. Methods: In a randomized crossover design, 12 healthy young recreationally active men completed single acute bouts of either sprint interval exercise (SIE; seven repeated 30-s maximal sprints at 130% over 35 mins) or moderate-intensity continuous exercise (MICE; cycling at 65% effort over 60 minutes), or a non-exercise control session (CON), on separate days. Acute changes in skeletal muscle insulin sensitivity were measured with a hyperinsulinemic euglycemic clamp. Muscle biopsies were performed to quantify changes in muscle glycogen content and insulin signaling proteins. Results: Despite a six-fold lower total mechanical work in SIE versus MICE, SIE elicited greater and more prolonged increases in whole-body insulin sensitivity, with greater pre-clamp muscle glycogen depletion and glycogen repletion during the clamp. We found reduced glycogen synthase and glycogen synthase kinase-3β phosphorylation, with no differences in Akt Thr308/Ser473 phosphorylation. Conclusions: A single session of sprint interval exercise elicits more pronounced effects on several measures of skeletal muscle insulin sensitivity than a single bout of moderate-intensity continuous exercise, despite substantially lower mechanical work and time commitment. These findings indicate that exercise intensity is a key mediator of acute skeletal muscle metabolic adaptations to exercise and suggest that sprint interval exercise represents a highly time-efficient stimulus for improving skeletal muscle insulin responsiveness.
    Keywords:  exercise intensity; insulin sensitivity; metabolism; moderate intensity exercie; sprint interval exercise
    DOI:  https://doi.org/10.1152/ajpendo.00548.2025
  11. Acta Physiol (Oxf). 2026 Apr;242(4): e70195
    Interaction of Sepsis, Disuse, and Aging on Skeletal Muscle Function and Remodeling in Male and Female Mice.
    Diana C Muller, Franccesco P Boeno, Gisienne Reis, Armina Azam, Malaica Ashley, Yumei Zhou, Feng Yue, Terence E Ryan, Philip A Efron, Orlando Laitano.
       BACKGROUND: Sepsis is associated with skeletal muscle weakness and atrophy, particularly in older and immobilized patients; however, how sepsis interacts with disuse, reloading, aging, and biological sex remains poorly defined.
    METHODS: Young (5 mo) and older (20 mo) male and female C57BL/6J mice underwent cecal ligation and puncture (CLP) or sham surgery followed by hindlimb suspension (HLS) or normal ambulation (NA) for 7 days (Experiment 1). A separate cohort underwent 3 days of reloading after HLS (REL; Experiment 2). Outcomes included survival, body mass, soleus force-frequency, myofiber cross-sectional area (CSA), macrophage infiltration (CD68+), extracellular matrix (ECM), and satellite cells (Pax7+).
    RESULTS: Survival was preserved in septic young mice (> 84%) but reduced in older septic mice (~51%-60% males; ~57% females). Disuse was the primary driver of body mass loss during HLS/REL, with older females exhibiting the greatest decline (day 11: -19.8% ± 6.8% Sham; -17.4% ± 6.5% CLP). Disuse reduced median fiber CSA by ~27%-46% across cohorts (e.g., young males: 1840 ± 189 to 997 ± 345 μm2). In Experiment 1, CD68+ macrophages increased most with combined sepsis and disuse, whereas ECM expansion was observed only in males. Pax7+ satellite cells were markedly reduced in young males with sepsis and disuse and in older mice of both sexes with sepsis. Following REL, older septic males retained force deficits, and septic females remained significantly atrophic.
    CONCLUSION: Muscle disuse amplifies sepsis-induced myopathy in an age- and sex-dependent manner, with incomplete early recovery after reloading.
    Keywords:  aging; inflammation; muscle stem cells; sarcopenia; sex differences
    DOI:  https://doi.org/10.1111/apha.70195
  12. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70255
    Phospholipid Glutathione Peroxidase Overexpression Mitigates Cancer Cachexia by Protecting Muscle Mass and Lowering Inflammation.
    Elizabeth Duggan, Jordan D Fuqua, Bo Hagy, Constantin Georgescu, Benjamin F Miller, Holly Van Remmen, Jacob L Brown.
       BACKGROUND: Cancer cachexia is a muscle wasting syndrome that occurs in ~80% of cancer patients and is the primary cause of death for 22%-30% of cancer patients. The primary challenge associated with cancer cachexia is that effective therapies to treat the associated muscle loss and dysfunction are lacking. Research exploring whether reactive oxygen species (ROS, i.e., superoxide anion and hydrogen peroxide) contributes to cancer cachexia has had mixed results. Lipid peroxidation is an underexplored component of oxidative stress that may contribute to cancer cachexia as markers of lipid peroxidation such as 4-hydroxyneoneal (4-HNE) and MDA (Malondialdehyde) are higher in muscle from tumour-bearing mice when compared to controls. Phospholipid hydroperoxide glutathione peroxidase (GPx4) is an antioxidant enzyme that reduces lipid hydroperoxides. We hypothesized that reducing lipid peroxidation via GPx4 overexpression would mitigate cancer cachexia in tumour-bearing mice.
    METHODS: One million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline was injected into the hind flank of wildtype or GPx4 transgenic (Tg) mice at 6 months of age and the tumour developed for 4 weeks. Muscle mass, contractile function, mitochondrial respiration, RNA-sequencing, inflammation and the oxylipin profile were assessed.
    RESULTS: Muscle mass and myofiber cross-sectional area were reduced ~25% in wildtype tumour-bearing mice compared to control mice but not changed in GPx4 Tg tumour-bearing mice. GPx4 overexpression (~3-fold) did not raise maximal or specific muscle force generation in LLC-tumour-bearing mice. Muscle mitochondrial respiration was reduced in wildtype tumour-bearing mice by ~40% when compared to control mice but not altered in tumour-bearing GPx4 Tg mice. Quadricep RNA seq analysis revealed that expression of inflammatory genes was elevated in wildtype tumour-bearing mice when compared to control mice, and the expression of these genes was reduced in tumour-bearing GPx4 Tg mice compared to wildtype tumour-bearing mice. Next, we found that protein content of IL-6 was ~5-fold greater in muscle from wildtype tumour-bearing mice compared to control mice, and GPx4 overexpression prevented this increase in IL-6. We assessed the muscle oxylipin profile and found that many oxylipins generated by 12/15-Lox were elevated in tumour-bearing mice but not impacted by GPx4 overexpression.
    CONCLUSIONS: Our results show that GPx4 overexpression protected muscle mass and mitochondrial respiration in tumour-bearing mice, possibly by reducing muscle inflammation. Future studies will explore the potential mechanisms for the protective effect of GPx4 in cancer cachexia.
    Keywords:  GPx4; atrophy; lipid peroxidation; lipoxygenase; oxylipin; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.70255
  13. Cell Death Dis. 2026 Mar 18.
    Impact of C4BPA on Muscle progenitor cell differentiation: insights for Duchenne muscular dystrophy treatment.
    Esther Fernández-Simón, Ainoa Tejedera-Villafranca, Xiomara Fernández-Garabay, James Clark, Panogiotis Katsikis, Priyanka Mehra, Andrew Galloway, Alexandra Monceau, Elisa Villalobos, Dan Cox, Javier Ramón-Azcón, Juan M Fernández-Costa, Jordi Díaz-Manera.
