bims-moremu 2026-02-15 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–02–15
thirty-six papers selected by
Anna Vainshtein, Craft Science Inc.

Sympathetic innervation regulates metabolic flexibility of skeletal muscle.
Mouse skeletal muscle satellite cells co-opt the tenogenic gene Scleraxis to instruct regeneration.
Single-nuclei RNA-sequencing uncovers sexually divergent exercise signatures partially mimicked by TFEB overexpression in mouse skeletal muscle.
Programmed Cell Death and its Implications for Skeletal Muscle Wasting.
Exercise Protects Skeletal Muscle Fibers from Age-Related Dysfunctional Remodeling of Mitochondrial Network and Sarcotubular System.
Macrophage Infiltration, Activation, and Therapeutic Implication in Skeletal Muscle Injury and Repair.
Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.
Mechanism of exercise-derived circulating exosomes as a target for sarcopenia management.
Muscle-Specific DNM2 Overexpression Improves Charcot-Marie-Tooth Disease In Vivo and Reveals a Narrow Therapeutic Window in Skeletal Muscle.
Exofacial Epitope-Specific Antibodies Detect GLUT4 Translocation in Adult Human, Rat, and Mouse Skeletal Muscle.
New Insights into Neuromuscular Junction Biology: Evidence from Human and Animal Research.
M-cadherin regulates the formation of adherens junctions and secondary myofibers during fetal myogenesis to determine adult myofiber number and muscle mass.
Reciprocal regulation between the protein arginine deiminases and mSWI/SNF chromatin remodelers controls skeletal muscle differentiation and regeneration.
Adiponectin upregulates irisin expression through the APPL1/p38MAPK/PGC-1α signalling pathway in murine skeletal muscle.
CD47 Promotes, While Exposure to Apoptotic Cells Destroys the Fusion Program of Differentiating Myoblasts.
The Drosophila Him gene is essential for adult muscle function and muscle stem cell maintenance.
Sarcopenia and Muscle Aging: Updated Insights into Molecular Mechanisms and Translational Therapeutics.
Calpain Mediated Proteolysis of Junctophilin-1 Produces an Aggregation Prone C-Terminal Fragment in Skeletal Muscle.
Donor-matched iPSC model reveals context-dependent T2D genetic signals in fibro-adipogenic progenitors.
Mechanical loading induces the longitudinal growth of muscle fibers via a rapamycin-insensitive mechanism.
The HIF-1α Pathway Regulates Satellite Cell Fate During Aging Through Histone Lactylation.
Dynamic balance of myoplasmic energetics, redox state and protons in a fast-twitch oxidative glycolytic skeletal muscle fibre.
Comprehensive Proteomics and β-Hydroxybutyrylation Profiling in Starvation-Induced Gastrocnemius Muscle Remodeling.
Missing the rhythm in skeletal muscle mitochondrial respiration.
Extracellular vesicles at the neuromuscular junction: messengers of synaptic health and disease.
Skeletal muscle myosin heavy chain fragmentation following exercise may be linked to post-exercise inflammation and remodelling.
Basics in clinical sports nutrition: Physical activity, muscle and clinical nutrition.
A multimodal stretchable bioelectronic system for simultaneous monitoring of skeletal-muscular and metabolic biomarkers.
Secretome Profiling of Young Multipotent Stem Cells Reveals Angiogenic and Immunomodulatory Mechanisms Supporting Aged Neuromuscular Health.
Transcriptomic profiling of co-cultured cancer-host cells identifies hypoxia as a driver of the skeletal muscle cell's anti-proliferative effect on cancer cells.
Unveiling FLNC variants: iPSC-derived myogenic cells as a model to study disease mechanisms.
RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio.
Single-Nucleus Transcriptome Reveals Cellular Heterogeneity and Transcriptional Response to Heat Stress in Skeletal Muscle.
The Relationship Between Prostate Cancer Treatments and Changes to Musculature: A Systematic Review.
Molecular Bases of Myopathies and Their Impact on Clinical Practice: Advances and Future Perspectives.
Inhibiting the NLRP3 inflammasome with MCC950 ameliorates muscle atrophy in cancer cachexia.

bioRxiv. 2026 Feb 04. pii: 2026.02.02.703364. [Epub ahead of print]

Sympathetic innervation regulates metabolic flexibility of skeletal muscle.

Jordan Owyoung, HaoMin Sima, Junwon Heo, Tess Klugherz, Tina Tian, Brittney Ward, Nikki Boon, Garrett W Cooper, Andrew L Hong, Jarrod Call, Patricia J Ward.

The sympathetic nervous system (SNS) is recognized for its role in the physiological regulation of organs, such as heart, vasculature and lungs, and has emerged as a potential player in skeletal muscle metabolic and neuromuscular junction (NMJ) health. However, the mechanism through which SNS signaling influences skeletal muscle function and adaptation to exercise remains unclear. Using molecular, electrophysiological, immunohistochemical, and high-resolution respirometry techniques, we tested the role of sympathetic innervation to skeletal muscle in response to exercise. Our findings reveal that sympathetic denervation disrupts the NMJ, reducing motor and sympathetic receptor expression, with concomitant deficits in skeletal muscle function. Mechanistically, these deficits are linked to diminished CPT1 enzyme activity, which impairs long-chain fatty acid-mediated oxidation in skeletal muscle mitochondria. These findings reveal a key role for sympathetic innervation in maintaining mitochondrial metabolic function and by extension, skeletal muscle performance, offering novel insight into the interplay between the SNS, exercise, and muscle mitochondria.

DOI: https://doi.org/10.64898/2026.02.02.703364
Elife. 2026 Feb 09. pii: RP95854. [Epub ahead of print]13

Mouse skeletal muscle satellite cells co-opt the tenogenic gene Scleraxis to instruct regeneration.

Yun Bai, Tyler Harvey, Colin Bilyou, Minjie Hu, Chen-Ming Fan.

  Skeletal muscles connect bones and tendons for locomotion and posture. Understanding the regenerative processes of muscle, bone, and tendon is of importance to basic research and clinical applications. Despite their interconnections, distinct transcription factors have been reported to orchestrate each tissue's developmental and regenerative processes. Here, using adult mouse skeletal muscles, we show that Scx expression is not detectable in adult muscle stem cells (also known as satellite cells, SCs) during quiescence. Scx expression begins in activated SCs and continues throughout regenerative myogenesis after injury. By SC-specific Scx gene inactivation (Scx cKO), we show that Scx function is required for SC expansion/renewal and robust new myofiber formation after injury. We combined single-cell RNA sequencing and CUT&RUN to identify direct Scx target genes during muscle regeneration. These target genes help explain the muscle regeneration defects of Scx cKO and are not overlapping with Scx-target genes identified in tendon development. Together with a recent finding of a subpopulation of Scx-expressing connective tissue fibroblasts with myogenic potential during early embryogenesis, we propose that regenerative and developmental myogenesis co-opt the Scx gene via different mechanisms.

Keywords:  Scleraxis; developmental biology; mouse; muscle differentiation; muscle regeneration; muscle stem cell; sc-RNA sequencing; tendon

DOI:  https://doi.org/10.7554/eLife.95854
bioRxiv. 2026 Jan 26. pii: 2026.01.23.700915. [Epub ahead of print]

Single-nuclei RNA-sequencing uncovers sexually divergent exercise signatures partially mimicked by TFEB overexpression in mouse skeletal muscle.

Katrina Granger, Kailin Liu, Tiarra Joseph, Ari Adler, Ian Matthews, Jocelyne Leon, Clayton Baker, Minhoo Kim, Hu Wang, Xianlin Han, Bérénice A Benayoun, Constanza J Cortes.

Exercise induces extensive, cell-type-specific transcriptional remodeling in skeletal muscle to support metabolic flexibility and adaptation. However, the regulatory mechanisms underlying these transcriptional programs, and the extent to which they differ between sexes, remain poorly defined. We previously reported that lifelong, muscle-specific overexpression of human Transcription Factor E-B (cTFEB;HSACre transgenic mice) recapitulates many adaptive features of endurance training in both sexes, leading to profound geroprotective effects during aging even in the absence of exercise. Here, we profile transcriptional adaptations to voluntary wheel running (VWR) and TFEB-overexpression at single-nucleus resolution in young male and female mouse tibialis anterior muscle. This represents, to our knowledge, the first integrated analysis of exercise and TFEB signaling using sex as a biological variable. Using robust bioinformatic and single-nuclei RNA-sequencing approaches, we profiled six muscle-resident cell populations and uncover previously unrecognized, sex-dependent signaling nodes governing exercise-associated metabolic plasticity. TFEB activation and endurance training by VWR elicit strongly correlated transcriptional programs enriched for lipid metabolism, mitochondrial remodeling, and immune modulation, establishing TFEB-overexpression as a partial exercise mimetic. In general, female muscle exhibited enhanced extracellular matrix and lipid-associated responses to endurance training and TFEB overexpression, whereas males preferentially engaged in angiogenic and oxidative networks, revealing distinct sex-specific, sex-dimorphic, or sex-agnostic regulatory routes to metabolic flexibility. Integration with independent multi-omics datasets from endurance-trained rats (MoTrPAC) confirms the conservation of TFEB-exercise transcriptional convergence in skeletal muscle across species and potentially muscle types. Together, these findings define TFEB as a regulator of exercise transcriptional programs and reveal sex-specific molecular frameworks that drive metabolic adaptation in skeletal muscle. Furthermore, the resulting sex-resolved, single-nucleus transcriptional atlas provides a unique resource for the field, enabling comparative, mechanistic, and hypothesis-driven exploration of exercise-responsive skeletal muscle regulatory networks across sexes.

