bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–04–19
forty-five papers selected by
Anna Vainshtein, Craft Science Inc.



  1. Aging Dis. 2026 Apr 03.
      Skeletal muscle homeostasis and regenerative capacity depend on efficient protein turnover, organelle quality control, and metabolic adaptation. Disruption of these processes contributes to muscle atrophy and functional decline during aging and various pathological conditions. Autophagy, a lysosome-dependent degradative pathway, maintains muscle integrity by clearing damaged proteins and organelles, preserving mitochondrial quality, and supporting muscle stem cell (MuSC) function. Both insufficient and excessive autophagy are detrimental: reduced flux impairs proteostasis, mitochondrial function, and regeneration, whereas hyperactivation drives excessive protein degradation, mitochondrial loss, and muscle wasting under stress. This review discusses molecular mechanisms regulating autophagy in skeletal muscle, including nutrient- and energy-sensing pathways (AMPK and mTORC1), transcriptional control of autophagy and lysosomal genes, and mitochondrial modulators. Evidence from genetic models and disease contexts indicates that both insufficient and excessive autophagy are associated with muscle degeneration, highlighting the need for balanced autophagic control rather than simple activation or inhibition. Together, these observations support a conceptual framework in which skeletal muscle health depends on maintaining autophagic activity within a context-dependent functional range, although this range is not yet quantitatively defined. This framework provides a useful basis for considering therapeutic strategies targeting muscle wasting.
    DOI:  https://doi.org/10.14336/AD.2026.0170
  2. Physiol Rep. 2026 Apr;14(8): e70874
      Skeletal muscle exhibits a remarkable adaptive capacity; endurance training enhances mitochondrial capacity, whereas resistance training improves mechanical strength. Despite these differences, both training impose repeated contractile and remodeling demands on skeletal muscle, suggesting a conserved transcriptional response that may underpin the muscle's capacity to endure long-term training. However, a systematic analysis of the universal gene signature common to both training types has not yet been conducted. We therefore reanalyzed microarray datasets from human skeletal muscle samples obtained before and after endurance and resistance training. We first identified differentially expressed genes in each dataset, then performed a cross-dataset comparison to determine reproducible transcriptional responses across heterogeneous training protocols. Our results identified extracellular matrix (ECM) remodeling-related genes as conserved transcriptional responses to both endurance and resistance training. Moreover, we observed modality-associated gene signatures: endurance training was associated with ECM-adhesion and matrix connectivity, whereas resistance training preferentially promoted ECM structural maturation and reinforcement. These findings suggest that ECM-centered transcriptional regulation is a conserved and reproducible feature of skeletal muscle responses to both endurance and resistance training. The central role of ECM remodeling in the plasticity of human skeletal muscle establishes a comprehensive framework for future mechanistic investigations into how exercise induces cellular adaptations.
    Keywords:  endurance training; exercise gene expression; extracellular matrix remodeling; muscle transcriptome; resistance training; skeletal muscle adaptation
    DOI:  https://doi.org/10.14814/phy2.70874
  3. Mol Metab. 2026 Apr 13. pii: S2212-8778(26)00051-7. [Epub ahead of print] 102367
      The transcriptional repressor B cell lymphoma 6 (BCL6) is highly expressed in skeletal muscle. Although transcriptome-wide studies have shown BCL6 dysregulation in muscular dystrophies, investigations into its endogenous roles in muscle biology remain scarce. We therefore generated skeletal muscle-specific Bcl6 knockout (M-Bcl6 KO) mice and used adeno-associated virus to knockdown (KD) Bcl6 selectively in limb muscles of mice. In both models, Bcl6 deficiency led to reduced muscle mass and contractility. Single-nucleus RNA sequencing and biochemical analyses revealed upregulation of Socs2, and inhibition of the IGF1/AKT pathway. Mitochondrial respiration was significantly reduced in permeabilized myofibers upon Bcl6 KO and KD, and electron microscopy showed decreased mitochondrial density and altered morphology. Pathways regulating mitochondrial quality control were also downregulated. While Bcl6 KO did not significantly impair baseline treadmill running capacity, it blunted the adaptive response to endurance training. These findings demonstrate that Bcl6 is a critical regulator of skeletal muscle mass and mitochondrial bioenergetics, acting through transcriptional control of signaling and metabolic pathways essential for the maintenance of muscle mass and function.
    Keywords:  BCL6; endurance training; mitochondria; muscle atrophy; oxidative phosphorylation; respiration; skeletal muscle; weakness
    DOI:  https://doi.org/10.1016/j.molmet.2026.102367
  4. Stem Cell Res Ther. 2026 Apr 15. pii: 139. [Epub ahead of print]17(1):
       BACKGROUND: Duchenne muscular dystrophy (DMD), caused by mutations of the DMD gene, is a lethal degenerative disease with no cure. Stimulating myogenesis of muscle stem cells (MuSCs) represents a promising strategy to ameliorate muscle pathology in DMD patients. Although previous work has revealed a role of N-terminal methyltransferase 1 (NTMT1) in myogenesis, its potential as a therapeutic target to ameliorate muscular dystrophy remains unexplored.
    METHOD: We employed GD433, a highly specific and potent pharmacological inhibitor of NTMT1, and evaluated its role in myogenesis using cell and animal models (mdx mice). C2C12 and primary myoblasts, and MuSCs were treated with GD433, and cell proliferation, differentiation, fusion, and gene expression were examined. Mdx mice were treated by intraperitoneal injection of GD433 (25 mg/kg, 5 days/week), and muscle pathology was evaluated. We finally employed co-immunoprecipitation (IP) and methylation-specific antibodies to identify NTMT1 substrates in myoblasts.
    RESULTS: A low dose of GD433 (300 nM) significantly enhances the differentiation and fusion of cultured C2C12 and primary myoblasts without affecting their proliferation. Similar effects are observed in myofiber-associated MuSCs. GD433 further enhances myogenic differentiation and muscle regeneration in mdx mice. Mechanistically, GD433 elevates expression of myogenic differentiation and fusion factors (Myog, Mymk, Mymx) through affecting KLHK31 methylation. Specifically, GD433 reduces the methylation level of KLHL31, promoting its interaction with MYOD and upregulating the expression of Myog, Mymk and Mymx.
    CONCLUSION: These results show that pharmacological inhibition of NTMT1 by GD433 promotes myogenic differentiation and enhances muscle regeneration in mdx mice. The pro-myogenic effect of GD433 is associated with reduced KLHL31 methylation, which strengthens KLHL31-MYOD interactions to upregulate genes related to myogenic differentiation. This study highlights NTMT1 inhibition as a potential therapeutic target to improve muscle repair in DMD patients.