      Fibroadipogenic precursor cells (FAPs) are key contributors to the fibrotic and adipogenic remodeling observed in Duchenne muscular dystrophy (DMD), yet their precise role in muscle degeneration remains unclear. In this study, we investigated how FAPs from DMD muscle influence myogenesis by conducting co-culture experiments using healthy myoblasts with FAPs derived from either healthy or DMD biopsies, in both direct and indirect contact conditions. We observed that healthy FAPs enhance myogenic differentiation, increasing myotube area, while DMD FAPs significantly inhibit it. To identify underlying molecular mechanisms, we performed mass spectrometry of the FAP secretome and found that 368 of 760 detected proteins were upregulated in DMD FAPs, including C4b-binding protein alpha chain (C4BPA), which showed a notable increase. In vitro treatment of myoblasts with recombinant C4BPA led to severe impairment of myotube formation, evidenced by reduced myotube area, fewer nuclei per myotube, and smaller myotube size. C4BPA exposure also downregulated myogenic markers and upregulated genes associated with muscle atrophy. These findings were further validated in a 3D engineered muscle model, where C4BPA significantly reduced contractile function. Importantly, silencing C4BPA in DMD-derived cultures partially restored myogenic capacity, improving both the differentiation index and nuclear content per myotube. Together, our data demonstrate that DMD FAPs exert anti-myogenic effects, at least in part, through elevated secretion of C4BPA, which interferes with muscle differentiation and function. This highlights C4BPA as a novel effector of muscle degeneration and a promising therapeutic target for modulating the fibrotic environment in DMD. Targeting specific secreted factors from pathological FAPs may help preserve muscle regeneration and mitigate disease progression in dystrophic muscles.
    DOI:  https://doi.org/10.1038/s41419-026-08588-2
  14. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70249
    Inhibition of N-Terminal Acetyltransferase C Mitigates Endoplasmic Reticulum Stress-Mediated Muscle Atrophy in Cancer Cachexia.
    Yusaku Kaneko, Tomohiro Hino, Shunta Taminishi, Yayoi Matoba, Daisuke Motooka, Atsushi Hoshino, Satoaki Matoba.
       BACKGROUND: Cancer cachexia is a complex syndrome marked by weight loss and muscle wasting, significantly impacting patient quality of life and survival. Mechanistically, it is characterized by suppressed protein synthesis and enhanced muscle catabolism, with the role of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) becoming increasingly evident. This study aimed to explore ER stress-tolerant factors in muscle wasting and evaluate their potential to prevent muscle loss in cancer cachexia.
    METHODS: A genome-wide CRISPR screening was conducted in the context of ER stress-mediated growth inhibition of C2C12 myoblasts. The candidate genes resistant to ER stress were further evaluated in C2C12 myotubes treated with conditioned medium of Lewis lung adenocarcinoma (LLC) cells. Twelve-week-old male mice were administered LLC cells and shRNA against Naa35 via adeno-associated virus. Four weeks later, tibialis anterior (TA) muscles were analysed for muscle mass, grip strength and molecular changes with quantitative polymerase chain reaction, western blotting and histological analysis.
    RESULTS: CRISPR screening identified Naa35, Naa38 and Naa30, all three components of N-terminal acetyltransferase C, as key molecules for resistance to ER stress. The atrophic muscles of mice bearing LLC demonstrated an elevation of UPR, as well as 1.64-fold upregulation of Naa35 protein (p = 0.0072). Among the three branches of the UPR, an ATF6 inhibitor, AEBSF, abolished upregulation of Naa35, Naa38 and Naa30, and an ATF6 activator, AA147, induced Naa35 expression in a dose-dependent manner (p < 0.001). In cells treated with LLC conditioned medium, Naa35 knockdown reduced the amount of cathepsin K (CTSK) protein, which subsequently resulted in the CTSK-mediated proteolysis of insulin receptor substrate 1. In LLC-bearing mice, Naa35 knockdown led to a 65.4% reduction in CTSK protein expression (p < 0.001) and preservation of the phosphorylation levels of protein kinase B (p < 0.0324) and anabolic-related S6 kinase (p < 0.0375). Concurrently, the expression of catabolism-related genes was repressed (MuRF1, p < 0.0015; MAFbx1, p < 0.0265). These alterations were associated with the restoration of TA muscle mass (2.52 ± 0.19 vs. 3.72 ± 0.45 mg/g, p = 0.0004), fibre area (1741 ± 992 vs. 2099 ± 1264 mm2, p < 0.0001), grip strength in all four limbs (0.0328 ± 0.0076 vs. 0.0506 ± 0.0130 N/g, p = 0.0295) and wire mesh hanging time (496 ± 331 vs. 1038 ± 370 s, p = 0.0406).
    CONCLUSIONS: Inhibition of N-terminal acetyltransferase C prevents ER stress-induced muscle wasting via the downregulation of CTSK and subsequent activation of the anabolic pathway. This suggests that N-terminal acetyltransferase C is a potential therapeutic target for combating muscle wasting in cancer cachexia.
    Keywords:  ER stress; N‐terminal acetyltransferase C; cachexia; muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.70249
  15. Toxicol Mech Methods. 2026 Mar 16. 1-9
    Cisplatin-associated transcriptional changes in ER stress-related genes in skeletal muscle and C2C12 myotubes.
    Hayato Nanri, Hiroyasu Sakai, Shinki Soga, Yuya Chigusa, Ryunosuke Ichikawa, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Kumiko Ogawa.
      Cisplatin is a widely used chemotherapeutic drug that causes severe side effects, including skeletal muscle atrophy; however, the cellular responses of skeletal muscle to cisplatin exposure remain incompletely characterized. This study aimed to comparatively characterize cisplatin-associated transcriptional responses in skeletal muscle in vivo and in vitro. Male mice receiving intraperitoneal cisplatin administration (3 mg/kg/day for four consecutive days) exhibited significant quadriceps muscle loss on day 4, accompanied by increased expression of the muscle-specific ubiquitin ligase genes MuRF1 and atrogin-1. Consistently, cisplatin-treated C2C12 myotubes showed elevated mRNA expression of these atrophy-related genes. In addition, multiple endoplasmic reticulum (ER) stress-related genes, including Ddit3/CHOP, Atf4, Hspa5/Bip, and Ppp1r15a/GADD34, were significantly upregulated in both models. Notably, the spliced form of Xbp1 was differentially regulated, being increased in mouse skeletal muscle but decreased in C2C12 myotubes, indicating model-dependent ER stress-associated transcriptional responses. These findings demonstrate that cisplatin exposure is associated with coordinated changes in atrophy- and ER stress-related gene expression in skeletal muscle and highlight important differences between in vivo and in vitro models that should be considered when evaluating cisplatin-associated skeletal muscle toxicity.
    Keywords:  C2C12 myotubes; Cisplatin; ER stress; Xbp1; skeletal muscle
    DOI:  https://doi.org/10.1080/15376516.2026.2639053
  16. iScience. 2026 Mar 20. 29(3): 115024
    Skeletal muscle metabolism in health and disease: Mechanisms, interventions, and clinical perspectives.
    Donghai Lin, Linglin Zhang, Caihua Huang, Wei Shao.