DOI: https://doi.org/10.64898/2026.01.23.700915
Indian J Clin Biochem. 2026 Feb;41(1): 31-41

Programmed Cell Death and its Implications for Skeletal Muscle Wasting.

Rajesh Dabur, Aarti Yadav.

  Skeletal muscle atrophy is an inevitable sequel of various factors such as cachexia, aging, fasting, denervation, and microgravity. It is characterized by reduced muscle protein through increased proteolysis and decreased protein synthesis. Recent research suggests that atrophy can significantly contribute to mortality among afflicted persons, and the hindrance of muscular deterioration is expected to extend lifespan. Programmed cell death or apoptosis is imperative for preserving the integrity of proliferative tissues. However, the exact role of apoptosis in post-mitotic tissues, such as skeletal muscle, remains less well-defined. Within the context of muscle atrophy, apoptosis occurs in both myonuclei as well as other types of muscle cells. The loss of muscle mass is likely attributed to the apoptotic demise of myonuclei, yet the mechanisms driving this process remain largely unknown. Both caspase-dependent and caspase-independent pathways have been implicated, with the specific mode of atrophy induction determining the apoptotic mechanisms utilized. Furthermore, it is still undetermined whether a reduction in apoptosis will ameliorate atrophy, necessitating distinct research strategies for various causes of skeletal muscle loss.

Keywords:  Appotosis; Caspase; Cell death; Muscle atrophy; Skeletal muscle

DOI:  https://doi.org/10.1007/s12291-024-01223-x
Cells. 2026 Jan 27. pii: 248. [Epub ahead of print]15(3):

Exercise Protects Skeletal Muscle Fibers from Age-Related Dysfunctional Remodeling of Mitochondrial Network and Sarcotubular System.

Feliciano Protasi, Matteo Serano, Alice Brasile, Laura Pietrangelo.

  In skeletal muscles fibers, cellular respiration, excitation-contraction (EC) coupling (the mechanism that translates action potentials in Ca2+ release), and store-operated Ca2+ entry (SOCE, a mechanism that allows recovery of external Ca2+ during fatigue) take place in organelles specifically dedicated to each function: (a) aerobic ATP production in mitochondria; (b) EC coupling in intracellular junctions formed by association between transverse tubules (TTs) and sarcoplasmic reticulum (SR) named triads; (c) SOCE in Ca2+entry units (CEUs), SR-TT junctions that are in continuity with membranes of triads, but that contain a different molecular machinery (see Graphical Abstract). In the past 20 years, we have studied skeletal muscle fibers by collecting biopsies from humans and isolating muscles from animal models (mouse, rat, rabbit) under different conditions of muscle inactivity (sedentary aging, denervation, immobilization by casting) and after exercise, either after voluntary training in humans (running, biking, etc.) or in mice kept in wheel cages or after running protocols on a treadmill. In all these studies, we have assessed the ultrastructure of the mitochondrial network and of the sarcotubular system (i.e., SR plus TTs) by electron microscopy (EM) and then collected functional data correlating (i) the changes occurring with aging and inactivity with a loss-of-function, and (ii) the structural improvement/rescue after exercise with a gain-of-function. The picture that emerged from this long journey points to the importance of the internal architecture of muscle fibers for their capability to function properly. Indeed, we discovered how the intracellular organization of the mitochondrial network and of the membrane systems involved in controlling intracellular calcium concentration (i[Ca2+]) is finely controlled and remodeled by inactivity and exercise. In this manuscript, we give an integrated picture of changes caused by inactivity and exercise and how they may affect muscle function.

Keywords:  Ca2+ release unit (CRU); excitation-contraction (EC) coupling; mitochondria; sarcoplasmic-reticulum (SR); store-operated Ca2+ entry (SOCE); transverse tubule (TT); triad

DOI:  https://doi.org/10.3390/cells15030248
Int J Mol Sci. 2026 Jan 29. pii: 1332. [Epub ahead of print]27(3):

Macrophage Infiltration, Activation, and Therapeutic Implication in Skeletal Muscle Injury and Repair.

Xingyu Wang, Lan Zhou.

  Skeletal muscle injury triggers inflammatory response, of which the accumulation of intramuscular monocytes/macrophages is a prominent feature. Macrophages in injured muscle comprise both blood monocytes-derived infiltrating macrophages, which are recruited through CCR2 signaling, and pre-existing muscle resident macrophages, which are established during embryogenesis and maintained until adulthood through self-renewal proliferation. During regenerative acute muscle injury, infiltrating monocytes/macrophages are heterogeneously activated in a temporal dynamic, responding to the changing microenvironment in injured muscle and contributing to the complete injury repair. Injury-associated monocytes/macrophages recede with the completion of muscle injury repair. In contrast, injury-associated monocytes/macrophages persist in dystrophic muscle of Duchenne muscular dystrophy (DMD), likely accounting for persistent inflammation and progressive fibrosis of DMD muscle. We review here the current knowledge on monocyte/macrophage infiltration and activation in both acutely injured skeletal muscle and dystrophic muscle with subsequent discussion of the potential therapeutic implication in treating muscular dystrophy.

Keywords:  infiltration; inflammation; macrophages; monocytes; muscle injury; muscular dystrophy

DOI:  https://doi.org/10.3390/ijms27031332
Front Cell Dev Biol. 2025 ;13 1699206

Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.

Fasih A Rahman, Joe Quadrilatero.

  Aging impairs the regenerative capacity of skeletal muscle in part through the functional decline of the resident stem cell population called satellite cells. With age, satellite cells exhibit a loss of quiescence, altered proliferation, and impaired differentiation, leading to incomplete myogenesis following injury. Mitochondria are central to stem cell function, providing ATP, regulating redox homeostasis, and integrating several signaling pathways during lineage progression. While mitochondrial remodeling and function is essential for supporting the metabolic demands of myogenesis, the extent to which these processes are altered in aged satellite cells across cell states remains unclear. To address this, we performed a comparative transcriptomic analysis of young and aged satellite cells in quiescent, proliferating, and early differentiating states using three publicly available microarray datasets. Our results reveal that aged satellite cells exhibit a dysregulated senescence profile, characterized by the simultaneous upregulation of both senescence-inducing and -inhibiting genes, suggestive of a metastable senescence state. These features persisted during early differentiation, where aged cells also displayed increased expression of senescence-associated secretory phenotype (SASP) components, potentially contributing to a pro-inflammatory niche. Mitochondrial gene expression was relatively stable in quiescent cells but showed marked remodeling upon activation, particularly in aged cells. While young satellite cells upregulated transcriptional programs related to mitochondrial function, aged cells exhibited broader and less coordinated responses enriched for stress, apoptotic, and metabolic pathways. Despite evidence of mitochondrial stress, mitophagy gene activation remained limited in aged cells, raising the possibility of impaired organelle quality control. Together, our findings highlight age-associated disruptions in both senescence and mitochondrial remodeling programs across the satellite cell lifecycle. These transcriptional changes likely underlie impaired regenerative responses in aging muscle and identify potential targets for rejuvenating muscle stem cell function.

Keywords:  SASP; aging; mitochondrial remodeling; satellite cell; senescence; skeletal muscle; skeletal muscle regeneration

DOI:  https://doi.org/10.3389/fcell.2025.1699206
Front Physiol. 2025 ;16 1680485

Mechanism of exercise-derived circulating exosomes as a target for sarcopenia management.

Xiangbo Wang, Hui Huang, Jie Chen, Qing Zhang, Zhichao Yuan, Mingyue Yin, Chenggen Peng, Songlin Liu.

  Sarcopenia, an age-related syndrome characterized by the progressive decline of skeletal muscle mass and function, threatens the health of older adults through underlying mechanisms that include dysregulated protein metabolism, autophagy-mitochondrial dysfunction, chronic inflammation, and impaired regenerative capacity of muscle stem cells. Exercise-derived circulating exosomes, which act as key mediators of intercellular communication, show considerable potential in mitigating sarcopenia-related damage. In this review, we summarize the biogenesis of exercise-induced exosomes, encompassing both ESCRT-dependent and independent pathways, secretion regulated by RAB and SNARE proteins, and their release mediated through mechanical, calcium, metabolic, and neuroendocrine signaling during exercise. We further elaborate on the systemic roles of these exosomes in muscle repair, including alleviating lipotoxicity via the FGF21-adiponectin axis, maintaining protein homeostasis through dual regulation by miR-29c, and ameliorating the inflammatory microenvironment via modulation of macrophage polarization. Finally, we discuss the translational promise of exosomes as therapeutic targets and outline future research directions, offering a conceptual framework for understanding exercise-mediated muscle protection and developing novel interventions.