    Keywords:  Mdx mice; Methyltransferase; Myogenesis; Regeneration; Satellite cells; Skeletal muscle
    DOI:  https://doi.org/10.1186/s13287-026-04934-5
  5. Aging Cell. 2026 Apr;25(4): e70485
      Aging impairs skeletal muscle mass and function, but the cell-type-resolved transcriptional states and intercellular signaling changes in human muscle aging remain incompletely mapped. Here, we constructed a single-nucleus RNA sequencing (snRNA-seq) atlas of human vastus lateralis muscle from adult (22-60 years) and elderly (99-101 years) male donors. We identified a comprehensive cellular census and discovered a profound reorganization of the myofiber transcriptional landscape. Aging was characterized by a shift from robust "young" states (MYLK4+ type II, LRP1B+ type I fibers) to dysfunctional "old" states (RYR3+ type II, RYR3+ type I fibers), accompanied by a marked emergence of hybrid fiber subtypes. We mechanistically linked these hybrid fibers to key aging pathologies: RUNX1+ hybrid fibers displayed a transcriptional signature of denervation, while SAA1+ hybrid fibers exhibited features of fatty infiltration, correlated with an expansion of fibro/adipogenic progenitors (FAPs). Pseudotime trajectory analysis supported the progression from young to degenerative or adipogenic fates. The aged microenvironment was globally altered, featuring impaired metabolic activity in muscle stem cells, compromised immune surveillance and function decline of vascular compartments. Critically, cell-cell communication analysis revealed enhanced BMP and Laminin signaling from FAPs to myofibers in aged tissue. Our work provided a high-resolution roadmap of human skeletal muscle aging, establishing denervation and FAP-driven fatty infiltration as key cellular mechanisms driving functional decline, and revealing novel targets for therapeutic intervention.
    Keywords:  denervation; fatty infiltration; muscle fiber types; single‐nucleus RNA sequencing; skeletal muscle aging
    DOI:  https://doi.org/10.1111/acel.70485
  6. J Clin Invest. 2026 Apr 15. pii: e205442. [Epub ahead of print]136(8):
      Skeletal muscle has the impressive capacity to completely regenerate even after relatively severe injuries in young individuals, but this process is dysregulated in multiple cell types in the microenvironment in numerous diseases and aging. In this issue of the JCI, Cao et al., using an elegant set of genetic mouse models and pharmacological approaches, demonstrated that gasdermin E (GSDME) was required in myeloid cells after sterile muscle injury to normally regenerate muscle and that downstream IL-18 release prevented intramuscular ectopic fat deposition. GSDME expression was reduced in human muscles from aged individuals, and Gsdme was increased after muscle injury in young, but not old, mice. The ability of IL-18 to partially improve regeneration in aged GSDME-knockout mice demonstrates the potential clinical relevance of this finding in dysregulated muscle regeneration associated with aging.
    DOI:  https://doi.org/10.1172/JCI205442
  7. Am J Physiol Cell Physiol. 2026 Apr 14.
      Background: Fibrosis accumulates in skeletal muscle over time and leads to greater muscle rigidity, stiffness, and increased risk of injuries. However, investigations of appropriate experimental models to study the mechanisms through which muscle fibrosis occurs are often confounded by injury or disease. The contribution of platelet-derived growth factor receptors alpha and beta (PDGFRα or PDGFRβ) to muscle fibrosis is yet to be clarified. We hypothesized that both receptors would promote extracellular matrix (ECM) deposition and fibrosis, causing muscle stiffening and weakness, with sex-specific differences arising due to hormonal influences on receptors. Methods: To test this hypothesis, we used a mouse model with inducible overactive PDGFRα or PDGFRβ signaling and assessed various indicators of muscle function, metabolism, motor coordination, exercise capacity, collagen deposition, and muscle stiffness. Results: Overactive PDGFRα led to higher collagen deposition, collagen crosslinking, and AGE/LOX protein levels, all of which correlated with greater muscle stiffness compared to controls. Overactive PDGFRβ resulted in greater muscle mass and lower fat mass and had higher collagen deposition in female mice compared to controls. There were also sex-specific differences with fibrotic remodeling, muscle stiffness, and muscle size in response to overactive PDGFRα and PDGFRβ signaling. Conclusion: These findings establish PDGFRα and PDGFRβ signaling as distinct regulators of muscle remodeling and establish overactive PDGFRα as a mouse model to study skeletal muscle fibrosis in the absence of other confounding variables.
    Keywords:  Collagen; Crosslinking; Isotope labelling; Muscle function; Muscle hypertrophy
    DOI:  https://doi.org/10.1152/ajpcell.00035.2026
  8. Int J Mol Sci. 2026 Mar 28. pii: 3080. [Epub ahead of print]27(7):
      CLN1 disease, caused by mutations in the PPT1 gene, is a fatal neurodegenerative lysosomal storage disorder. While central nervous system (CNS) pathology is well documented, the impact on peripheral tissues remains unclear. Having previously described severe spinal cord pathology, we investigated whether PPT1 deficiency also impacts the neuromuscular junction (NMJ) and skeletal muscle, and whether early systemic gene therapy can prevent these disease manifestations. NMJ morphology, terminal Schwann cell (tSC) coverage, and skeletal muscle structure were examined in symptomatic and end-stage Ppt1-/- mice. Neonatal mice received systemic AAV9-hCLN1 gene therapy via intravenous injection. Untreated Ppt1-/- mice exhibited pronounced NMJ pathology, including progressive tSC loss, apparently reduced innervation, and increased abnormal acetylcholine receptor clustering. In parallel, we observed skeletal muscle atrophy, with decreased myofiber diameter and reduced myonuclear content, despite preserved sciatic nerve morphology. Systemic AAV9-hCLN1 therapy partially prevented or ameliorated these phenotypes, preserving NMJ innervation and muscle fiber structure. These findings identify peripheral NMJ and muscle abnormalities as previously unrecognized features of CLN1 disease and provide proof-of-concept that early systemic gene therapy can mitigate these effects. Our results highlight the systemic nature of CLN1 pathology and support the need for treatments that address both CNS and peripheral targets for comprehensive disease modification.