      Skeletal muscle is a vital metabolic organ that regulates systemic energy homeostasis by coordinating glucose uptake, fatty acid oxidation, and amino acid metabolism. Its remarkable capacity for dynamic adaptation, termed metabolic flexibility, underpins physical performance and protects against metabolic diseases such as obesity, type 2 diabetes, and sarcopenia. This review provides an integrative synthesis of the molecular and signaling networks that orchestrate skeletal muscle metabolism, focusing on key regulators including insulin, AMPK, mTOR, and PGC-1α. We also examine how disruptions in these pathways lead to mitochondrial dysfunction, lipid dysregulation, and muscle wasting. We explore the therapeutic landscape across pharmacological, exercise-based, and nutritional interventions, emphasizing mitochondrial-targeted strategies and myokine-mediated communication as emerging modalities for restoring metabolic resilience. Additionally, we emphasize the growing importance of multi-omics technologies and inter-tissue communication in improving mechanistic understanding and advancing precision medicine. This review integrates mechanistic, translational, and clinical perspectives to underscore the importance of a systems-level approach to skeletal muscle metabolism. This approach is essential for developing targeted, multidimensional therapies aimed at enhancing metabolic health and extending healthspan.
    Keywords:  endocrinology; health sciences; medical specialty; medicine
    DOI:  https://doi.org/10.1016/j.isci.2026.115024
  17. J Cell Physiol. 2026 Mar;241(3): e70155
    PIEZO1 Channels Modulate the Small Extracellular Vesicle Release in C2C12 Cells.
    Bernareggi Annalisa, Zhang Wen Ru, Sanchez-Sanchez Laura, Norbedo Alessia, Fracassi Anna, Lucafò Marianna, Sciancalepore Marina, Alberto Griffoni, Russell K William, Taglialatela Giulio, Lorenzon Paola, Limon Agenor.
      PIEZO1 are mechanically-activated ion channels expressed in many cell types. Their pharmacological activation by the selective agonist Yoda1 has been reported to favor skeletal muscle regeneration by controlling the fate of myogenic precursors cells, but the underlying mechanisms remain largely unknown. Hereby, we investigated the possibility that PIEZO1 could control the release of small extracellular vesicles in myogenic C2C12 cells. Myoblasts and differentiated myotubes were treated with the PIEZO1 agonist Yoda1 (5 μM) for 24 hours. Released small extracellular vesicles were isolated by ultracentrifugation methods, and characterized by Western blotting, Nano Tracking and proteomic analysis. Pharmacological activation of PIEZO1 showed cell-type-specific effects: In myoblasts, Yoda1 treatment did not significantly affect the size or release of the small extracellular vesicles and resulted in only minor alterations to their proteomic profile. In myotubes Yoda1 treatment significantly increased small extracellular vesicles release and caused subtsantial alterations to the proteomic cargo. Notably, small extracellular vesicles released from both myoblasts and myotubes under PIEZO1 activation promoted myotube formation, though they did so through different capacities. Interestingly, in myotubes, Yoda1 also increased the expression of PIEZO1 protein of the vesicles suggesting a different biogenesis in undifferentiated and differentiated myogenic cells. Here, we propose PIEZO1 as a key element in controlling the release of small extracellular vesicles in myogenic precursors. Given the critical role of small extracellular vesicles in intercellular communication during muscle regeneration, our findings contribute to a better understanding of the role of PIEZO1 in the physiopathology of skeletal muscle tissue.
    Keywords:  C2C12; PIEZO1; Yoda1; extracellular vesicles; muscle regeneration; myogenic precursors; myotubes
    DOI:  https://doi.org/10.1002/jcp.70155
  18. bioRxiv. 2026 Mar 11. pii: 2026.03.02.704798. [Epub ahead of print]
    Blood Biochemical Responses to Acute Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).
    MoTrPAC Study Group
      Exercise benefits numerous organ systems and tissues, however limited knowledge exists about its underlying molecular pathways. Identifying the exercise-induced biochemical changes that occur in the circulation may provide further insights into how exercise confers systemic health changes. Here, we perform large-scale plasma proteomic, metabolomic, and whole blood transcriptional profiling in sedentary human participants undergoing acute endurance exercise (EE), resistance exercise (RE), or a non-exercise control (CON) in up to 7 timepoints over a 24 hour period. We observe 7066 transcript, 189 protein, and 448 metabolite changes in response to EE or RE compared to CON. Our analyses reveal numerous shared biochemical responses between EE and RE modes, but also differences in immune cell responses, lipid metabolism, and pathways reflective of tissue repair and angiogenesis. Taken together, our findings highlight novel temporal and exercise mode-specific blood-based molecular responses to acute exercise, and provide a new resource for the scientific community.
    Keywords:  acute exercise response; adipose tissue; biomarkers; cross-tissue analysis; endurance exercise; exercise physiology; exerkines; metabolomics; molecular mechanisms; multi-omics; physical activity; precision medicine; proteomics; resistance exercise; skeletal muscle; systems biology; transcriptomics
    DOI:  https://doi.org/10.64898/2026.03.02.704798
  19. Eur J Appl Physiol. 2026 Mar 14.
    Mechanisms underlying age-related changes in the human skeletal muscle bioenergetic system.
    Bernard Korzeniewski, Richie P Goulding.
      
    Keywords:  All-out exercise; Bioenergetics; Computer model; Inorganic phosphate; Isotonic exercise; Muscle fatigue; Old individuals; Power output; Skeletal muscle; pH
    DOI:  https://doi.org/10.1007/s00421-026-06189-7
  20. Matrix Biol. 2026 Mar 17. pii: S0945-053X(26)00024-7. [Epub ahead of print]
    Laminin-α2 is required for the maintenance of the myotendinous junction in vivo.
    Julia Schedel, Shuo Lin, Thomas Bock, Dominik Burri, Markus A Rüegg.
      The myotendinous junction (MTJ) is a critical interface between muscle fibers and tendons, essential for force transmission between muscle and bone. Laminin-α2, a key extracellular matrix (ECM) component, is strongly enriched at this interface. Mutations in the LAMA2 gene cause LAMA2-related muscular dystrophy (LAMA2 MD), an early-onset severe congenital muscular dystrophy. Here, we examined the MTJ in dyW/dyW mice, a mouse model for LAMA2 MD. We find a strong disruption of MTJ morphology, including altered muscle fiber tips, collagen XXII mislocalization, and reduced muscle tendon interface. As MTJ loading is altered in dyW/dyW mice and MTJ maintenance requires loading and unloading, we also examined MTJ structures upon denervation-induced unloading. While muscle fiber tip morphology resembled that of dyW/dyW mice, collagen XXII distribution was not affected and the muscle-tendon interface was preserved. Finally, proteomic profiling via laser capture microdissection and mass spectrometry revealed significant regional and global shifts in MTJ protein composition in dyW/dyW and denervated mice. Across both models, we identified integrin-associated remodeling as a shared response linked to the perturbed muscle fiber tip morphology. These findings demonstrate that laminin-α2 is required for MTJ stability, and that mechanical unloading contributes to the observed phenotype. Importantly, our results suggest that disruptions in MTJ structure and protein composition may contribute to the pathology observed in LAMA2 MD.
    Keywords:  ECM; LAMA2 MD; MTJ; collagen XXII; denervation; dy(W)/dy(W) mice; extracellular matrix; laminin-α2; myotendinous junction
    DOI:  https://doi.org/10.1016/j.matbio.2026.03.003
  21. PLoS One. 2026 ;21(3): e0345305
    Myofibrillar protein accumulation but reduced protein synthesis in PDCD4-depleted myotubes.
    Stephen Mora, Lilia Alihemmat, Logan D Davari, Termeh Ataie, Parsa Nafari Mehranjani, Luke Flewwelling, Arthur J Cheng, Olasunkanmi A J Adegoke.