Keywords:  exercise; exosomes; extracellular vesicles; muscle repair; sarcopenia

DOI:  https://doi.org/10.3389/fphys.2025.1680485
Int J Mol Sci. 2026 Feb 02. pii: 1471. [Epub ahead of print]27(3):

Muscle-Specific DNM2 Overexpression Improves Charcot-Marie-Tooth Disease In Vivo and Reveals a Narrow Therapeutic Window in Skeletal Muscle.

Marie Goret, Gwenaelle Piccolo, Jocelyn Laporte.

  Charcot-Marie-Tooth disease (CMT), caused by dominant loss-of-function mutations in DNM2, encoding the GTPase dynamin-2, impairs motor and sensory function. However, the respective contributions of muscle and nerve pathology, and the therapeutic potential of increasing DNM2 expression, remain unresolved. We evaluated tissue-targeted and systemic approaches to increase DNM2 in a mouse model carrying the common K562E-CMT mutation. Muscle-specific DNM2 overexpression from embryogenesis in Dnm2K562E/+ mice ameliorated desmin and integrin mislocalization, membrane trafficking defects, mitochondrial abnormalities, and fibrosis in skeletal muscle, resulting in improved locomotor coordination despite persistent muscle atrophy. Conversely, systemic postnatal AAV delivery of human DNM2 increased DNM2 in muscle but failed to transduce nerves and paradoxically worsened the muscle pathology, producing centronuclear myopathy-like features. These findings reveal a primary pathogenic impact of DNM2-CMT mutation within skeletal muscle, independent of nerve involvement. Collectively, they underscore that precise DNM2 dosage is critical for neuromuscular homeostasis and reveal a narrow therapeutic window for safe and effective therapeutic intervention. This paradox, in which efforts to compensate for a loss-of-function neuropathy risk inducing a gain-of-function myopathy, highlights the need for tightly controlled modulation of DNM2 activity in future therapeutic strategies.

Keywords:  AAV; CMT; Charcot–Marie–Tooth neuropathy; GTPase; HMSN; Hereditary motor and sensory neuropathy; adeno-associated virus; dynamin; gene therapy; muscle; myopathy

DOI:  https://doi.org/10.3390/ijms27031471
Diabetes. 2026 Feb 13. pii: db250567. [Epub ahead of print]

Exofacial Epitope-Specific Antibodies Detect GLUT4 Translocation in Adult Human, Rat, and Mouse Skeletal Muscle.

Kaspar W Persson, Casper Fjeldsøe, Lukas W Frandsen, Jonas R Knudsen, SeongEun Kwak, Haiyan Wang, Christian T Voldstedlund, Magnus R Leandersson, Carol A Witczak, Jørgen F P Wojtaszewski, Erik A Richter, Gregory D Cartee, Thomas E Jensen.

ARTICLE HIGHLIGHTS: Reliable quantification of glucose transporter 4 (GLUT4) translocation in intact skeletal muscle is essential for understanding insulin and exercise responses but remains technically challenging. We aimed to test whether exofacial GLUT4 antibodies can specifically detect sarcolemmal GLUT4 translocation in fixed, nonpermeabilized muscle fibers from humans and rodents. GLUT4 translocation in response to insulin, AMPK activation, and exercise was detectable in human and rodent muscles. Insulin-stimulated translocation correlated with 2-deoxyglucose uptake and was abolished in TBC1D4-knockout muscle. Exofacial GLUT4 antibodies enable straightforward, specific quantification of endogenous GLUT4 translocation in rodent and human muscles in healthy and insulin-resistant states.

DOI: https://doi.org/10.2337/db25-0567
Int J Mol Sci. 2026 Jan 27. pii: 1253. [Epub ahead of print]27(3):

New Insights into Neuromuscular Junction Biology: Evidence from Human and Animal Research.

Zhanyang Liang, Xiaoying Chen, Mahtab Nourbakhsh.

  Neuromuscular junctions (NMJs) are highly specialized synapses that enable efficient communication between motor neurons and skeletal muscle fibers. Impaired formation or maintenance of NMJs is implicated in the pathogenesis of multiple neuromuscular disorders and contributes to age-related declines in skeletal muscle mass and strength. NMJ functionality is governed by complex regulatory crosstalk among different cells and is mediated by a diverse network of proteins. Moreover, immune cells often reside at NMJs and exhibit phenotypically different characteristics depending on the regenerative state of the muscle. These complex interfaces have posed a significant challenge for elucidating pathogenic mechanisms and developing biomarkers or effective targeted treatments. Many animal models have been developed to address this challenge by characterizing the fundamental structural features of neuromuscular junctions (NMJs) and their transmission capacity under both healthy and disease conditions. In contrast, studies of human NMJs remain limited, although emerging evidence is increasingly revealing substantial morphological and functional differences from animal NMJs. This review provides an overview of animal research on NMJs over the past decades, highlighting interspecies differences and key advances in our understanding of human NMJs.

Keywords:  acetylcholine receptor; neuromuscular junction; regeneration; remodeling; synaptic vesicle protein; transduction

DOI:  https://doi.org/10.3390/ijms27031253
Stem Cell Reports. 2026 Feb 12. pii: S2213-6711(26)00023-8. [Epub ahead of print] 102812

M-cadherin regulates the formation of adherens junctions and secondary myofibers during fetal myogenesis to determine adult myofiber number and muscle mass.

David R Golann, Patrick J Ferrara, Naveen P Khan, Margaret Hung, Virginia Hughes, Samer Nuwayhid, Jonas Bovijn, Peter Dornbos, Luca Lotta, Peisheng Shi, Qi Su, Yajun Tang, Mark W Sleeman, Michael J Stec.

  Cadherin-mediated adhesion of skeletal muscle stem cells within their niche is necessary for normal adult muscle maintenance and regeneration; however, the role of cadherins in regulating muscle development and growth has not yet been elucidated. Here, we show that M-cadherin protein is localized to adherens junctions in developing muscle and that deletion of Cdh15, the gene encoding M-cadherin, results in the loss of adherens junctions in fetal mouse muscle. This loss of adherens junctions is associated with reduced secondary myofiber formation, ultimately resulting in reduced adult myofiber number and muscle mass. Concordantly, via large-scale exome sequencing, we found that humans with predicted loss-of-function variants in the CDH15 gene had significantly reduced lean mass, indicating that M-cadherin functions to regulate muscle mass in both mice and humans. Overall, these data highlight a previously unrecognized role of M-cadherin in controlling fetal myofiber formation and establishment of adult muscle mass.

Keywords:  adherens junctions; cadherin; human genetics; muscle development; myogenesis; secondary myofiber

DOI:  https://doi.org/10.1016/j.stemcr.2026.102812
bioRxiv. 2026 Jan 21. pii: 2026.01.20.700682. [Epub ahead of print]

Reciprocal regulation between the protein arginine deiminases and mSWI/SNF chromatin remodelers controls skeletal muscle differentiation and regeneration.

Monserrat Olea-Flores, Tapan Sharma, Anand Parikh, Leonard Barasa, Sarah Hachmer, F Jeffrey Dilworth, Teresita Padilla-Benavides, Paul R Thompson, Anthony N Imbalzano.

Protein arginine deiminases (PADs) post-translationally convert arginine to citrulline on target proteins and serve as regulators of multiple cellular functions. PAD enzymes have been implicated in autoimmune disorders, cancer, and other diseases. Inhibiting PAD activity is currently being pursued clinically for therapeutic purposes. However, little is known about PAD function in normal developmental or homeostatic processes. Here we show that multiple PAD isoforms contribute to primary myoblast differentiation by binding to regulatory regions of target genes. Furthermore, we demonstrate a novel, reciprocal requirement for PADs and mammalian SWI/SNF (mSWI/SNF) chromatin remodeling enzymes; PAD enzymes are required for the expression and binding of specific mSWI/SNF enzyme subunits to target gene regulatory sequences while mSWI/SNF enzymes are required for the expression and binding of PAD enzymes. In vivo , the PADs contribute to mouse skeletal muscle regeneration after injury, with PAD4 specifically identified as a required regulator. This work identifies the PADs as critical cofactors in the initiation of skeletal muscle differentiation and reveals previously unappreciated connections between two major co-activator families during normal tissue development. Moreover, the results reveal important considerations for ongoing therapeutic approaches to myriad human diseases that utilize inhibitors of each enzyme family.

DOI: https://doi.org/10.64898/2026.01.20.700682
Mol Cell Endocrinol. 2026 Feb 05. pii: S0303-7207(26)00020-1. [Epub ahead of print] 112743

Adiponectin upregulates irisin expression through the APPL1/p38MAPK/PGC-1α signalling pathway in murine skeletal muscle.