    Keywords:  AAV9 gene therapy; CLN1 disease; muscle atrophy; neuromuscular junction; peripheral nervous system; terminal Schwann cells
    DOI:  https://doi.org/10.3390/ijms27073080
  9. Br J Sports Med. 2026 Apr 15. pii: bjsports-2025-111213. [Epub ahead of print]
      
    Keywords:  Aging; Creatine; Exercise training; Longevity; Muscle, Skeletal
    DOI:  https://doi.org/10.1136/bjsports-2025-111213
  10. FASEB J. 2026 Apr 30. 40(8): e71777
      Mitochondria are composed of phospholipid bilayers rich in phosphatidylcholine (PC). StAR-related lipid transfer domain-containing protein 7 (STARD7) functions as a lipid transfer protein that plays a crucial role in maintaining mitochondrial PC homeostasis. In this study, we investigated the physiological role of STARD7 in skeletal muscle using muscle-specific knockout (mKO) mice. STARD7 expression was markedly higher in the soleus, a mitochondria-dense slow-twitch muscle, compared with fast-twitch fibers. Although muscle fibers from mKO mice exhibited no apparent structural abnormalities, their endurance exercise capacity was markedly reduced. RNA-seq analysis revealed suppressed expression of fast-twitch-related genes accompanied by a reduction in fast-twitch fibers. At the mitochondrial level, respiratory chain complexes remained intact, but oxygen consumption was consistently decreased. Targeted lipidomic analysis showed decreased levels of PC, cardiolipin (CL), and coenzyme Q in mKO mitochondria, particularly in the soleus. Conversely, expression of CL biosynthetic enzymes was unchanged, and an in vitro binding assay indicated that STARD7 preferentially transfers linoleic acid-containing PC required for CL remodeling. Furthermore, electron microscopy revealed disorganized cristae structures, whereas 4-HNE-modified proteins, mtDNA content, and OPA1 processing remained unaffected. Together, these findings demonstrate that STARD7 plays an essential role in maintaining mitochondrial integrity and function in skeletal muscle, and its loss likely contributes to the pathogenesis of mitochondrial myopathy.
    Keywords:  cardiolipin; lipid transfer protein; mitochondria; phosphatidylcholine; phospholipid; skeletal muscle; soleus
    DOI:  https://doi.org/10.1096/fj.202504528R
  11. Nat Commun. 2026 Apr 11. pii: 3436. [Epub ahead of print]17(1):
      Myofibrillar myopathy 6 is a rare, autosomal-dominant neuromuscular disorder caused by an amino acid exchange Pro209Leu in the co-chaperone BAG3, which disrupts muscle protein turnover and causes severe muscle weakness and shortened lifespan. We generated transgenic mice overexpressing the human mutant BAG3P209L-GFP, which rapidly develop skeletal muscle weakness unlike controls expressing BAG3WT-GFP. Here we show that mutant mice exhibit sarcomere breakdown, inflammation, protein aggregates, centralized nuclei and mitochondrial defects in their skeletal muscles, thereby reducing contraction force by ~90%. Omics profiling uncovered impaired protein synthesis, blocked autophagy, impaired mitophagy and loss of sarcomere proteins. Pathway modulation in vitro and in vivo showed autophagy dysfunction as the primary driver for the pathology, while BAG3 knockdown gene therapy markedly restored muscle function in vivo. In summary, this model recapitulates core disease features, revealing how BAG3 aggregates and loss of BAG3 function impair autophagy to drive muscle degeneration.
    DOI:  https://doi.org/10.1038/s41467-026-71749-6
  12. Nat Commun. 2026 Apr 14.
      Muscle stem cells (MuSCs) fuse to form myofibers to repair skeletal muscle after injury. Within the regenerative MuSC niche, restorative macrophages stimulate MuSC fusion, although the molecular mechanisms involved are largely unknown. Here, we show that restorative macrophages secrete ribonuclease T2 (RNAseT2) to stimulate MuSC fusion. RNAseT2 enters MuSCs via the mannose receptor and induces the formation of actin bundles in MuSCs, enabling cell/cell fusion. Mechanistically, RNAseT2 binds to Ste20-like kinase (SLK), which itself triggers the phosphorylation-mediated activation of N-WASP, through Paxillin phosphorylation, allowing actin bundling necessary for MuSC fusion. In vivo, overexpressing RNAseT2 in regenerating muscle increases fusion in newly formed myofibers in mouse and zebrafish while macrophages deficient for RNAseT2 gene lead to fusion defect and smaller myofibers. This study reveals a new function for the highly conserved RNAseT2 and provides a new molecular mechanism by which restorative macrophages support MuSC fusion during muscle repair.
    DOI:  https://doi.org/10.1038/s41467-026-71990-z
  13. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70269
      Skeletal muscle accounts for approximately 40% of total body mass and is essential for locomotion, metabolic regulation and systemic homeostasis. Adipose tissue is increasingly recognized as an active component of the muscle's regenerative microenvironment. During muscle repair, adipose tissue contributes to local metabolic support and paracrine signalling, but its effects are highly context dependent. Tightly regulated presence of adipose tissue accompanies effective regeneration, whereas excessive or dysregulated ectopic fat accumulation leads to persistent functional impairment. This review synthesizes recent experimental and translational studies investigating the cellular origins, regulatory mechanisms and functional consequences of adipose tissue during skeletal muscle repair. We propose three potential therapeutic directions to improve pathological muscle repair by modulation of the adipose-related intramuscular regenerative microenvironment: (1) targeted modulation of fibro-adipogenic progenitors (FAPs) to curb pathological adipogenesis and fibrosis while leveraging beneficial mediators such as adiponectin and leptin; (2) adipose-derived stem cell transplantation and exosome-based approaches to deliver multipotent cells and remodel the repair microenvironment; and (3) induction of adipose browning to enhance energy availability, immune tone and vascularization while recognizing its context-dependent liabilities. Together, these strategies position adipose tissue as a plastic and environment-sensitive regulator of muscle regeneration and provide a framework for precision interventions to improve structural and functional outcomes.
    Keywords:  adipokines; adipose tissue; adipose‐derived stem cells; browning; fatty infiltration; fibro‐adipogenic progenitors; skeletal muscle repair
    DOI:  https://doi.org/10.1002/jcsm.70269
  14. Biochem Biophys Res Commun. 2026 Apr 07. pii: S0006-291X(26)00501-2. [Epub ahead of print]817 153737
      Skeletal muscle lipid metabolic homeostasis is essential for normal function and physical performance. Ubiquitin-fold modifier 1 ligase 1 (UFL1), the sole E3 ligase in the UFMylation system, is widely involved in lipid metabolism across various cell types, yet its specific role in skeletal muscle remains unclear. Using skeletal muscle-specific UFL1 knockout mice and UFL1-manipulated C2C12 cells, we found that UFL1 deficiency led to marked lipid droplet accumulation, elevated triglyceride (TG) and total cholesterol (TCH) levels, and upregulation of the lipid droplet coat protein perilipin 2 (PLIN2), whereas UFL1 overexpression reversed these effects. Mechanistically, expression of the lipogenic enzymes acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) was significantly increased in UFL1-deficient tissues and cells, whereas protein levels of peroxisome proliferator-activated receptor alpha (PPARα) and its downstream target carnitine palmitoyltransferase 1A (CPT1A) remained unchanged, effects reversed by UFL1 overexpression. Collectively, these findings establish UFL1 as a critical regulator of skeletal muscle lipid homeostasis through the ACC1-FASN axis, independent of fatty acid oxidation, revealing a novel target for treating skeletal muscle lipid metabolic dysfunction.