      Skeletal muscle is critical to whole-body functionality and homeostasis. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient/growth-factor sensitive positive regulator of skeletal muscle mass. Amongst other substrates, mTORC1 phosphorylates the ribosomal protein S6 kinase (S6K1). Activated S6K1 acts through multiple effectors, including programmed cell death 4 (PDCD4), to promote mRNA translation and protein synthesis. Much of what is known about PDCD4 is in non-muscle cells. We previously demonstrated that the effect of PDCD4 differs between myoblasts and myotubes. Here, we showed that PDCD4 depletion in myotubes enhanced myotube diameter (+36%) and accumulation of myofibrillar proteins (+163-237%). These effects occurred along with increased phosphorylation of AKTser473 (+85%) and of the mTORC1 substrate S6K1thr389 (+152%), but protein synthesis was suppressed. There was increased phosphorylation of FoxO3aser253 (+250%) and a corresponding reduction in the expression of the muscle protein ubiquitin ligase MuRF1 (-44%), but there was no significant effect on measures of proteolysis or autophagy. In starved myotubes treated with the proteasome inhibitor MG132, accumulation of ubiquitinated proteins was attenuated in PDCD4-depleted cells. PDCD4 depletion did not augment sarcoplasmic reticulum (SR) Ca2+ release capacity but was associated with reduced ATP and intracellular amino acid levels. Finally, AKT inhibition partially attenuated the effect of PDCD4 depletion on myofibrillar protein abundance. In summary, myofibrillar protein accumulation in PDCD4-depleted myotubes did not lead to improved intracellular Ca2+ handling, likely due to reduced energy level. Our data point to a pivotal role for PDCD4 in regulating myotube size.
    DOI:  https://doi.org/10.1371/journal.pone.0345305
  22. Exp Biol Med (Maywood). 2026 ;251 10835
    Skeletal muscle reprogramming in peripheral nerve injury: mechanisms, therapeutic roles, and complication management.
    Fuqiang Long, Xiaoru Pan, Anxin He, Xinlu Wang, Zairong Wei, Shaoying Gao.
      Peripheral nerve injury (PNI) presents a significant clinical challenge, frequently leading to long-term neuromuscular dysfunction, muscle atrophy, fibrosis, and chronic pain. Traditional repair strategies, including microsurgical reconnection and neurotrophic support, often yield limited functional recovery, especially in cases of delayed or incomplete reinnervation. In this context, skeletal muscle reprogramming-defined as the intentional modulation of cellular fate, function, or metabolic state in muscle-resident cells-has emerged as a promising strategy to enhance regenerative outcomes. This process involves transcriptional, epigenetic, and metabolic interventions targeting myogenic progenitors, fibro-adipogenic progenitors (FAPs), satellite cells (MuSCs), and the broader muscle microenvironment. Recent studies demonstrate that reprogramming strategies can mitigate denervation-induced muscle atrophy, delay fibrotic remodeling, promote neuromuscular junction (NMJ) reconstruction, and even stimulate endogenous nerve regrowth via retrograde signaling. Mechanistic insights have uncovered pivotal roles for signaling pathways such as Wnt/β-catenin, TGF-β, Notch, and HDAC-regulated chromatin dynamics. Furthermore, innovations in small molecule cocktails, CRISPR-based transcriptional reactivation, and metabolic rewiring have expanded the therapeutic toolkit for muscle preservation and regeneration. This review comprehensively examines the molecular mechanisms, therapeutic roles, and translational challenges of skeletal muscle reprogramming in the context of PNI. We explore how muscle-targeted interventions can address complications of denervation, improve the efficacy of nerve repair, and offer a synergistic axis of regeneration when integrated with nerve-centric strategies. Finally, we identify key knowledge gaps and outline future research directions required to translate reprogramming-based therapies into clinical practice.
    Keywords:  complications; peripheral nerve injury; regeneration medicine; skeletal muscle reprogramming; therapeutic strategies
    DOI:  https://doi.org/10.3389/ebm.2026.10835
  23. Mol Metab. 2026 Mar 13. pii: S2212-8778(26)00035-9. [Epub ahead of print] 102351
    Picalm Coordinates Clathrin-Mediated Endocytosis And Actin Remodeling During Myogenesis.
    Jasmin Gaugel, Neele Haacke, Benno Kuropka, Markus Jähnert, Julia Rominger, Wenke Jonas, Thilo Speckmann, Niclas Rausch, Maximilian Kleinert, Cora Weigert, Francisco Garcia-Carrizo, Tim J Schulz, Michael Ebner, Christian Freund, Annette Schürmann, Heike Vogel.
       OBJECTIVE: Skeletal muscle is a central regulator of metabolic health, serving as the primary site of postprandial glucose uptake and playing a critical role in whole-body insulin sensitivity. Despite its importance, the molecular mechanisms governing muscle differentiation (myogenesis) and their modulation by metabolic interventions remain poorly defined. This study identifies the clathrin adaptor protein Picalm (phosphatidylinositol-binding clathrin assembly protein) as a novel regulator of myogenesis and investigates its regulation in response to exercise training and intermittent fasting.
    METHODS: Functional characterization of Picalm was conducted in C2C12 myoblasts and primary myocytes using siRNA-mediated knockdown. Clathrin-mediated endocytosis was performed using dynamin inhibition (Dyngo-4a) and an EGF internalization assay. Surface proteome alterations were analyzed by plasma membrane proteomics, and autophagy dynamics were assessed via immunoblotting and fluorescence imaging. Jasplakinolide was used to rescue differentiation defects by enhancing actin polymerization.
    RESULTS: Picalm-depleted C2C12 myoblasts exhibited impaired differentiation, presumably due to diminished intracellular trafficking dynamics of cell surface proteins. Inhibition of dynamin-dependent endocytosis phenocopied the differentiation defect and further aggravated myogenesis in Picalm-depleted cells, indicating that Picalm-dependent endocytic function is required for efficient differentiation. Consistent with this, Picalm knockdown significantly decreased clathrin-dependent uptake of EGF. Proteome analysis of a plasma membrane-enriched fraction revealed increased abundance of over 100 proteins after Picalm knockdown, particularly candidates involved in vesicular trafficking (Vamp3, Vamp5), actin remodeling (Actn1, Actn4, Rhog, Rock1, Rock2) and cell adhesion (integrin receptors). In line with this, Picalm knockdown resulted in impaired maturation and lysosomal degradation of autophagic vesicles. Remarkably, pharmacological stabilization of actin filaments with Jasplakinolide restored myogenic differentiation in Picalm-deficient cells, highlighting a functional link between actin remodeling and myogenesis.
    CONCLUSION: Picalm regulates skeletal muscle differentiation by supporting clathrin-mediated endocytosis and plasma membrane remodeling, thereby maintaining trafficking-dependent control of actin organization. Its expression is responsive to metabolic cues such as exercise and intermittent fasting. These findings reveal a novel molecular link between nutrient signaling and myogenesis, with implications for metabolic disease and muscle regeneration.
    Keywords:  Picalm; endocytosis; exercise; intermittent fasting; myogenesis; skeletal muscle
    DOI:  https://doi.org/10.1016/j.molmet.2026.102351
  24. Front Physiol. 2026 ;17 1773632
    Exercise modality-dependent non-hypertrophic anabolic adaptations in skeletal muscle of rats with type 2 diabetes.
    Yi-Dan Zhang, Xiang-Xing Zhao, Xia Liu.