Ruiqi Huang, Sitong Xu, Qi Guo, Shicheng Cao, Donghui Tang, Xuejie Yi.

  Adiponectin and irisin regulate energy homeostasis and interact with peroxisome proliferator-activated receptor coactivator 1α (PGC-1α). However, whether they establish a signal connection via PGC-1α is unclear. In the current study, the expression of irisin was significantly decreased in the skeletal muscle of adiponectin knockout (KO) mice, accompanied by a de crease in APPL1/p38 mitogen-activated protein kinase (MAPK)/PGC-1α. However, adiponectin administration reversed this effect. In vitro, the p38 MAPK/PGC-1α signalling pathway mediated adiponectin-induced FNDC5 expression and irisin release in mouse-derived C2C12 myotube cells. Moreover, obesity caused dysregulation of the adiponectin/APPL1/p38 MAPK/PGC-1α signalling pathway in murine skeletal muscle, ultimately inhibiting irisin synthesis and secretion; meanwhile, prolonged exercise or exogenous recombinant adiponectin intervention activated this pathway in mouse skeletal muscle. This corresponded with an apparent improvement in high-fat diet-induced insulin resistance. The effect of mechanically stretching C2C12 myotube cells was consistent with in vivo findings. Hence, adiponectin upregulates irisin through the APPL1/p38MAPK/PGC-1α signalling pathway in murine skeletal muscle, which may enhance insulin sensitivity.

Keywords:  Adiponectin; C2C12 cell; Insulin resistance; Irisin; Obesity; Skeletal muscle

DOI:  https://doi.org/10.1016/j.mce.2026.112743
FASEB J. 2026 Feb 28. 40(4): e71578

CD47 Promotes, While Exposure to Apoptotic Cells Destroys the Fusion Program of Differentiating Myoblasts.

Maysaa Adil Ali, Albert Bálint Papp, Éva Garabuczi, Áron Károly Gere, Beatrix Dienes, Mónika Gönczi, György Vámosi, Krisztina Köröskényi, László Csernoch, Zsuzsa Szondy, Zsolt Sarang.

  Cell fusion requires the activity of several phagocytic receptors and the temporary exposure of phosphatidylserine (PS) on the surface of viable myoblasts. Recently, we reported that these receptors turn myoblasts into potent phagocytic cells. Since cell fusion and phagocytosis share many molecules and mechanisms in myoblasts, we aimed to investigate how myoblasts choose between the two pathways during fusion. To prevent accidental uptake, viable cells express "don't eat-me" signals. By analyzing RNA sequencing data, we found that differentiation affected the expression of multiple "don't eat-me" genes in the C2C12 mouse myoblast cells, including upregulation of Sirpα, a receptor for CD47. The same was observed in differentiating myoblasts in vivo following cardiotoxin-induced injury in mouse skeletal muscle. Treatment of differentiating C2C12 cells with anti-CD47 antibody significantly reduced cell fusion but did not affect cell survival or differentiation. Both CD47 and SIRPα appeared at contact points of fusing myoblasts. Blocking CD47 signaling increased the uptake of viable red blood cells but only slightly increased the uptake of viable myoblasts. Blocking thrombospondin-1, another CD47 ligand, also inhibited fusion. Inhibiting CD47 signaling did not impact the engulfment of apoptotic cells. However, long-term exposure to continuously PS-expressing apoptotic cells disrupted myotube formation by inhibiting PIEZO1 activation, leading to syncytia formation. Overall, our data show that differentiating myoblasts upregulate CD47 to avoid accidental phagocytosis of live cells but mainly to promote myoblast fusion. Therefore, the activity of this signaling pathway contributes to the decision-making between the two processes that would compete with each other during myoblast differentiation.

Keywords:  CD47; PIEZO1; Sirp1α; apoptotic cells; efferocytosis; myoblast differentiation; myoblast fusion; phosphatidylserine; thrombospondin‐1; “don't‐eat‐me” signals

DOI:  https://doi.org/10.1096/fj.202503809R
iScience. 2026 Feb 20. 29(2): 114670

The Drosophila Him gene is essential for adult muscle function and muscle stem cell maintenance.

Robert Mitchell-Gee, Robert Hoff, Kumar Vishal, Daniel Hancock, Sam McKitrick, Cristina V Newnes-Querejeta, Antonio Aguayo, David Liotta, Jennifer A Waters, TyAnna L Lovato, Richard M Cripps, Michael V Taylor.

  Muscle stem cells (MuSCs), or "satellite cells," are vital for vertebrate muscle growth, homeostasis, and repair. The discovery of analogous cells in Drosophila opens experimental opportunities in this genetically tractable model. Here, we show that the myogenic inhibitor gene Him, as well as being expressed in the myoblasts that form the flight and jump muscles, is expressed in flight muscle MuSCs. This makes Him only the second marker of these insect adult MuSCs. Furthermore, Him mutants exhibit disrupted jump muscle organization, impaired jumping ability, and a reduced pool of flight muscle myoblasts. In the flight muscles themselves, Him mutants show an age-dependent decrease in MuSC number, indicating Him is required for MuSC maintenance. This decrease coincides with reduced flight performance. Thus, Him is a new marker of Drosophila adult MuSCs and is the first gene shown to be required as flies age to maintain both MuSC number and flight ability.

Keywords:  cell biology; genetics

DOI:  https://doi.org/10.1016/j.isci.2026.114670
Endocrinol Metab (Seoul). 2026 Feb 12.

Sarcopenia and Muscle Aging: Updated Insights into Molecular Mechanisms and Translational Therapeutics.

Thanh T Nguyen, Tam Dao, Ha Thu Nguyen, Jun-Hyeon Park, Seung-Jun Jeong, Sei Kim, Yunju Jo, Nhung T H Thieu, Jiangqi Zhao, Fuan Ding, Ying Yu, Vu Chi Dung, Karim Gariani, Beom-Jun Kim, Dongryeol Ryu.

  Sarcopenia is a progressive, age-related condition characterized by the loss of skeletal muscle mass, strength, and function, which increases the risk of falls, frailty, and loss of independence. Despite growing recognition and its incorporation into geriatric assessments, there is still no approved pharmacological treatment. This review provides an updated overview of sarcopenia, encompassing diagnostic criteria, biological mechanisms, and emerging therapeutic strategies. Key molecular features include mitochondrial dysfunction, nicotinamide adenine dinucleotide (NAD⁺) decline, fiber-type alterations, and dysregulation of myokines. Recent singlecell and multi-omics studies have revealed the heterogeneity of muscle tissue and distinct cell-type-specific aging patterns. Therapeutic efforts are evolving beyond lifestyle interventions toward targeted approaches, including myostatin inhibitors, NAD⁺ boosters, senolytics, and microbiome modulators. However, clinical translation remains constrained by heterogeneity in trial design and the absence of standardized outcome measures. Future sarcopenia care will likely involve precision medicine guided by biomarkers and supported by digital monitoring tools. Progressing from molecular discovery to clinical application will be essential for preserving muscle health and function in aging populations.

Keywords:  Aging; Mitochondria; Muscle weakness; Myokines; Protein metabolism; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.3803/EnM.2025.2656
Res Sq. 2026 Feb 03. pii: rs.3.rs-8663093. [Epub ahead of print]

Calpain Mediated Proteolysis of Junctophilin-1 Produces an Aggregation Prone C-Terminal Fragment in Skeletal Muscle.

Eshwar Reddy Tammineni, Lourdes Figueroa, Carlo Manno.

Junctophilin-1 (JPh1) is an essential structural protein of the calcium release units required for excitation-contraction coupling in skeletal muscle. In myopathic conditions associated with elevated intracellular calcium, calcium-activated calpains target multiple proteins. Although JPh1 is known to be a calpain substrate, the precise molecular identity of its calpain cleavage sites and the (patho)physiological roles of the resulting proteolytic fragments remain poorly defined. Here, we combined in-silico prediction with in vitro calpain cleavage analysis of dual-tagged JPh1 to identify multiple calpain cleavage sites within JPh1. We further show that a 44-kDa C-terminal fragment of JPh1 (JPh44) is intrinsically prone to aggregation. Using a combination of biophysical, biochemical, and imaging approaches, we demonstrate that under stress conditions JPh44 progressively forms aggregates that localize predominantly to perinuclear regions. Aggregated JPh44 colocalizes with HSP70 and resides near HDAC6. Pharmacological activation or overexpression of HSP70 promotes clearance of JPh44 aggregates and enhances JPh44 nuclear translocation. Finally, we identify the transmembrane domain of JPh44 as a key determinant driving its aggregation propensity. Together, these findings reveal that stress-induced proteolysis of JPh1 generates aggregation-prone fragments whose handling by heat shock proteins and autophagy-related machinery may play an important role in skeletal muscle adaptation and pathology.