    Keywords:  ACC1-FASN axis; Lipid metabolism; Skeletal muscle; UFL1
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153737
  15. Autophagy Rep. 2026 ;5(1): 2649064
      Skeletal muscle atrophy is a pathological condition characterized by the progressive loss of muscle mass and function, driven by factors such as disuse, inflammation, and aging. While the ubiquitin-proteasome system is established as the central mediator of myofibrillar protein degradation, the role of selective autophagy and the degradation of organelles remains underexplored in this context. To address this, we employed a quantitative, time-resolved in vitro analysis of protein synthesis and degradation in C2C12 myotubes undergoing TNF-α-induced atrophy, using dynamic Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) coupled with LC-MS/MS. Our data challenges the classical view of atrophy as a uniform, degradation-centric process. Instead, we reveal temporally distinct patterns of selective protein turnover, including differential degradation of myofibrillar, ribosomal, and endoplasmic reticulum (ER)-resident proteins. Early atrophy is characterized by suppressed short-term protein synthesis, increased ubiquitin-ligase expression, proteasomal activation, and ribosome turnover. In contrast, late atrophy features proteasome-dependent myofibrillar protein degradation, selective synthesis, and degradation of mitochondrial and cytoplasmic ribosomes, indicative of metabolic adaptation. Moreover, we identify a temporal shift in autophagic selectivity: from ER homeostasis to a stress-induced ER-degradation program. Notably, autophagy inhibition during atrophy leads to the accumulation of ER-phagy receptors Tex264 and Calcoco1, implicating ER-phagy as a key contributor to atrophic remodeling and highlighting receptor-mediated selective autophagy as a regulatory axis in muscle proteostasis. By elucidating the role of ER-phagy, this study opens avenues for therapeutic interventions targeting proteostasis in inflammation-induced muscle-wasting, contributing to a refined understanding of muscle atrophy beyond proteasomal degradation, particularly in acute inflammatory conditions such as sepsis.
    Keywords:  Dynamic SILAC; ER-phagy; TNF-α; autophagy; inflammation; muscle atrophy; proteostasis
    DOI:  https://doi.org/10.1080/27694127.2026.2649064
  16. Cancer Cell. 2026 Apr 16. pii: S1535-6108(26)00166-2. [Epub ahead of print]
      Cancer cachexia is a systemic metabolic syndrome driven by tumor-induced disruption of whole-body homeostasis. Characterized by skeletal muscle atrophy and adipose tissue loss, cachexia leads to functional decline, impaired quality of life, reduced treatment tolerance, and poor survival across multiple malignancies. Emerging evidence indicates that cachexia arises from complex and dynamic interactions between tumors and host organ systems, including immune, metabolic, endocrine, and neural networks, that collectively reshape energy balance, immune function, and tissue integrity. Despite its profound clinical impact, effective therapies remain limited, reflecting incomplete mechanistic understanding and the absence of integrated clinical frameworks. Here, we review recent advances in cachexia biology, including tumor-host signaling, multiorgan metabolic remodeling, and neuroendocrine regulation. We further propose a tumor-centric framework in which cachexia represents a progressive collapse of systemic homeostasis and outline translational strategies to guide mechanism-informed therapeutic interventions.
    Keywords:  adipose tissue loss; anorexia; cancer cachexia; energy balance; metabolic reprogramming; neuroendocrine regulation; skeletal muscle wasting; systemic inflammation; tumor-host interactions; whole-body homeostasis
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.012
  17. Ageing Res Rev. 2026 Apr 15. pii: S1568-1637(26)00135-2. [Epub ahead of print] 103143
      Aging is a complex biological process characterized by the loss of metabolic homeostasis, epigenetic drift, and systemic functional decline. Although exercise is widely recognized as a potent non-pharmacological intervention for aging, the mechanisms by which it translates transient metabolic fluctuations into long-term systemic adaptations remain incompletely understood. During physical activity, skeletal muscle exhibits significantly enhanced glycolytic flux, leading to the accumulation of lactate. This key metabolite is dynamically distributed across tissues via monocarboxylate transporters, acting as a pivotal signaling hub that links exercise load to systemic metabolic remodeling. The discovery of lysine lactylation (Kla) has redefined the biological significance of lactate, identifying it as a signaling molecule that functions as a molecular interface between cellular metabolic states and epigenetic regulation.Here, we systematically review the core "Exercise-Lactate-Kla" regulatory axis. We elucidate how exercise-induced lactylation retards the aging process at the molecular level by orchestrating mitochondrial quality control, maintaining immune homeostasis, promoting stem cell regeneration, and suppressing the senescence-associated secretory phenotype (SASP). Furthermore, we provide a comprehensive analysis of the cross-organ anti-aging effects of this axis across multiple physiological domains, including the neurological, cardiovascular, musculoskeletal, and metabolic systems. Concurrently, this review systematically evaluates existing research using a three-tier evidence grading framework, clarifying the differences in evidence strength across various mechanisms and identifying core causal gaps. This provides a novel theoretical framework for understanding the "metabolism-epigenetics" coupling mechanism by which exercise delays aging, and establishes a scientific foundation for formulating precise exercise prescriptions and developing lactylation-targeted anti-aging strategies in the future.
    Keywords:  Anti-aging; Epigenetics; Exercise; Lactylation; Metabolic reprogramming; Mitochondria
    DOI:  https://doi.org/10.1016/j.arr.2026.103143
  18. Immun Inflamm Dis. 2026 Apr;14(4): e70425
      Recent studies have shown that significant expression of PrPC protein is also present in skeletal muscle, and it plays a significant role in maintaining skeletal muscle homeostasis. Although the expression of PrPC in skeletal muscle has been clarified, the effects of PrPSc-mediated prion protein infection on sarcopenia in mice and its potential regulatory mechanisms remain unclear. This study investigated the role of PrPC in Prion-induced sarcopenia, using an animal model of prion disease based on intraperitoneal injection of the scrapie strain ME7 into wild-type mice and Prnp knockout mice. The results indicate that prion infection-induced sarcopenia exhibits muscle fiber type specificity, and that the lack of PrPC can prevent prion protein infection-induced sarcopenia, although the lack of PrPC may lead to reduced mitochondrial-endoplasmic reticulum homeostasis. These data provide novel evidence that prion infection affects skeletal muscle system health through myofiber-specific mechanisms.