       Background: Type 2 diabetes mellitus (T2DM) is frequently accompanied by progressive skeletal muscle loss and dysfunction, commonly referred to as diabetic sarcopenia. Exercise is an established non-pharmacological therapy for T2DM; however, how different exercise modalities differentially influence skeletal muscle protein regulation and anabolic signaling remains unclear. This study compared the effects of aerobic exercise, resistance exercise, and their combination on skeletal muscle protein content and irisin-associated anabolic signaling in a rat model of T2DM.
    Methods: Male rats with diet- and streptozotocin-induced T2DM were assigned to aerobic exercise, resistance exercise, combined aerobic-resistance exercise, or sedentary diabetic control for 8 weeks. Metabolic indices, skeletal muscle mass and morphology, and molecular markers related to muscle protein content, proteolytic signaling, and anabolic pathways were assessed using biochemical, histological, and protein expression analyses.
    Results: Diabetic rats exhibited impaired metabolic profiles, reduced skeletal muscle mass and protein content, and increased muscle fibrosis. All exercise modalities improved selected metabolic indices. Exercise intervention significantly increased skeletal muscle protein content across all exercise groups, despite minimal changes in muscle fiber cross-sectional area and no detectable suppression of canonical ubiquitin-proteasome atrophy markers. Resistance-containing exercise modalities showed greater engagement of integrin α7β1 and PI3K-related signaling components, whereas AKT and mTOR responses were observed across exercise modalities. Exercise increased skeletal muscle irisin expression.
    Conclusion: Exercise intervention in diabetic skeletal muscle induces a non-hypertrophic anabolic adaptation characterized by increased muscle protein content and patterned activation of anabolic signaling pathways. Resistance-containing exercise preferentially engaged select mechanotransduction-related signaling components without conferring global superiority across outcomes.
    Keywords:  aerobic exercise; irisin; muscle fibrosis; muscle protein turnover; resistance exercise; skeletal muscle atrophy; ubiquitin–proteasome system
    DOI:  https://doi.org/10.3389/fphys.2026.1773632
  25. Acta Physiol (Oxf). 2026 Apr;242(4): e70203
    Sepsis, Disuse, Aging, and Sex: A Toxic Quartet Crippling Muscle Recovery.
    Alexandra M Winant, Julien Ochala.
      
    DOI:  https://doi.org/10.1111/apha.70203
  26. J Vis Exp. 2026 Feb 24.
    Isolation of Skeletal Muscle Satellite Cells for In Vitro Myogenesis Studies.
    Lilya Lehka, Carlos Acosta-Gallo, Grzegorz Sumara, Maria Jolanta Rędowicz.
      Skeletal muscle regeneration and growth depend on satellite cells, the muscle tissue's resident stem cells. Currently, these cells serve as the in vitro model that most accurately represents natural myogenic processes. Nonetheless, the isolation of satellite cells is technically challenging as they exist in only small numbers within skeletal muscle and the typically heterogeneous nature of the isolated cell populations. In this study, we describe a standardized method for isolating and enriching primary myoblasts from skeletal muscles of both adult and neonatal mice. The procedure outlines muscle dissection, enzymatic dissociation, sequential filtration, preplating steps to limit non-myogenic cells, and defined culture conditions for establishing satellite cell-derived myoblast cultures. The protocol provides practical guidance on timing, handling, and critical steps for establishing a successful culture. Primary myoblasts generated using this protocol can be used for a variety of downstream applications, including studies of myogenesis, functional analysis, genetic manipulation, live-cell imaging, or drug testing. The cells reliably fuse and mature, making them well-suited for studying myoblast fusion, muscle development, regenerative mechanisms to restore skeletal muscle function, as well as their metabolism.
    DOI:  https://doi.org/10.3791/70277
  27. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70256
    IL-15 Links Muscle-Kidney Crosstalk to Preserving Podocyte Mitochondrial Fusion and Attenuating Diabetic Nephropathy.
    Yin Li, Jialing Rao, Weiyan Lai, Yuxiang Sun, Hongchun Lin, Jun Zhang, Zengchun Ye, Zhaoyong Hu, Hui Peng.
       OBJECTIVES: High glucose induces mitochondrial dysfunction in podocytes, contributing to the development of diabetic nephropathy (DN). There is increasing evidence that muscles play a protective role by secreting myokines into the kidneys. Here, we investigated how skeletal muscle influences podocyte health via muscle-kidney crosstalk.
    METHODS: To increase myokine release, we overexpressed PGC-1α specifically in skeletal muscle (mPGC-1α) and crossed these mice with db/m mice to generate diabetic mPGC-1α:db/db mice. In parallel, db/db mice were treated intraperitoneally with recombinant murine interleukin-15 (IL-15). Mechanistic studies were performed using isolated primary podocytes and cultured podocyte cell lines.
    RESULTS: Compared with db/db controls, mPGC-1α:db/db mice exhibited reduced urinary albumin excretion (p < 0.001), mesangial matrix expansion (p < 0.001), glomerular basement membrane thickening (p < 0.001) and urinary podocin excretion (p < 0.001), along with increased podocyte number (p < 0.001). Podocytes from mPGC-1α:db/db mice showed higher expression of Nephrin and COX IV (p < 0.05) and upregulation of multiple mitochondrial function-related genes, notably OPA1 (p < 0.05). Skeletal muscle from mPGC-1α:db/db mice displayed elevated IL-15 mRNA (p < 0.05) and protein (p < 0.01) levels, accompanied by increased plasma IL-15 concentrations (p < 0.05). IL-15 treatment enhanced podocyte mitochondrial respiration, including basal oxygen consumption rate (OCR, p < 0.05), ATP-coupled respiration (p < 0.05) and maximal respiration (p < 0.05). IL-15 preserved mitochondrial fusion under high-glucose conditions by increasing OPA1 expression (p < 0.05) and promoted OPA1 transcription via histone H3 acetylation at its promoter (p < 0.05).
    CONCLUSIONS: Skeletal muscle-derived IL-15 mediates renal protection by maintaining mitochondrial fusion in podocytes during DN progression. Targeting this pathway may offer a therapeutic strategy to preserve kidney function and slow progression to end-stage renal disease.
    Keywords:  diabetic nephropathy; interleukin‐15; mitochondria; optic atrophy 1; podocyte
    DOI:  https://doi.org/10.1002/jcsm.70256
  28. bioRxiv. 2026 Mar 05. pii: 2026.03.02.709089. [Epub ahead of print]
    Myosin binding protein-C limits strain induced cross-bridge detachment in response to rapid stretch in cardiac and skeletal muscle.
    Nichlas M Engels, Rachel L Sadler, Michel N Kuehn, Devin L Nissen, Dylan Reichert, Marius Meinhold, Wolfgang A Linke, Weikang Ma, Anthony L Hessel, Samantha P Harris.