DOI: https://doi.org/10.21203/rs.3.rs-8663093/v1
bioRxiv. 2026 Feb 06. pii: 2026.02.04.702388. [Epub ahead of print]

Donor-matched iPSC model reveals context-dependent T2D genetic signals in fibro-adipogenic progenitors.

Christa Ventresca, Arushi Varshney, Peter Orchard, Ha T H Vu, Yao-Chang Tsan, Andre Monteiro da Rocha, Michael R Erdos, Leena Kinnunen, Timo A Lakka, Jouko Saramies, Markku Laakso, Jaakko Tuomilehto, Karen L Mohlke, Michael Boehnke, Laura J Scott, Heikki A Koistinen, Francis S Collins, Todd Herron, Stephanie Bielas, Stephen C J Parker.

Fibro-adipogenic progenitors (FAPs) in skeletal muscle have been implicated in type 2 diabetes (T2D) risk, yet their heterogeneity and context-dependent regulation remain poorly understood. Here, we establish induced pluripotent stem cell (iPSC)-derived FAPs as a faithful model of primary FAPs by leveraging a unique resource: iPSC lines and skeletal muscle biopsies obtained from the same 30 individuals. Donor-matched comparisons reveal that iPSC-FAPs recapitulate the transcriptome, epigenome, and subtype composition of muscle tissue FAPs. Using single-nucleus multiomics, we show that high-insulin exposure drives iPSC-FAPs toward an adipogenic fate - and that this adipogenic subtype is enriched for T2D GWAS signals, an enrichment undetectable under baseline conditions. We map the T2D-associated rs3814707 non-coding signal to LTBP3 , a gene that influences FAP adipogenic differentiation. These findings reveal how disease-relevant regulatory mechanisms can be masked in unstimulated cells and establish iPSC-FAPs as a powerful platform for dissecting the state-dependent biology of complex metabolic disease.

DOI: https://doi.org/10.64898/2026.02.04.702388
Sci Adv. 2026 Feb 13. 12(7): eaec5134

Mechanical loading induces the longitudinal growth of muscle fibers via a rapamycin-insensitive mechanism.

Jamie E Hibbert, Kent W Jorgenson, Ramy K A Sayed, Hector G Paez, Marius Meinhold, Corey G K Flynn, Anthony N Lange, Garrison T Lindley, Philip M Flejsierowicz, Troy A Hornberger.

Mechanical loading drives skeletal muscle growth, yet the mechanisms that regulate this process remain undefined. Here, we show that an increase in mechanical loading induces muscle fiber growth through two distinct mechanisms. Radial growth, reflected by an increase in fiber cross-sectional area, is mediated through a rapamycin-sensitive signaling pathway, whereas longitudinal growth, marked by the in-series addition of sarcomeres, is mediated through a rapamycin-insensitive signaling pathway. To gain further insight into the events that drive longitudinal growth, we combined BONCAT-based labeling of synthesized proteins with high-resolution imaging and determined that the in-series addition of sarcomeres is mediated by a process that involves transverse splitting at the Z-lines of preexisting sarcomeres. Collectively, our findings not only challenge the long-standing view that mechanically induced growth is uniformly governed by mTORC1 but also lay the framework for a revised understanding of the molecular and structural events that drive this process.

DOI: https://doi.org/10.1126/sciadv.aec5134
Aging Cell. 2026 Feb;25(2): e70411

The HIF-1α Pathway Regulates Satellite Cell Fate During Aging Through Histone Lactylation.

Marco Piccoli, Lorenzo Mornatti, Ivana Lavota, Monica Risuglia, Pasquale Creo, Elena Vizzino, Paola Rota, Adriana Tarantino, Laura Mangiavini, Giuseppe Ciconte, Paola Signorelli, Giuseppe Maria Peretti, Simone Cenci, Carlo Pappone, Luigi Anastasia, Federica Cirillo.

  Aging-associated sarcopenia is driven in part by the progressive loss of type II glycolytic fibers and the functional decline of their resident stem cells, the satellite cells (SCs). We show here that these defects result from attenuation of the hypoxia-inducible factor-1α (HIF-1α) signaling pathway and can be reversed by pharmacological HIF-1α reactivation. In the tibialis anterior muscle of 18-month-old C57BL/6J mice, HIF-1α protein abundance decreased by ≈46% and canonical targets (Vegfa, Egln1) were downregulated in freshly isolated SCs. Treatment of aged SCs with the prolyl hydroxylase inhibitor roxadustat (FG-4592) for 48 h restored HIF signaling, upregulated glycolytic enzymes (HK2, GAPDH, ALDO) and the lactate transporter MCT4, and increased intracellular lactate by 1.9-fold. Increased lactate enhanced global histone lactylation, an epigenetic mark that decreased with age. The effect was attenuated by the LDHA inhibitor oxamate, establishing a link between HIF-driven metabolism and chromatin remodeling. HIF-1α activation slowed old SC proliferation (S phase -60%), but decreased the senescence marker p16Ink4a (-54%) and increased the stem cell factor Pax7 (+1.8-fold), indicating a shift from senescence to a quiescent, regenerative state. When differentiation was induced without drugs, pretreated aged SCs formed hypertrophic myotubes (differentiation index +1.7), exhibited higher ATP content (+1.54-fold), and activated the IGF-1/PI3K-Akt-mTOR pathway, leading to an increase in tropomyosin (Tpm1) in fast fibers. These results suggest a HIF-1α-lactate-lactylation axis that rejuvenates aged satellite cells and enhances myogenic performance, providing a mechanistic rationale for repurposing roxadustat to alleviate sarcopenia.

Keywords:  FG‐4592; aging; hypoxia‐inducible factor‐1α; lactylation; quiescence; satellite cells

DOI:  https://doi.org/10.1111/acel.70411
J Physiol. 2026 Feb 14.

Dynamic balance of myoplasmic energetics, redox state and protons in a fast-twitch oxidative glycolytic skeletal muscle fibre.

Jana Disch, Jeroen A L Jeneson, Daniel A Beard, Oliver Röhrle, Thomas Klotz.

  To investigate the mechanisms governing energy and redox balance in skeletal muscle, we developed a computational model describing the coupled biochemical reaction network of glycolysis and mitochondrial oxidative phosphorylation (OxPhos) in fast-twitch oxidative glycolytic (FOG) muscle fibres. The model was identified against dynamic in vivo recordings of phosphocreatine (PCr), inorganic phosphate (Pi) and pH in rodent hindlimb muscle and verified against independent data from in vivo experiments and muscle biopsies. Step response testing reveals that mass action kinetics in combination with feedback control are sufficient to accomplish myoplasmic ATP homeostasis over a 100-fold range of ATP turnover rates. This vital emergent property of the metabolic model is associated with intermediary metabolite dynamics typical of a second-order underdamped system, which has been previously reported for the glycolytic pathway. Lactate dehydrogenase (LDH) knockout simulations suggest that the contribution of the LDH reaction to redox balance is more fundamental to muscle function than its role in counteracting myoplasmic acidification across the physiological range of ATP demands in this myofibre phenotype. Furthermore, LDH knockout simulations confirm that mitochondrial uptake of myoplasmic NADH and H+ in and by itself is sufficient to maintain redox balance and proton balance over ATP turnover rates in the range of mitochondrial ATP synthesis. We conclude that aerobic lactate production in working muscles is a by-product of the metabolic flexibility of FOG myofibres afforded by expression of high levels of LDH and OxPhos enzymes to support continual myoplasmic redox balance and ATP synthesis under conditions of high-intensity mechanical work. KEY POINTS: Feedback regulation suffices to accomplish myoplasmic ATP homeostasis over a 100-fold range of ATP turnover. Second-order underdamped behaviour is predicted to arise as a generic trait of the ATP metabolic network in mammalian cells. Aerobic lactate is a by-product of the metabolic and functional flexibility. LDH's role in maintaining redox balance is more important than its role in counteracting cellular acidification.

Keywords:  ATP metabolism; LDH knockout; aerobic lactate production; computer simulation; magnetic resonance spectroscopy; mathematical model; muscle fatigue; skeletal muscle

DOI:  https://doi.org/10.1113/JP289702
Biology (Basel). 2026 Feb 06. pii: 289. [Epub ahead of print]15(3):

Comprehensive Proteomics and β-Hydroxybutyrylation Profiling in Starvation-Induced Gastrocnemius Muscle Remodeling.

Leilei Cui, Chunping Huang, Yu Su, Shiqi Xu, Liang Zha, Qiuyuan Zhao, Wu Quan, Xinqiang Lan, Yang Xiang, Qiquan Wang.