    Keywords:  PrPC protein; Prnp knockout; mitochondria; sarcopenia; scrapie strain ME7; skeletal muscle
    DOI:  https://doi.org/10.1002/iid3.70425
  19. Sci Rep. 2026 Apr 16.
      Mitochondria are vital organelles that produce ATP through oxidative phosphorylation, sustaining skeletal muscle, a tissue with high energy demand. When mitochondrial function is impaired, intracellular energy and nutrient balance are disrupted, activating metabolic signaling pathways. However, these responses vary across models, and the relationship between muscle pathology and signaling remains unclear. To address this, we compared soleus muscle pathology in Polgmut/mut mice, a premature aging model, and Mito-mice∆, a mitochondrial disease model. Both exhibited abnormal histochemical activity in mitochondrial respiration complex II and IV, yet differed in severity of mitochondrial accumulation and fiber-type-specific vulnerability. To explore the basis of these differences, we examined metabolic signaling pathways. Notably, phosphorylation levels of AMPK, a key sensor activated in response to altered AMP/ATP ratios, were significantly different between the two models. These findings suggest that muscle pathology induced by mitochondrial dysfunction is determined less by the extent of abnormalities in mitochondrial respiration complexes than by the specific metabolic signaling pathways engaged. This highlights the importance of signaling context in shaping disease mechanisms and underscores the need to consider pathway-specific responses when investigating mitochondrial dysfunction in skeletal muscle.
    Keywords:  Metaboloc signaling; Mitochondria; Mouse models; Muscle pathology
    DOI:  https://doi.org/10.1038/s41598-026-48532-0
  20. Nucleic Acids Res. 2026 Apr 13. pii: gkag301. [Epub ahead of print]54(7):
      Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disease in which genetic mutations activate DUX4 expression in skeletal muscle. Currently, there are no approved therapies for FSHD. We developed Delpacibart braxlosiran (del-brax, also known as AOC 1020), an antibody oligonucleotide conjugate (AOC), for the treatment of FSHD that is designed to specifically target and reduce DUX4 mRNA in skeletal muscle. AOC 1020 is composed of DUX4 mRNA-targeting small interfering RNA (siRNA), siDUX4.6, conjugated to a human transferrin receptor 1 (TfR1)-targeting monoclonal antibody to facilitate productive siRNA delivery to muscle. We demonstrate that siDUX4.6 reduces DUX4-regulated gene expression in FSHD patient-derived myotubes in vitro and in skeletal muscle of the ACTA1-MCM; FLExDUX4 FSHD mouse model in vivo. Single systemic intravenous treatment was sufficient to prevent DUX4-induced muscle weakness and fibrosis in this FSHD mouse model and reduce DUX4-regulated genes by ∼75% 8 weeks post-dose. The pharmacokinetic profiles of AOCs with siDUX4.6 were comparable in murine and non-human primate muscle. These data demonstrate the potential of AOC 1020 to treat the underlying cause of FSHD by suppressing DUX4 expression in muscles of patients with FSHD. The safety and efficacy of AOC 1020 is currently being investigated in clinical trials.
    DOI:  https://doi.org/10.1093/nar/gkag301
  21. FASEB J. 2026 Apr 30. 40(8): e71808
      Skeletal muscle is the largest organ by mass in the human body, and its functional capacity depends on the precise coordination of protein synthesis, mitochondrial bioenergetics, and regenerative potential. Eukaryotic translation initiation factor 3 (eIF3), a 13-subunit complex (~800 kDa) best known for its multifaceted roles in cancer, is now emerging as a key translational regulator in skeletal muscle physiology and disease. Here, we present a perspective that synthesizes recent advances into a unifying "dual-phase guardian" model. In the first phase, eIF3f acts at the level of translation initiation as a scaffold bridging mTORC1 and S6K1, integrating anabolic and catabolic signals, particularly the MAFbx/Atrogin-1 ubiquitin-proteasome axis, to govern net protein synthesis and muscle mass. In the second phase, eIF3e remains bound to 80S ribosomes during early translation elongation (codons 1-60) of approximately 2700 mRNAs encoding mitochondrial and membrane-associated proteins, facilitating co-translational quality control through chaperone recruitment (e.g., CCT/TRiC). Haploinsufficiency of eIF3e in mice produces mitochondrial hyperfusion, diminished respiratory complex I activity, sarcomeric degeneration, and progressive loss of grip strength, a phenotype recapitulating features of mitochondrial myopathy. Complementing these findings, eIF3b supports satellite cell-mediated muscle regeneration by resolving RNA G-quadruplex structures in the 5'-UTR of Anp32e mRNA, while eIF3a modulates fibrotic remodeling through TGF-β/Smad3 signaling. We situate these subunit-level findings within the broader landscape of translational regulators in muscle (eIF2α/ISR, eIF5A, eEF2) and critically evaluate the translational potential and therapeutic challenges, including the absence of human clinical data, tissue-selectivity concerns, and species-specific limitations, that must be addressed before these mechanistic insights can inform treatment of sarcopenia, disuse atrophy, and mitochondrial myopathy.
    Keywords:  co‐translational quality control; eIF3; mTORC1; mitochondrial homeostasis; muscle atrophy; protein synthesis; skeletal muscle; translation elongation
    DOI:  https://doi.org/10.1096/fj.202600039R
  22. Redox Biol. 2026 Apr 08. pii: S2213-2317(26)00163-1. [Epub ahead of print]93 104165
      The mitochondrial selenoenzyme thioredoxin reductase 2 (TXNRD2) plays a critical role in redox homeostasis and reactive oxygen species (ROS) scavenging. While heart-specific deletion of Txnrd2 in mice resulted in cardiac dysfunction, TXNRD2 function in skeletal muscle, the major component of lean body mass, remains unclear. In human GWAS the TXNRD2 locus is associated with total lean mass. Here, we show that Txnrd2 muscle-specific knockout (mTKO) induces a lean phenotype characterized by muscle atrophy and diminished adipose tissues. mTKO mice were resistant to weight gain on standard and high-fat diet. Whole body glucose clearance was increased, and ATP levels in muscle were decreased, suggesting impaired mitochondrial energy production. Transcriptomic and metabolomic analyses revealed alterations in one-carbon metabolism and related pathways. Despite elevated glutathione levels, changes in key factors of cellular detoxification were consistent with compromised antioxidant defence system. In sum, we unravel that Txnrd2 deficiency in skeletal muscle rewires whole-body energy metabolism through mitochondrial dysfunction and impaired redox capacity.