      Myosin binding protein-C (MyBP-C) consists of a family of regulatory proteins expressed in sarcomeres of cardiac, fast and slow twitch skeletal muscles. The 3 MyBP-C paralogs expressed in each muscle type are encoded by separate genes but maintain a similar structure. Given the overall similarity in structure and localization of each of paralog, it is assumed that MyBP-C expressed in different muscles have similar functional effects. Here we directly tested this assumption by making use of our cut and paste approach to remove and replace N-terminal regions of MyBP-C in sarcomeres of different muscle types. We found that the different MyBP-C paralogs similarly slowed cross-bridge cycling kinetics, increased Ca 2+ sensitivity of tension, and damped force oscillations. However, responses to a rapid stretch in actively contracting fibers, taken as indices of cross-bridge detachment and attachment kinetics, differed in each muscle type and responses depended on the presence or absence of a given paralog of MyBP-C. Altered responses to stretch were most evident for fast MyBP-C where loss of MyBP-C in psoas muscle resulted in transient responses to stretch that resembled those found in cardiomyocytes. Replacement of cardiac MyBP-C with fast MyBP-C in cardiomyocytes led to responses similar to psoas muscle. In separate X-ray diffraction experiments we also found that loss of MyBP-C in Ca 2+- activated psoas muscle increased lattice disorder, reduced the ordering of myosin heads, and decreased thin filament length. Taken together, these results indicate that the different MyBP-C paralogs exert both common and unique effects on myosin cross-bridge kinetics.
    Significance Statement: MyBP-C is a family of regulatory proteins found in muscle sarcomeres, where they regulate contraction and relaxation. Mutations in all MyBP-C paralogs cause disease in skeletal and cardiac muscles. We used a powerful "cut and paste" strategy to selectively remove MyBP-C from slow-twitch, fast-twitch, and cardiac muscle to show that each MyBP-C effects cross-bridge behavior similarly, though to varying degrees. Each MyBP-C had a notable effect on transient responses to rapid stretch, where MyBP-C was found to limit strain-induced cross-bridge detachment, especially in fast-twitch muscles. Strain-induced cross-bridge detachment is critical for rapid filling of the left ventricle in diastole and for sustained contraction in skeletal muscle. MyBP-C paralogs appear adapted to meet the mechanical demands of each muscle type.
    DOI:  https://doi.org/10.64898/2026.03.02.709089
  29. Am J Physiol Cell Physiol. 2026 Mar 19.
    CTLA4-Ig reduces proliferation and inflammatory gene expression in muscle fibroblasts, corresponding to less fibrosis and inflammation in mdx muscular dystrophy.
    Michelle Wehling-Henricks, Pranav Kannan, Connor Thomas, Harsimer Bal, Vedant Balu, Eisuke Ochi, Kenneth Dorshkind, James G Tidball.
      Muscle pathology in Duchenne muscular dystrophy (DMD) is greatly amplified by the immune response to dystrophic muscle, which provides the rationale for targeting the immune system in DMD therapies. Much of immune-driven pathology in the mdx mouse model of DMD is caused by T-lymphocytes and macrophages; thus, preventing T-cell activation by blocking pathways that cause their activation has the potential to reduce muscle damage and fibrosis in muscular dystrophy. CTLA4-Ig is a recombinant protein that blocks co-stimulatory signaling between T-cells and antigen presenting cells, such as macrophages. In this investigation, we tested whether treatment of mdx mice until they reach advanced, fibrotic stages of the disease reduces pathology. Our findings show that CTLA4-Ig treatments reduced muscle damage and inflammation and also reduced numbers of fibrogenic cells and fibrosis of muscles in aging, mdx mice. However, the treatments did not reduce numbers of CD8+ T-cells or activated CD25+ cells, suggesting that the reduced pathology was not mediated by affecting T-cell activation. Complete blood counts and clinical histopathological scoring also showed that the treatments had little effect on hematopoietic tissues. In vitro, CTLA4-Ig acted directly on muscle fibroblasts, reducing their expression of pro-inflammatory genes without affecting the expression of genes encoding connective tissue proteins, assayed by qPCR. However, CTLA4-Ig treated fibroblasts were less proliferative in vitro. Collectively, these findings show that CTLA4-Ig acts directly on fibroblasts to produce changes in proliferation and gene expression that are consistent with the reductions in muscle pathology that occurs in aging, mdx mice treated with CTLA4-Ig.
    Keywords:  Duchenne muscular dystrophy; muscular dystrophy; myositis; skeletal muscle fibrosis
    DOI:  https://doi.org/10.1152/ajpcell.00860.2025
  30. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70254
    Mitochondrial Adaptations in Skeletal Muscle Following Incretin-Based Therapies: In Vitro.
    Victoria Old, Melanie Davies, Matthew Denniff, Pratik Choudhary, Nicholas Eastley, Robert U Ashford, Emma Watson.
       BACKGROUND: Incretin-based therapies such as glucagon-like peptide-1 receptor agonists (GLP-1Ras), dual GLP-1/GIP agonists and amylin analogues have demonstrated significant weight loss benefits. However, their impact on skeletal muscle mitochondrial function, particularly under metabolic stress, remains unclear. This study aimed to investigate the effects of semaglutide (GLP-1RA), tirzepatide (dual GLP-1/GIP agonist) and cagrilintide (amylin analogue) on mitochondrial function in C2C12 skeletal muscle myotubes under both healthy and lipotoxic (palmitic acid-treated) conditions.
    METHODS: Differentiated C2C12 myotubes were treated with doses of each drug for 48 h and 5 days. Mitochondrial respiration was assessed using the Seahorse XFp analyser, mitochondrial DNA (mtDNA) copy number and oxidative phosphorylation (OXPHOS) complex protein expression were measured by qPCR and western blotting. Key findings were repeated in primary human skeletal muscle cells.
    RESULTS: Palmitic acid (PA) significantly impaired mitochondrial function, reducing basal oxygen consumption rate (OCR) by 22% (p = 0.0056) and ATP production by 25% (p = 0.0022). In healthy myotubes, semaglutide and cagrilintide transiently reduced basal respiration (↓21%-28%, p < 0.05) and ATP production (↓24%-31%, p < 0.01) at 48 h, along with reductions in Complexes I, III and IV protein expression, all of which resolved by 5 days. Tirzepatide significantly increased maximal respiration (↑20%-25%, p < 0.005) and spare respiratory capacity (↑22%-30%, p < 0.005) after 5 days. In PA-treated myotubes, semaglutide and cagrilintide acutely worsened mitochondrial impairment (↓ATP production by ~20%-25%, p < 0.01), but these effects resolved by Day 5. Tirzepatide initially suppressed mitochondrial function (↓ATP production, p = 0.0087) but reversed these effects by Day 5, significantly improving ATP production (↑27%-30%, p < 0.005), basal respiration (↑20%, p = 0.0152), and coupling efficiency. mtDNA content remained unchanged across all conditions. Similar responses were noted in human myotubes, with a transient reduction in respiration for semaglutide and cagrilintide (↓30%-62%, p < 0.05) at 48 h and a significant improvement in maximal respiration for tirzepatide at 5 days (↑42%-52%, p = 0.0022).
    CONCLUSION: Incretin-based therapies exert distinct, time and dose-dependent effects on skeletal muscle mitochondrial function. Tirzepatide promoted sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions, indicating potential benefits for maintaining skeletal muscle bioenergetic function. These findings underscore the need for further mechanistic studies and suggest that tirzepatide may have the potential to support skeletal muscle health in metabolic disease.
    Keywords:  GLP‐1RA; mitochondrial health; obesity; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.70254
  31. Oncol Lett. 2026 May;31(5): 160
    Tumor-muscle communication in cancer-associated cachexia (Review).
    Lily Berríos-Contreras, Matías Meza-Valenzuela, Nelson Brown, Claudio Valenzuela, Silvia Busquets, Francisco Javier López-Soriano, Andrew Fg Quest, Rodrigo Moore-Carrasco.