  Starvation elicits profound metabolic adaptations in skeletal muscle, enabling survival during nutrient scarcity. While global proteomic changes underpinning muscle atrophy have been studied, the role of lysine β-hydroxybutyrylation (Kbhb), a novel metabolite-derived post-translational modification linked to ketone metabolism, remains largely unexplored. In this study, we subjected mice to 72 h of food deprivation and performed integrative quantitative proteomics and Kbhb-modified peptide profiling on gastrocnemius muscle. Starvation induced significant body weight and muscle mass loss, accompanied by increased systemic β-hydroxybutyrate levels and widespread Kbhb modification of muscle proteins. Proteomic analysis revealed extensive downregulation of ribosomal and translation-associated proteins, coupled with upregulation of autophagy and lipid catabolism pathways, highlighting a coordinated shift from anabolic processes to catabolic and oxidative metabolism. Deep Kbhb profiling identified over 7500 modified lysine sites across 2000 proteins, with starvation triggering a global increase in Kbhb on key metabolic enzymes involved in glycolysis, TCA cycle, fatty acid β-oxidation, and amino acid metabolism. Notably, starvation-enhanced Kbhb preferentially targeted evolutionarily conserved lysines proximal to catalytic or cofactor-binding domains, implicating a regulatory role in enzymatic activity modulation. Conversely, Kbhb on structural and contractile proteins was downregulated, suggesting functional reprioritization of muscle physiology during fasting. Our findings uncover lysine β-hydroxybutyrylation as a dynamic, metabolically responsive PTM mediating gastrocnemius muscle adaptation to energy deficiency, expanding the paradigm of potentially metabolite-driven epigenetic and non-epigenetic regulatory mechanisms in muscle metabolism.

Keywords:  ketone body; lysine β-hydroxybutyrylation (Kbhb); proteomics; skeletal muscle; starvation

DOI:  https://doi.org/10.3390/biology15030289
Am J Physiol Endocrinol Metab. 2026 Feb 01. 330(2): E265-E266

Missing the rhythm in skeletal muscle mitochondrial respiration.

Jan-Frieder Harmsen, Andries Kalsbeek.



Keywords:  circadian; diabetes; energy metabolism; exercise; sex differences

DOI:  https://doi.org/10.1152/ajpendo.00469.2025
Cell Tissue Res. 2026 Feb 13. 403(2): 20

Extracellular vesicles at the neuromuscular junction: messengers of synaptic health and disease.

Rizwan Qaisar.

  Extracellular vesicles (EVs) have emerged as pivotal modulators of neuromuscular junction (NMJ) biology, reshaping our understanding of synaptic communication, maintenance, and degeneration. This review consolidates current insights into the roles of EVs derived from motor neurons, muscle fibers, and Schwann cells in regulating NMJ integrity. In healthy states, EVs deliver trophic factors, structural proteins, and regulatory RNAs that promote the clustering of acetylcholine receptors, presynaptic stability, and axonal growth. Motor neuron EVs carry Wnt7a, synaptophysin, and PGC-1α, while muscle-derived EVs deliver miR-206, agrin, and caveolin-3. Schwann cell EVs contribute neurotrophic support via NRG1 and GDNF. In contrast, diseased or aged NMJs exhibit EV cargo dysregulation, marked by the presence of misfolded proteins (e.g., SOD1, TDP-43), pro-inflammatory cytokines, and reduced regenerative miRNAs. These changes contribute to synaptic dismantling, neuroinflammation, and impaired repair in conditions such as ALS, SMA, MG, and sarcopenia. The review highlights the bidirectional nature of EV signalling and its dynamic regulation by neuronal activity and stress. Emerging therapeutic strategies include engineering EVs to deliver protective cargo, targeting them to NMJ components, and designing biomaterial-based depots for sustained release. Furthermore, EV signatures in blood and muscle hold promise as non-invasive biomarkers for early detection of NMJ decline in ALS, SMA, MG, and sarcopenia. Despite promising preclinical data, challenges remain in EV characterization, targeting specificity, and clinical translation. This review underscores a paradigm shift: EVs are not passive byproducts but active messengers of neuromuscular health and disease, with realistic applications in diagnostics, regenerative therapy, and personalized medicine.

Keywords:  EV-based therapeutics; Extracellular vesicles; Motor neuron disease; Neuromuscular junction; Sarcopenia

DOI:  https://doi.org/10.1007/s00441-026-04050-z
Exp Physiol. 2026 Feb 11.

Skeletal muscle myosin heavy chain fragmentation following exercise may be linked to post-exercise inflammation and remodelling.

Dakota R Tiede, Diego Bittencourt, J Max Michel, Daniel L Plotkin, Madison L Mattingly, Derick A Anglin, Christopher G Vann, Zachary A Graham, Timothy J Broderick, Marcas M Bamman, Michael D Roberts.

  The purpose of this exploratory investigation was to determine if acute post-exercise skeletal muscle myosin heavy chain fragmentation (MyHCfrag) coincides with alterations in molecular chaperones and proteolytic enzymes, select markers of mammalian target of rapamycin complex 1 (mTORC1) signalling, and/or specific gene expression signatures. Untrained males (n = 10, 23 ± 2 years) and females (n = 10, 23 ± 3 years) completed a bout of combined endurance and resistance exercise. Vastus lateralis muscle biopsies were taken before, 3 h and 24 h post-exercise. Tissue was fractioned into myofibrillar (MF) and sarcoplasmic protein (SF) fractions for protein analysis. Differential RNA expression (DE) from those who experienced high and low MyHCfrag post-exercise was also analysed via bulk RNA-sequencing. MyHCfrag increased 24 h post-exercise, albeit only four of 20 chaperone and proteolytic markers were concomitantly altered and none significantly correlated with 24 h post-exercise MyHCfrag. Given these null findings, we explored six participants who experienced the most post-exercise MyHCfrag versus six who experienced the least MyHCfrag with the intent of examining if post-exercise gene signatures or signalling differed. Although mTORC1 signalling markers were similar, 799 DE transcripts were identified 24 h post-exercise. Pathway analysis on DE differences indicated that nine of the top 10 pathways enriched in high-MyHCfrag participants were related to inflammation. High MyHCfrag participants also presented an upregulation in extracellular matrix remodelling genes at the 24 h post-exercise time point. Though we lack immunohistochemical data, these findings suggest that post-exercise MyHCfrag is associated with an upregulation in an inflammatory and remodelling signature, and longer-term studies are needed to determine if these acute outcomes align with unique adaptive responses.

Keywords:  fragmentation; inflammation; myosin heavy chain; resistance training

DOI:  https://doi.org/10.1113/EP093340
Clin Nutr ESPEN. 2026 Feb 07. pii: S2405-4577(26)00016-1. [Epub ahead of print] 102921

Basics in clinical sports nutrition: Physical activity, muscle and clinical nutrition.

Nada Rotovnik Kozjek, Gašper Tonin, Carla Prado, Ronald J Maughan.

  Physical activity and nutrition are inextricably linked in maintaining muscle and overall health, enhancing metabolic resilience, and preventing age-related muscle loss. Exercise acts as a powerful physiological stressor, inducing acute metabolic, endocrine, and immunological responses, while long-term training elicits structural and functional adaptations at the muscular, cardiovascular, and systemic levels. Proper nutritional strategies, aligned with the type, intensity, and duration of physical activity, provide the necessary substrates to fuel exercise, optimize recovery, and support muscle protein synthesis and immune resilience. This integrative approach not only enhances athletic performance but also serves as a critical tool in the prevention and management of chronic diseases, including obesity, type 2 diabetes and cardiovascular disease. Emerging evidence further underscores the importance of skeletal muscle as a metabolic and endocrine organ, producing myokines which, with other exerkines, mediate the systemic health benefits of exercise. As a result, the evolving field of clinical sports nutrition bridges the gap between performance-oriented sports nutrition and evidence-based clinical care for physically active individuals across the health spectrum. By combining exercise physiology, clinical nutrition, and applied sports science, this multidisciplinary model provides a robust framework for advancing metabolic health, functional capacity, and performance in diverse populations.

Keywords:  clinical sports nutrition; exercise; exercise endocrinology; exercise physiology; muscle

DOI:  https://doi.org/10.1016/j.clnesp.2026.102921
Biosens Bioelectron. 2026 Feb 05. pii: S0956-5663(26)00106-5. [Epub ahead of print]300 118474

A multimodal stretchable bioelectronic system for simultaneous monitoring of skeletal-muscular and metabolic biomarkers.

Jian Cai, Chong-Bo Ma, Jing Bai, Xiangjie Bo, Ming Zhou.

  Physical activity involves coordinated skeletal muscle contraction and metabolic regulation, with its impact on human health determined by complex interactions between mechanical motion and biochemical processes. Monitoring these interactions requires real-time tracking of skeletal muscle activity that regulates movement and the associated metabolites produced during exercise. Here, we present iTrainer, a stand-alone, multimodal, stretchable, and wearable bioelectronic system that enables non-invasive and dynamic monitoring of skeletal-muscular and metabolic biomarkers. The device simultaneously captures physiological signals of skeletal muscle (motion frequency, skin strain, joint bending angle, and temperature) and sweat-based metabolic biomarkers (lactate and Na+) during both aerobic and anaerobic exercise. The iTrainer integrates three key components: an epidermal microfluidic module for skin-worn sweat collection and transport, a multimodal sensing array module for skin-on physicochemical biomarkers monitoring, and an integrated electronic module for data processing and wireless transmission. Human trials in aerobic (e.g., running) and anaerobic (e.g., bench press) exercise validated the system's capability to measure synchronized mechanical and biochemical signals. We also evaluate the utility of iTrainer as a partial substitute for professional coaches in the iTrainer-assisted self-exercise training management for novice individuals.