    DOI:  https://doi.org/10.1016/j.redox.2026.104165
  23. Physiol Rep. 2026 Apr;14(7): e70851
      Sequestosome 1 (p62/SQSTM1) is a multifunctional scaffolding protein at the intersection of autophagy and metabolic regulation. While p62 deficiency causes mature-onset obesity and insulin resistance, its effects on skeletal muscle mass and function remain poorly understood. Male p62 knockout (p62-/-) and wildtype control mice (n = 9/group) were studied from 14 to 34 weeks of age. p62-/- mice exhibited greater food intake (+19.1%, p = 0.016), progressive weight gain (+41.5%, p < 0.001), and markedly elevated fat mass (+72.2%, p = 0.001), while lean mass was unchanged. Fasting hyperglycemia and impaired glucose tolerance (p < 0.05) confirmed systemic metabolic dysfunction. Despite this, p62-/- mice maintained grip strength, skeletal muscle weights, and myofiber cross-sectional areas comparable to controls. Molecular analysis revealed significantly elevated NBR1 (+61.6%, p = 0.020) and phospho-mTOR (+78.2%, p = 0.033) in soleus muscle, suggesting altered autophagic flux. p62-deficient male mice developed severe obesity and insulin resistance while maintaining skeletal muscle mass and grip strength at this intermediate timepoint. This phenotype was associated with altered mTOR and autophagy signaling. Whether muscle preservation is sustained long-term warrants further investigation, as chronic obesity and metabolic dysfunction may ultimately impair muscle health.
    Keywords:  NBR1; autophagy; insulin resistance; mTOR signaling; metabolic dysfunction; neuromuscular health; obesity; sequestosome 1; skeletal muscle preservation
    DOI:  https://doi.org/10.14814/phy2.70851
  24. Hum Mol Genet. 2026 Apr 15. pii: ddag029. [Epub ahead of print]35(7):
      Emery-Dreifuss Muscular Dystrophy (EDMD) is a progressive disease characterized by cardiac and skeletal muscle dysfunction. A primary cause of EDMD is loss of function of the X-chromosome gene emerin (EMD). Although emerin mutations were discovered over three decades ago, X-linked EDMD (X-EDMD) remains understudied largely due to the absence of an animal model with pathological features found in humans. Here, we show that rats lacking emerin (EMD(-/y)) develop motor issues and suddenly die, a major risk factor for patients with X-EDMD. Additionally, EMD(-/y) rats present with other hallmarks of X-EDMD. We found significant fibrosis, abnormal nuclear morphologies, functional deficits and left ventricular wall thinning in the heart of EMD(-/y) rats. Skeletal muscles of EMD(-/y) rats also exhibit altered myonuclei morphology in addition to reduced muscle fiber size. In both cardiac and skeletal muscles of EMD(-/y) rats, we identified altered expression of genes with roles in the cytoskeleton, fibrosis, and muscle contraction. Some of these genes have been previously found to be dysregulated in human muscles lacking emerin. Altogether, these findings identify EMD(-/y) rats as a preclinical model of X-EDMD that phenocopies many aspects of the disease in humans. This work also revealed genes that could potentially be used as biomarkers and targets to treat X-EDMD.
    Keywords:  Cardiac Disease; Genetic Disorders; Muscular Dystrophy; Skeletal Muscle Disease
    DOI:  https://doi.org/10.1093/hmg/ddag029
  25. Res Sq. 2026 Apr 08. pii: rs.3.rs-4934147. [Epub ahead of print]
      Single cell/nuclei technologies have revolutionized our understanding of the remodeling of complex multi-cellular tissue that accompanies injury, regeneration, and disease. Duchenne muscular dystrophy (DMD) is a fatal genetic disease of childhood characterized by progressive skeletal muscle weakness resulting from mutation of DMD and loss of functional dystrophin. Here we report, at single nuclei/cell resolution, on intramuscular cell and gene expression dynamics within a broad cohort of needle muscle biopsies obtained from DMD individuals with varying degrees of severity, including a subset with low levels of dystrophin. We report a strong negative correlation between expression of dystrophin and disease severity and report substantial differences in cellularity and cell type-specific gene expression in DMD severity groups versus healthy muscle. Expression signatures indicate that DMD myofibers become immunologically alert, upregulating innate and adaptive immune sensors, including TLR4, IL15, TNF family receptors and MHC and costimulators. In this cohort, dystrophic muscle was remodeled with 50% fewer myofibers with expansion and diversification of fibroblasts and myeloid cells. We identify a DMD-specific TNFα-responsive Thy-1+/C3+ fibroblast subpopulation which we propose are inflammatory tissue priming fibroblasts and three DMD-specific myeloid populations which express signatures of innate immune memory. There is an 8-fold increase in CD8+GZMK+/GZMB+ T cells (Tek), with characteristics of both adaptive and innate immune activity. We propose that these non-myofiber muscle resident cells interact and epigenetically instill long-term tissue memory to perpetuate and amplify a hyper-inflammatory state in DMD muscle, contributing to impaired regeneration, myofiber death and fibrosis. This compendium of single/cell nuclei serves as a valuable reference and has immediate impact for biomarker discovery, clinical trial design, identification of barriers to dystrophin replacement therapies and novel druggable cell mechanisms operating in DMD.
    DOI:  https://doi.org/10.21203/rs.3.rs-4934147/v1
  26. Aging Cell. 2026 Apr;25(4): e70472
      Sarcopenia is characterized by age-related declines in muscle strength and mass, along with impaired physical function. It remains an unmet medical need, and there are no pharmacological interventions approved for this indication. The activation of growth hormone secretagogue receptor (GHSR)-1a, also known as ghrelin receptor, stimulates food intake and has acute anabolic effects. However, its impact on aging muscles remains uncertain. We examined the effects of GHSR-1a deletion on sarcopenia measurements (muscle mass, strength, and endurance) by comparing young and aged male GHSR-1a knockout (KO) and wildtype (WT) mice (6-, 24-, and 28-month-old). Deletion of GHSR-1a improved muscle fatigue resistance, endurance, and muscle strength during aging without affecting muscle mass or longevity. Since muscle endurance is closely related to mitochondrial function, we examined mitochondrial biogenesis marker PGC-1α and mitophagy signaling via PINK1/p62 and found them improved in old mice with GHSR deletion. Proteomics analysis also revealed that mitochondrial components remain central for maintaining muscle mass and function. We further investigated the effects of pharmacological inhibition of GHSR-1a by its inverse agonist, PF-5190457, in male WT mice. PF-5190457 mimicked the effects of GHSR-1a deletion, including improved endurance and increased markers of mitochondrial biogenesis (PGC-1α) and different mitophagy markers (LC3II and Bnip3). PF-5190457 also reduced body weight and adiposity, which were not observed with GHSR-1a deletion. Overall, these findings suggest that GHSR-1a is a promising therapeutic target for age-related sarcopenia.