      Cancer progression is characterized by the ability of cancer cells to grow uncontrollably, invade adjacent tissues and eventually metastasize, which is typically accompanied by systemic effects. Cachexia, a catabolic state characterized by the loss of skeletal muscle mass and anorexia, is thought to result from the release of inflammatory molecules and other mediators from the tumor niche. The loss of skeletal muscle mass that characterizes cachexia is due to an exacerbation of proteolysis in muscle cells, a catabolic process that is dependent on inflammatory factors and extracellular vesicles (EVs) released by tumor cells. EVs activate various cellular signaling pathways that result in the nuclear translocation of NF-κB. These EVs carry various cargoes, including interleukins, microRNAs and receptors for advanced glycation end-products. When reaching muscle cells, these factors lead to an energy imbalance, increased oxidative stress, and the transcription of ubiquitin ligases such as muscle RING finger 1 and muscle atrophy F-box (Atrogin-1). While EVs appear to play an important role in cachexia, more evidence is needed to determine the interaction of the different cellular signaling pathways involved in the communication between the tumor cells and skeletal muscle cells, as well as to characterize the EVs derived from tumor cells and understand how they may contribute to the varying severity levels of cachexia syndrome. In cachexia, muscle wasting is driven by pro-inflammatory and catabolic factors released by tumor cells, leading to a negative energy balance. These factors activate the ubiquitin-proteasome pathway and suppress the PI3K/AKT/mTOR pathway. This line of research may lead to the development of new therapeutic strategies aimed at improving survival in patients with cancer with cachexia.
    Keywords:  cachexia; cancer; catabolism; extracellular vesicles; muscle wasting
    DOI:  https://doi.org/10.3892/ol.2026.15513
  32. Front Physiol. 2026 ;17 1796142
    Transcriptomic insights into aerobic exercise-mediated attenuation of high-fat diet-induced muscle wasting.
    Weihao Hong, Jianrong Zheng, Yisheng Luan, Haibin Yu, Yueyun Xu, Bing Zhang.
      Chronic consumption of high-fat diets (HFDs) induces obesity and metabolic dysfunction and is accompanied by progressive skeletal muscle wasting. Although aerobic exercise is generally considered less effective for maintaining muscle mass, accumulating evidence suggests that it can attenuate HFD-induced muscle wasting. However, the molecular mechanisms underlying this protective effect remain poorly defined. In this study, we investigated the effects of moderate-intensity continuous training (MICT) on HFD-induced muscle wasting and characterized the associated transcriptomic adaptations in the mouse gastrocnemius muscle. 21 weeks of HFD feeding increased body weight and serum glucose levels and induced marked muscle wasting, as evidenced by reduced gastrocnemius muscle index, impaired forelimb grip strength, decreased muscle fiber cross-sectional area, and excessive intramuscular lipid accumulation. These pathological alterations were significantly attenuated by an 8-week MICT intervention. RNA sequencing revealed that HFD predominantly induced a lipid-centered transcriptional program characterized by enhanced fatty acid uptake, trafficking, and β-oxidation. In contrast, MICT predominantly suppressed atrophy-associated genes (Foxo1, Fbxo32, and Trim63), while exerting minimal effects on myogenic genes (Pax7, Myod1, and Myog). Functional enrichment analyses further indicated that MICT modulated signaling pathways related to FoxO, PI3K-Akt, MAPK, and insulin signaling, together with biological processes associated with angiogenesis and calcium signaling. Collectively, these results suggest that MICT mitigates HFD-induced muscle wasting primarily by reprogramming the transcriptome from a lipotoxic, atrophic state toward a more insulin-sensitive, pro-angiogenic profile, with limited myogenic activation.
    Keywords:  MICT; aerobic exercise; high-fat diet; muscle wasting; transcriptome
    DOI:  https://doi.org/10.3389/fphys.2026.1796142
  33. Acta Physiol (Oxf). 2026 Apr;242(4): e70182
    Progranulin Regulates Protein Synthesis in Myocytes Through an Ephrin Type A Receptor 2-Dependent Pathway.
    Ka Chon Chan, Hiong-Ping Hii, Hsin-Yu Kuo, Chung-Teng Wang, Kai-Pi Cheng, Horng-Yih Ou, Hung-Tsung Wu.
       AIM: Sarcopenia is associated with metabolic dysregulation, yet the molecular mediators remain poorly defined. This study aimed to identify relevant regulators of muscle mass and to elucidate the role and underlying mechanism of progranulin in skeletal muscle protein synthesis.
    METHODS: We combined transcriptomic profiling of muscles from high-fat diet-fed mice with human genetic data from the HugeAMP Type 2 Diabetes Knowledge Portal to identify potential regulators. Clinically, 172 participants were stratified into low muscle mass (LMM) and normal muscle mass (NMM) groups according to the Asian Working Group for Sarcopenia criteria, and serum progranulin was measured. In vitro, recombinant progranulin was applied to L6 myoblasts to assess proliferation and differentiation and to differentiated L6 myotubes to evaluate protein synthesis and mTOR/S6K/S6 signaling. We performed shRNA-mediated knockdown of Ephrin type-A receptor 2 (EphA2), a functional progranulin receptor, to determine its impact on progranulin-induced effects in L6 myotubes.
    RESULTS: Transcriptomics identified Grn as a top downregulated gene in metabolically stressed muscle. Clinically, serum progranulin levels were significantly lower in the LMM group than the NMM group (280.71 ± 148.09 vs. 378.96 ± 139.65 ng/mL, p < 0.001). In vitro, progranulin did not affect the proliferation or differentiation of L6 myoblasts. However, it dose-dependently enhanced protein synthesis and increased phosphorylation of mTOR, S6K, and S6 in L6 myotubes. Furthermore, EphA2 knockdown attenuated progranulin-induced protein synthesis and phosphorylation of mTOR, S6K, and S6.
    CONCLUSION: Progranulin acts as a novel regulator of skeletal muscle metabolism, which enhances protein synthesis through EphA2-mediated activation of the mTOR signaling cascade.
    Keywords:  EphA2; progranulin; protein synthesis; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.70182
  34. Compr Physiol. 2026 Apr;16(2): e70126
    Glucagon-Like Peptide-1 Receptor Agonism and Muscle Health: Vascular and Myocellular Effects on Glucose and Protein Metabolism.
    Christos S Katsanos, Zhenqi Liu, Philip J Atherton.
      Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) improve glycaemia and reduce body weight, yet their organ-level actions on skeletal muscle remain incompletely defined. Framing skeletal muscle as an integrated unit of vasculature and muscle cells, we synthesize evidence with emphasis on glucose and protein metabolism. GLP-1 and GLP-1 RAs recruit microvasculature in muscle, expanding capillary surface area and increasing delivery of insulin, glucose, and amino acids. Microvascular recruitment increases interstitial insulin availability and potentiates insulin-stimulated glucose uptake and glycogen synthesis, whereas direct effects of GLP-1 on muscle cells remain under investigation. For protein metabolism, microvascular recruitment can enhance muscle protein synthesis when plasma amino acid availability is elevated, whereas effects under basal (fasted) conditions remain unclear. Elucidating the uncertainty regarding GLP-1 receptor localization in human muscle cells will clarify whether direct signaling occurs within muscle cells, thereby improving our understanding of the relative contribution of direct versus perfusion-mediated actions of GLP-1 RAs. Clinically, GLP-1 RAs reduce lean body mass, likely reflecting energy-deficit-mediated effects, but studies directly assessing muscle mass are still limited. Overall, current evidence indicates that GLP-1 RAs exert beneficial effects on muscle vasculature and muscle glucose metabolism. However, their influence on muscle protein turnover remains unclear-primarily due to observed reductions in muscle mass-despite preclinical data suggesting potential favorable effects on muscle protein metabolism that remain to be confirmed in humans.