Keywords:  Bioelectronic; Metabolic; Multimodal; Skeletal-muscular; Sweat; Wearable

DOI:  https://doi.org/10.1016/j.bios.2026.118474
Aging Cell. 2026 Feb;25(2): e70408

Secretome Profiling of Young Multipotent Stem Cells Reveals Angiogenic and Immunomodulatory Mechanisms Supporting Aged Neuromuscular Health.

Seth D Thompson, Chelsea L Rugel, Maddlyn R Haller, Jodi L Curtin, Sudarshan Dayanidhi, Mitra Lavasani.

  Aging is the primary risk factor for many neuromuscular (NM) diseases that impair motor and cognitive function. Transplantation of young muscle-derived stem/progenitor cells (MDSPCs) has shown remarkable therapeutic potential across a range of age-related diseases, primarily through paracrine mechanisms. In this study, secretome profiling of young MDSPCs revealed a unique enrichment of pro-angiogenic and immunomodulatory proteins compared to their aged counterparts. Our systemic transplantation experiments also demonstrate that young MDSPCs activate biological pathways linked to these secreted factors, providing strong mechanistic evidence of their contribution to the reversal of age-associated NM decline at molecular, structural, and functional levels. Systemic transplantation of young MDSPCs into naturally aged mice enhanced motor function and reduced anxiety-like behavior. Structural improvements in aged NM tissues were partially mediated by phosphorylating protein sites involved in muscle neovascularization and regulation of blood-brain barrier integrity in the motor cortex. Paracrine signaling from young MDSPCs enhanced the endogenous regenerative capacity of aged tissues, with effects sustained for up to 2 months post-transplantation. Overall, this study elucidates the molecular basis of MDSPC-mediated NM rejuvenation and provides a foundation for developing novel protein-based therapies to combat age-related functional decline.

Keywords:  aging; angiogenesis; immune‐modulation; neuromuscular diseases; rejuvenation; secretome; stem cells; systemic transplantation

DOI:  https://doi.org/10.1111/acel.70408
Oncogenesis. 2026 Feb 07. 15(1): 7

Transcriptomic profiling of co-cultured cancer-host cells identifies hypoxia as a driver of the skeletal muscle cell's anti-proliferative effect on cancer cells.

Anine Aunan, Charlotte Claeyssen, Mohamed Abdelhalim, Jérôme Ruzzin.

Cancer metastasis is the leading cause of cancer-related death. While organs such as the lung are hotspots for metastases, others -like skeletal muscle- remain rarely colonized, a phenomenon that remains poorly understood. In this study, we show that EO771 breast cancer cells proliferated robustly when co-cultured with MLg lung stromal cells, whereas their proliferation was restrained when maintained in direct contact with differentiated C2C12 skeletal muscle myotubes. Notably, these effects were not cell-type-specific, as similar results were obtained with 4T1 breast cancer cells and Sol8 myotubes. After two days of co-culture, both cancer and host cells (MLg and C2C12) exhibited distinct niche-specific transcriptional remodeling. Strikingly, the poorly proliferative EO771 cells co-cultured with C2C12 myotubes acquired a hypoxia-associated gene-expression signature despite normoxic conditions (~20% O₂), showing that muscle cells reprogram cancer cells into a hypoxic, anti-proliferative state. Under hypoxic conditions, we confirmed that the depletion of oxygen allows C2C12 cells to nearly abolish EO771 proliferation. Neither exogenous lactate, culture acidosis, their combination, altered glucose levels, nor conditioned medium could reproduce the suppressive environment created by C2C12 myotubes. In contrast, MLg cells induced minimal transcriptional changes in EO771 cells and were themselves broadly reprogrammed by the cancer cells. Moreover, hypoxia enhanced EO771 proliferation in MLg co-cultures, emphasizing the permissive nature of the MLg environment. Collectively, these findings uncover a unique, paradoxical, muscle-induced pseudo-hypoxic program that restricts cancer cell proliferation. They also highlight the need for caution in targeting hypoxia signaling in anti-metastatic therapies, as such interventions could weaken skeletal muscle's natural defense against tumor colonization.

DOI: https://doi.org/10.1038/s41389-026-00601-9
Skelet Muscle. 2026 Feb 12.

Unveiling FLNC variants: iPSC-derived myogenic cells as a model to study disease mechanisms.

Nassam M Daya, Anne Schänzer, Andreas Hentschel, Marie-Cecile Kienitz, Dominik Sellung, Nicolina Suedkamp, Karsten Krause, Jaqueline C Kinold, Leon Volke, Anja Schreiner, Hanna Schlierbach, Christopher Nelke, Felix Kleefeld, Anne-Katrin Guettsches, Holm Zaehres, Tobias Ruck, Lampros Mavrommatis, Andreas Roos, Matthias Vorgerd.

   BACKGROUND: Filaminopathies, caused by pathogenic FLNC variants, are rare neuromuscular disorders characterized by protein aggregation, z-disk pathology and lead to progressive muscle weakness and/or cardiomyopathies.
METHODS: To address the lack of existing filaminopathy models in skeletal muscle, we developed a patient-specific cellular platform using induced pluripotent stem cells (iPSCs) harboring two truncating filamin C (FLNc) variants (p.Q1662X, p.Y2704X). Employing a developmental human skeletal muscle organoid hSMO model, we enrich for myogenic progenitor cells that are further differentiated into functional myotubes through 2D and 3D approaches (myotubes and musculoids).
RESULTS: The 2D myotubes exhibited poor sarcomeric organization and hallmarks of filaminopathies, including protein aggregation and proteostatic dysfunction, marked by elevated aggresome formation and an increased basal autophagic flux. The 3D musculoids revealed ultrastructural abnormalities and enabled the identification of novel disease-associated proteins involved in ER stress and protein folding (e.g. DNAJC10) through proteomic analysis. Proteomic findings were additionally validated in 2D cultures and in corresponding patient-derived muscle biopsies enhancing the model's translational value.
CONCLUSIONS: Our model is suitable to monitor aspects of filaminopathies' pathogenesis and to investigate possible therapeutic interventions with quantitative readouts.

Keywords:  Disease modeling; Filaminopathies; Organoid; iPSC

DOI:  https://doi.org/10.1186/s13395-026-00418-5
Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00039-2. [Epub ahead of print]45(2): 116961

RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio.

CHARGE Hemostasis Working Group

  Skeletal muscle capillary density is correlated with physical performance and whole-body metabolic properties. Thus, we performed a genome-wide association study of skeletal muscle capillary-to-fiber ratio (C:F) (n = 603 males) and found that the rs115660502 G allele was associated (p < 5 × 10-8) with increased C:F and reduced skeletal muscle expression of RAB3 GTPase-activating non-catalytic protein subunit 2 (RAB3GAP2). The capillary-increasing G allele was more prevalent in elite endurance athletes than in power athletes and non-athlete controls in two independent cohorts. Low-muscle-expressing RAB3GAP2 expression quantitative trait locus (eQTL) alleles were associated with muscle damage in athletes. In healthy individuals, RAB3GAP2 expression was reduced by high-intensity intermittent training. RAB3GAP2 protein was not uniformly expressed in muscle but predominantly expressed in the endothelium and capillaries. RAB3GAP2 expression was lower in endurance compared with power athletes and was negatively associated with type I (oxidative) muscle fiber density. Experimental reduction of RAB3GAP2 in human endothelial cells led to (1) increased proliferation and tube formation in vitro, (2) regulation of secreted factors (e.g., CD70 and TNC) promoting angiogenesis and T cell activation, and (3) increased in vivo endothelial cell density in mice. RAB3GAP2 expression in skeletal muscle was negatively correlated with exercise-induced release of TNC in vivo in humans. In conclusion, RAB3GAP2 is expressed in the microvascular endothelium and is suggested to be a negative regulator of angiogenesis through a decrease in endothelial cell proliferation, possibly mediated by RAB18, with its low-expressing variant associated with higher muscle C:F and elite endurance performance.

Keywords:  CP: genomics; CP: metabolism; RAB18; RAB3 GTPase-activating non-catalytic protein subunit 2; RAB3GAP2; angiogenesis; capillary density; elite athletes; exercise; genetics; microvascular endothelium; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2026.116961
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70217

Single-Nucleus Transcriptome Reveals Cellular Heterogeneity and Transcriptional Response to Heat Stress in Skeletal Muscle.

Ziyin Han, Li Chen, Zhiyu Lei, Jiaman Zhang, Ziyu Chen, Xiaolan Fan, Bo Zeng, Anan Jiang, Hai Xiang, Hua Li, Mingzhou Li, Long Jin.