    Keywords:  GHSR‐1a; aging; mice; mitochondria; mitophagy; sarcopenia
    DOI:  https://doi.org/10.1111/acel.70472
  27. Cells. 2026 Apr 01. pii: 635. [Epub ahead of print]15(7):
      Tubular aggregate myopathy (TAM) is a rare inherited muscle disorder characterized by the abnormal accumulation of tubular aggregates (TAs) within skeletal muscle fibers. These aggregates, composed of compacted sarcoplasmic reticulum (SR) tubules, are strongly linked to disturbances in calcium (Ca2+) homeostasis. Clinically, TAM manifests with slowly progressive proximal muscle weakness, exercise intolerance, cramps, and myalgia, frequently beginning in childhood and often present with elevated serum creatine kinase levels. These symptoms can also be associated with some additional disorders, such as thrombocytopathy, miosis, hypocalcemia, hyposplenism, and ichthyosis, thereby resulting in a clinical picture that overlaps with symptoms of Stormorken (STRMK) syndrome. Considerable heterogeneity exists in age of onset, severity, and extra-muscular involvement, suggesting that TAM and STRMK represent a continuum rather than distinct entities. Histopathological hallmarks include TAs staining positive for SR proteins and displaying a honeycomb-like ultrastructure, consistent with aberrant SR remodeling. Mutations in genes encoding key regulators of store-operated calcium entry (SOCE), including STIM1 and ORAI1 have been identified as major contributors to TAM and its broader clinical spectrum, which encompasses STRMK syndrome, whereas mutations in CASQ1 and RYR1, have been described in only a minority of patients. Despite advances in delineating the genetic and molecular basis of TAM, key questions remain regarding the mechanisms that drive TAs formation and translate Ca2+ dysregulation into muscle dysfunction and multisystem disease. Understanding the molecular mechanisms underlying TAM and STRMK syndrome is crucial for developing targeted therapies. Moreover, further research is needed to elucidate additional pathways involved in disease progression and to refine genotype-phenotype correlations. This review summarizes current knowledge on the genetics, pathophysiology, clinical features, and diagnostic hallmarks of TAM, with particular emphasis on the role of Ca2+ homeostasis.
    Keywords:  calsequestrin1 (CASQ1); myopathy; skeletal muscle contraction; tubular aggregate myopathy (TAM)
    DOI:  https://doi.org/10.3390/cells15070635
  28. Metabolism. 2026 Apr 14. pii: S0026-0495(26)00130-7. [Epub ahead of print] 156620
       OBJECTIVE: The mechanisms by which skeletal muscle activity during exercise state modulates vascular function and atherosclerosis remain poorly understood. The aim of this study was to investigate the function of skeletal muscle/endothelium axis and determine whether and how skeletal muscle-derived Meteorin-like (Metrnl), a myokine implicated in metabolism and inflammation, exerts endothelioprotective and anti-atherosclerotic effects.
    METHODS: In in vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of skeletal muscle-derived Metrnl on vascular endothelial function and atherosclerosis. For loss-of-function, we generated skeletal muscle-targeted Metrnl-null mice on an apolipoprotein E gene knockout background. For gain-of-function, we restored skeletal muscle-derived Metrnl by systemic plasma administration and skeletal muscle-specific Metrnl overexpression mouse. In in vitro and ex-vivo experiments were conducted.
    RESULTS: The expression of Metrnl from skeletal muscle markedly increased in human and mice, thereby increased circulating Metrnl levels, mitigated inflammation responses and improved vascular endothelial function, consequently ameliorated atherosclerosis under chronic aerobic exercise condition. Importantly, the Metrnl loss-of-function experiments by skeletal muscle-specific Metrnl deficiency and neutralizing antibody against Metrnl exacerbated vascular inflammation, promoted leukocyte homing, and increased endothelial injury and atherosclerosis in mice. Conversely, the gain of skeletal muscle Metrnl function experiment by adeno-associated virus assay reversed these issues. In vitro and ex-vivo experiments exhibited that Metrnl decreased inflammation and endothelial damage. Mechanistically, the KIT/protein kinase B (Akt)/nuclear factor-κB signaling is essential for the benefits of Metrnl on endothelial cells.
    CONCLUSIONS: The findings concluded that skeletal muscle/artery axis exists and skeletal muscle modulates cardiovascular function via skeletal muscle-derived Metrnl under chronic aerobic exercise, and skeletal muscle-derived Metrnl may serve as a novel therapeutic target for metabolic disorders.
    Keywords:  Atherosclerosis; Chronic aerobic exercise; Endothelium; Inflammation; Skeletal muscle-derived Metrnl
    DOI:  https://doi.org/10.1016/j.metabol.2026.156620
  29. Am J Physiol Cell Physiol. 2026 Apr 14.
      Cancer cachexia is a multifactorial metabolic syndrome that profoundly reduces muscle mass, strength, efficacy of chemotherapy, and survival, yet no effective therapy exists. Unacylated ghrelin (UnAG), the predominant form of circulating ghrelin, promotes muscle growth and mitochondrial bioenergetics, but its role in cancer cachexia remains unknown. Four- to five-month-old male C57Bl/6N mice were assigned to three groups: non-tumor-bearing (NTB), tumor-bearing (TB), and tumor-bearing treated with UnAG (TB+UnAG). Lewis Lung Carcinoma cells were inoculated subcutaneously in the flank of the mice. Body weight, food intake, and tumor size were monitored for four weeks. Lower limb muscle mass, contractile function, mitochondrial respiration, and reactive oxygen species (ROS) production were measured, in conjunction with western blot, proteomic, and immunohistochemical analyses. Compared with NTB controls, TB mice exhibited marked loss of muscle mass and function, whereas UnAG treatment preserved ~50% of the muscle mass and ~70% of the contractile force. UnAG enhanced mitochondrial oxygen consumption, reduced ROS generation, and preserved mitochondrial DNA copy number and downregulated DNA mutation frequency. TB mice demonstrated increased oxidative stress and activation of protein degradation pathways, along with neuromuscular junction disruption-both of which were normalized by UnAG. These findings collectively demonstrate that UnAG mitigates cancer cachexia by modulating mitochondrial bioenergetics, oxidative and proteolytic stress, and neuromuscular junction integrity. UnAG represents a promising therapeutic candidate that may mitigate cachexia and improve both chemotherapy efficacy and the quality of life of cancer patients.