    Keywords:  GLP‐1 RA; insulin sensitivity; microvascular perfusion; muscle metabolism; protein turnover
    DOI:  https://doi.org/10.1002/cph4.70126
  35. J Cell Sci. 2026 Mar 18. pii: jcs.264416. [Epub ahead of print]
    Baculovirus-mediated gene transfer enables functional expression of the PIEZO1 ion channel in isolated muscle satellite cells.
    Akira Murakami, Ayuno Masuda, Takumi Hirakawa, Riku Nakanishi, Kotaro Hirano, Masaki Tsuchiya, Keiko Nonomura, Yusuke Ono, Takashi Murayama, Yuji Hara.
      Primary tissue stem cells are useful not only for basic cell biological research but also for therapeutic applications: however, their broader utility is often limited by technical challenges, such as a low efficiency of exogenous gene expression. PIEZO1 is a large mechanosensitive ion channel that plays an important role in muscle-resident stem cells, known as muscle satellite cells (MuSCs), during muscle regeneration. In this study, we developed a method for the ectopic expression of PIEZO1 in isolated MuSCs. Using a baculovirus vector system, we expressed PIEZO1 in myoblast C2C12 cells. Following optimization of the infection condition, we achieved robust PIEZO1 expression in isolated MuSCs during activated and differentiated states, with appropriate subcellular localization and ion channel activity. Importantly, the baculovirus-mediated PIEZO1 expression restored the defective cell functions in Piezo1-deficient MuSCs to a level comparable to wild-type cells, indicating that the exogenously expressed PIEZO1 is functionally equivalent to the endogenous protein. Overall, we established an efficient method for the transfer of the Piezo1 gene into isolated MuSCs, which should provide a versatile platform to study other large proteins in MuSCs.
    Keywords:  Baculovirus vector; Muscle satellite cell; PIEZO1
    DOI:  https://doi.org/10.1242/jcs.264416
  36. Med Sci Sports Exerc. 2026 Apr 01. 58(4): 851-872
    American College of Sports Medicine Position Stand. Resistance Training Prescription for Muscle Function, Hypertrophy, and Physical Performance in Healthy Adults: An Overview of Reviews.
    Brad S Currier, Alysha C D'Souza, Maria A Fiatarone Singh, Caroline V Lowisz, Eric S Rawson, Brad J Schoenfeld, Abbie E Smith-Ryan, Jeremy P Steen, Gwendolyn A Thomas, N Travis Triplett, Tyrone A Washington, Timothy J Werner, Stuart M Phillips.
       PURPOSE: The aim of this overview of reviews was to determine the impact of resistance training (RT) prescription on muscle function and hypertrophy, utilizing evidence synthesis methods. It updates the American College of Sports Medicine 2009 Position Stand, "Progression models in resistance training for healthy adults."
    DATA SOURCES: Ovid MEDLINE(R) ALL, Ovid Emcare, Ovid Embase, Cochrane Database of Systematic Reviews, EBSCOhost SPORTDiscus, and Web of Science Core Collection current to October 2024.
    ELIGIBILITY CRITERIA: Eligible systematic reviews synthesized randomized trials of healthy adults (≥18 yr) who completed RT (≥6 wk; range: 6-52 wk), compared with a group that completed no exercise or an alternative RT program, and reported the change in muscle function, size, or physical performance.
    RESULTS: We synthesized data from 137 systematic reviews (>30,000 participants). Compared with no exercise (control), RT significantly improved muscle strength, size (hypertrophy), power, endurance, contraction velocity, gait speed, balance, and multiple physical function outcomes. Few RT prescription (RTx) variables affected primary adaptations. However, voluntary strength was enhanced by lifting heavier loads (≥80% one-repetition maximum), through a complete range of motion, for 2-3 sets, at the beginning of training sessions, and ≥2 sessions/wk. Muscle hypertrophy was enhanced by higher volumes (≥10 sets/wk) and eccentric overload. Power was enhanced by moderate loads (30%-70% one-repetition maximum), low-to-moderate volume (≤24 repetitions⋅sets), Olympic-style weightlifting, and power RT (fast concentric phase). Power RT enhanced physical function. Training to momentary muscle fatigue, equipment type, exercise complexity, set structure, time under tension, blood flow restriction, and periodization did not consistently impact training outcomes.
    CONCLUSIONS: Healthy adults should perform progressive RT, with variable prescription consistent with our findings, to improve muscle function, size, and physical performance. Muscle strength, hypertrophy, power, and certain components of physical function can be enhanced by manipulating the RT variables highlighted.
    Keywords:  HYPERTROPHY; PHYSICAL FUNCTION; RESISTANCE TRAINING; SKELETAL MUSCLE; STRENGTH
    DOI:  https://doi.org/10.1249/MSS.0000000000003897
  37. J Physiol. 2026 Mar 17.
    Increasing protein intake without increased physical activity is unlikely to improve muscle health: the new U.S. dietary guidelines.
    Grith Højfeldt, Paul T Morgan, Casper Soendenbroe.
      
    Keywords:  RDA; ageing; dietary guidelines; health; protein intake
    DOI:  https://doi.org/10.1113/JP290972
  38. Sci Rep. 2026 Mar 19.
    Hot melt extruded Kyungohkgo attenuates skeletal muscle atrophy by downregulating the FOXO3a/MuRF-1/atrogin-1 axis.
    Young Mi Seok, Bo-Ram Jin, Tae-Young Gil, Suji Ryu, Chan-Yeong Ju, Yoonah Jeong, Jinyoung Son, Man Sop Shim, Hyo Jung Kim, Hyo-Jin An, Jong-Suep Baek, Yun-Yeop Cha.
      Skeletal muscle atrophy is a common and debilitating consequence of chronic diseases and aging, yet effective treatment alternatives remain limited. Kyungohkgo (KOG), a traditional oriental medicine, has been shown to have potential therapeutic benefits for muscle health, but its therapeutic efficacy is restricted caused by poor bioavailability. This study aimed to enhance both the bioavailability and efficacy of KOG by applying hot-melt extrusion (HME) processing, creating a modified formulation to evaluate its effectiveness in treating skeletal muscle atrophy. Network pharmacology analysis was conducted to illustrate the relationships between the traditional medicine KOG and sarcopenia. Both in vivo and in vitro models of skeletal muscle atrophy were employed to compare the effects of conventional KOG and HME-processed KOG (HOG3). HME processing yielded an optimized formulation, HOG3, characterized by nanoscale particle size and a marked increase in minor ginsenoside content. In this study, HOG3 showed significantly higher ginsenoside levels than KOG, with Rg3, compound K, and Rh2 increasing approximately 19-, 78-, and 18-fold, respectively. In cellular and animal models, HOG3 outperformed KOG in preserving muscle mass, reducing muscle degradation markers, and decreasing collagen deposition. HOG3 administration was associated with decreased expression level of FOXO3a, MuRF-1, and atrogin-1. Overall, these findings show that HOG3 indicates enhanced protective effects against skeletal muscle atrophy and is associated with modulation of downstream molecular markers related to muscle degradation.
    Keywords:  Dexamethasone; Ginsenoside; Hot-melt extrusion; Kyungohkgo; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1038/s41598-026-43874-1
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