   BACKGROUND: Heat stress can induce skeletal muscle injury. Typical characteristics of heat-exposed muscle tissues include apoptosis, oxidative stress and autophagy. The understanding of molecular mechanisms underlying heat stress-induced muscle injury is limited, especially at the single-cell transcription level.
METHODS: We collected skeletal muscles from 12-week-old female C57BL/6J mice in control (NC) and four heat stress groups. The experimental scheme comprised five groups: NC (25.5°C ± 0.5°C), HS0 (after ~3-h heat exposure, 41.5°C ± 0.5°C), HS8, HS16 and HS24 group (recovery at 25.5°C ± 0.5°C for 8, 16 and 24 h, respectively). Skeletal muscles were subjected to HE staining (n = 6), TUNEL staining (n = 3) and transmission electron microscopy (n = 3). Transcripts were measured at the tissue (n = 5 or 6) and single-nucleus levels (n = 2).
RESULTS: Histologically, myofibrillar structure deformation, mitochondrial swelling and fusion, intramuscular triglyceride accumulation and autophagy occurred in the muscles subjected to heat stress. At the tissue level, a gene cluster associated with the response to heat exhibited an increasing trend of transcription in the HS0 versus NC groups, and the levels decreased to those in the NC group after 16 h. At the single-cell level, 134 320 high-quality myonuclei were collected from the muscles and annotated as seven cell types, including myonuclei, muscle stem cells (MuSCs) and immune cells. We identified the larger number of differentially expressed genes in the myonuclei. After heat stress, new cell clusters appeared in type IIa/IIx (HS8 group) and IIb (HS0 group) myonuclei but not in type I myonuclei. Generally, immediate early genes, highly expressed genes and transcription factor regulons identified in new cell clusters induced by heat were related to responses to heat, heat shock, oxidative stress and antioxidative stress. To repair the injured muscles, MuSCs highly expressed the development-related genes, such as Atp2a1, Ckm, Myh1, Aldoa, Pde4d and Pdlim5. Analysis of cell-cell communication showed that Dag1 and Egf signals associated with myonuclei were the underlying pathways that participated in repair tissues.
CONCLUSIONS: We constructed the largest transcriptomic dataset, to date, for heat-exposed skeletal muscles. At tissue resolution, the response of muscles to heat stress was eliminated after a recovery period of 16 h. At single-nucleus resolution, the myofibre was the most heat-sensitive cell type, and type IIb myonuclei were the most heat-sensitive subtype of myonuclei. To our knowledge, this is the first study to reveal the molecular mechanisms underlying heat-induced muscle injury and repair at the single-cell transcriptional level.

Keywords:  bulk RNA‐seq; cell–cell communication; heat stress; muscle stem cells; myonuclei; snRNA‐seq

DOI:  https://doi.org/10.1002/jcsm.70217
Clin Oncol (R Coll Radiol). 2026 Jan 22. pii: S0936-6555(26)00021-X. [Epub ahead of print] 104050

The Relationship Between Prostate Cancer Treatments and Changes to Musculature: A Systematic Review.

L Partridge, A Vickers, D McSweeney, J Shortall, A McWilliam.

   AIMS: The aim of this systematic review is to investigate how androgen deprivation therapy (ADT) and radiotherapy (RT), for men with prostate cancer (PCa), receiving curative intent treatment, affect musculature, and if these changes consequently affect mortality and progression-free survival.
METHODS: Embase and Medline were searched via Ovid using appropriate keywords andBoolean operators, between 2014 and 2024. The PRISMA guidelines were followed, and articles were removed if they did not meet inclusion criteria on review. Bias was assessed in line with an established quality assessment tool: the National Institute of Health (2021): Study Quality Assessment Tools.
RESULTS: 509 studies were identified, with eight studies meeting the inclusion criteria. Of these eight studies included in narrative synthesis, 1176 patients were included in total. Despite limitations within individual studies, namely small cohort sizes, some studies identified significant relationships between PCa treatment outcomes and musculature. An indirect relationship was noted between declining skeletal muscle and increased risk of non-cancer death, with one study estimating a 1% decline in skeletal muscle index (SMI) was independently associated with a 9% increase in non-cancer death. Results emphasise the need for consistency in definitions of sarcopenia and further research into the associations between muscle and survival for men with prostate cancer.
CONCLUSIONS: The lack of a consistent definition of sarcopenia means studies cannot be directly compared, limiting generalisability of results. The relationship between changes in musculature and ADT and/or radiotherapy stresses the importance of screening for sarcopenia. However, current best practices are not established to provide guidance on how to identify patients for targeted interventions to minimise the risk of increased mortality and decreased quality of life.

Keywords:  Androgen-deprivation therapy; mortality; muscle; prostate cancer; radiotherapy; sarcopenia

DOI:  https://doi.org/10.1016/j.clon.2026.104050
Int J Mol Sci. 2026 Jan 30. pii: 1392. [Epub ahead of print]27(3):

Molecular Bases of Myopathies and Their Impact on Clinical Practice: Advances and Future Perspectives.

Martín Campuzano-Donoso, Claudia Reytor-González, Melannie Toral-Noristz, Yamilia González, Daniel Simancas-Racines.

  Myopathies represent a highly heterogeneous group of primary muscle disorders, traditionally classified based on clinical presentation and histopathological findings. Recent breakthroughs in molecular genetics, immunology, and pathophysiology have revolutionized the understanding, diagnosis, and management of these conditions. Both inherited and acquired forms of myopathy, including structural, metabolic, inflammatory, endocrine, and mitochondrial subtypes, are now recognized to arise from diverse pathogenic mechanisms such as impaired calcium handling, mitochondrial dysfunction, chronic inflammation, altered metabolism, and defective muscle regeneration. The advent of next-generation sequencing technologies has enabled more precise diagnosis of genetic forms, while the discovery of novel molecular biomarkers and immunological signatures offers promising avenues for disease monitoring and stratification across the broader spectrum. Importantly, molecular and mechanistic insights have redefined clinical classifications, allowing for better prognostic predictions and patient-tailored therapeutic approaches. Innovative treatments, including gene therapy, antisense oligonucleotide therapies, immune-modulating agents, metabolic support strategies, and targeted pharmacological interventions, are progressively translating molecular knowledge into clinical applications. However, technical limitations, biological variability, and ethical considerations continue to pose significant challenges to the implementation of precision medicine in myopathies. In this narrative review, we comprehensively discuss the latest molecular findings, their integration into clinical practice, and the emerging therapeutic strategies based on these discoveries. We also highlight current limitations and propose future research directions aimed at bridging the gap between molecular insights and effective, equitable patient care.

Keywords:  molecular genetics; myopathies; next-generation sequencing; precision medicine; therapeutic strategies

DOI:  https://doi.org/10.3390/ijms27031392
Eur J Pharmacol. 2026 Feb 10. pii: S0014-2999(26)00136-6. [Epub ahead of print] 178654

Inhibiting the NLRP3 inflammasome with MCC950 ameliorates muscle atrophy in cancer cachexia.

Xiaojuan Pan, Junjie Fu, Xiaofan Gu, Meng Fan, Lixuan Pan, Yun Zhao, Xuan Liu, Xiongwen Zhang.

  Cancer cachexia-associated muscle atrophy represents a critical clinical challenge in advanced malignancies. Cancer cachexia is known as an inflammation-related disease, and the NoD-like receptor family pyrin domain-3 (NLRP3) inflammasome plays a significant role in cancer cachexia, especially in muscle atrophy. In the present study, the efficacy of MCC950, a selective NLRP3 inhibitor, on cancer cachexia-associated muscle atrophy was observed both in cultured C2C12 myotubes underwent various simulated cancer cachexia injuries and in cancer cachexia model mice bearing C26 colon tumor cells. In vitro, MCC950 alleviated C2C12 myotube atrophy induced by conditioned medium from tumor or tumor-macrophage co-cultures. In vivo, MCC950 markedly attenuated cachexia symptoms such as body weight loss and muscle atrophy in C26 tumor-bearing mice. Mechanistically, in tumor or tumor-macrophage co-culture, MCC950 suppresses NLRP3 inflammasome activation, reduces IL-1β and IL-18 release, subsequently decreases the potency of inducing NF-κB activation and Atrogin-1-mediated ubiquitin-proteasome degradation in myotubes, thereby attenuates C2C12 myotube atrophy. Furthermore, in muscle cells, MCC950 directly silences NLRP3 inflammasome signaling, inhibits pyroptosis and IL-1β/IL-18 secretion, suppresses muscle protein degradation to rescue cancer cachexia-driven muscle atrophy. These findings revealed the important role of NLRP3 inflammasome in cancer cachexia and also suggested the possibility of developing NLRP3 inflammasome inhibitors such as MCC950 to be novel therapeutic candidates for cancer cachexia treatment.

Keywords:  Cancer Cachexia; MCC950; Muscle atrophy; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.ejphar.2026.178654