    Keywords:  Cancer cachexia; contractile properties; mitochondria; mitochondrial DNA; muscle wasting; unacylated ghrelin
    DOI:  https://doi.org/10.1152/ajpcell.00917.2025
  30. NPJ Regen Med. 2026 Apr 14.
    Core Outcome Set Review Group
      Biologically representative three-dimensional (3D) skeletal muscle models are required to understand the mechanisms underpinning muscle disease. The primary aim of this systematic review is to evaluate the current literature on 3D skeletal muscle models under tension. Its secondary aim is to explore injury mechanisms and generate a novel Core Outcome Set (COS) for reporting of such models. In vitro studies that utilised any skeletal muscle cell types cultured with an anchor system imposing axial strain were eligible for inclusion. A modified Delphi approach using corresponding authors of included studies was then developed to obtain a COS. This systematic review was reported in compliance with the PRISMA 2020 checklist. 37 articles were included. Of these, 7 articles induced an injury in their model. Cell lines used were both human and animal. Immunohistochemical testing on models revealed greatest concordance for myosin heavy chain (MHC), alpha actinin, and Pax7 as a means of demonstrating striated muscle. The final COS agreed on multiple reporting criteria for the validation of models based on morphology, phenotype and function. This systematic review summarises the current literature and has developed core outcome reporting for models of 3D skeletal muscle that impose axial strain.
    DOI:  https://doi.org/10.1038/s41536-026-00464-z
  31. J Appl Physiol (1985). 2026 Apr 14.
      Mechanistic target of rapamycin complex I (mTORC1) is a key regulator of cell growth and metabolism, and its activity increases with aging. Hyperactivation of mTORC1 is associated with the pathology of sarcopenia and mitochondrial dysfunction. Exercise training has been shown to improve muscle quality and function in people with sarcopenia. However, it is unknown if hyperactive mTORC1 will alter exercise training-induced adaptations. In this study, we examined the effect of endurance training on muscle function and metabolism in a mouse model of hyperactive mTORC1 (DEP Domain-Containing Protein 5 muscle-specific knockout (DEPDC5 mKO)). After 8 weeks of exercise training, DEPDC5 mKO mice had increased mitochondrial activity and TA muscle mass, despite no change in physical function. Furthermore, DEPDC5 mKO mice had a trend for reduction in the phosphorylation of the mTORC1 downstream target, ribosomal protein S6, which may have contributed to the lack of functional adaptations. In addition, there was a reduction in triglycerides (TGs) and phosphatidylcholines (PCs) in DEPDC5 mKO mice, suggesting an increase in lipid fuel use and alterations in lipid membrane composition due to an increase in mitochondrial activity. We conclude that hyperactive mTORC1 in muscle may attenuate functional adaptations to endurance exercise training, despite increasing mitochondrial respiration and alterations in lipid metabolism.
    Keywords:  exercise; mTORC1; metabolism; mitochondria; muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00730.2025
  32. Exp Gerontol. 2026 Apr 13. pii: S0531-5565(26)00110-5. [Epub ahead of print] 113131
       BACKGROUND: The current study explored the impact of high-intensity interval training (HIIT) and the administration of post-exercise plasma from young-either trained or sedentary-rats on skeletal muscle morphology and circulating irisin levels in aged rats.
    OBJECTIVE: This study investigates the effects of HIIT and plasma from both sedentary and trained young rats on skeletal muscle morphology, strength, and circulating irisin levels in aged rats.
    METHODS: Thirty-five aged male Wistar rats were divided into five groups: HIIT, plasma from trained young rats (PT), plasma from sedentary young rats (PC), Control Group (CT), and saline (S). Interventions lasted six weeks; outcome measures included body weight, grip strength, plasma irisin, and muscle histology.
    RESULTS: Both HIIT and PT significantly increased plasma irisin levels and improved muscle morphology. Plasma interventions reduced body weight; however, grip strength changes were not significant.
    CONCLUSION: HIIT and plasma from young trained rats may offer protective or restorative benefits against sarcopenia. These findings highlight the therapeutic potential of combining or alternating exercise and plasma-based strategies in elderly populations.
    Keywords:  Aging; High-intensity interval training (HIIT); Irisin; Morphology; Plasma injection; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.exger.2026.113131
  33. Nutrients. 2026 Mar 27. pii: 1076. [Epub ahead of print]18(7):
      Background: Extracellular vesicles (EVs) released from skeletal muscle mediate metabolic communication via microRNAs (miRNAs). While both circadian rhythms and exercise influence metabolism, the joint modulation of the muscle-derived EV miRNA landscape by circadian rhythms and chronic exercise remains undefined, particularly under the metabolic stress of obesity. Methods: Employing a 2 × 2 factorial design (Phase: ZT3 vs. ZT15; Condition: sedentary vs. exercise; ZT, Zeitgeber Time), EV-enriched fractions were isolated from ex vivo quadriceps muscle (QUA) cultures of high-fat diet-fed mice following an 8-week treadmill training regimen using polymer-based precipitation, and comprehensive miRNA profiling was performed by small RNA sequencing. Results: Principal component analysis (PCA) revealed that circadian phase accounted for a greater proportion of global variance in EV miRNA profiles than exercise. Differential expression analysis identified miR-1a-3p and miR-1b-5p as upregulated across both composite phase and exercise contrasts; however, condition-specific analyses indicated that this signal was primarily driven by the sedentary-phase comparison (ZT15-sed vs. ZT3-sed), in which the miR-29 family was also prominently co-upregulated, rather than constituting independent phase and exercise effects; this phase-associated signature was absent in the corresponding exercise-condition comparison. Exploratory functional enrichment of experimentally validated targets revealed phase-preferential association with metabolic and iron-heme pathways, whereas exercise-associated miRNAs mapped to signaling, inflammatory, and transcription-related networks. Conclusions: Circadian phase was the dominant contributor to global variance in muscle-derived EV-enriched miRNA profiles in obesity, as reflected by the phase-associated separation along principal component 1 (PC1, 33.47% of total variance), with exercise introducing context-dependent adaptive modulation. This study provides a foundational basis for investigating the temporal regulation of muscle secretome dynamics under high-fat diet conditions, highlighting temporal specificity as a key dimension in EV-mediated exercise physiology research.
    Keywords:  circadian rhythm; exercise; extracellular vesicles; high-fat diet; microRNA; skeletal muscle
    DOI:  https://doi.org/10.3390/nu18071076
  34. Cell Death Dis. 2026 Apr 11.
      Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the dystrophin gene. DMD manifests with progressive skeletal muscle wasting, cardiac dysfunction, and cognitive and neuropsychiatric symptoms. As the disease progresses, affected boys lose their ability to walk and die prematurely. All DMD patients lack the full-length DP427 dystrophin, whereas approximately 10% lose all dystrophins, including DP71, synthesized in various cell types, including myoblasts. There is evidence that the cognitive symptoms of DMD patients vary depending on the location of the mutation site and the number of missing dystrophins, and there is some indication that this may also be the case in skeletal muscle. We therefore investigated the roles of DP427 and DP71 during cell proliferation and fibre differentiation. We included paralogous utrophins in our analyses, particularly the UP395 isoform, owing to its presence in muscle and its partial ability to compensate for the lack of DP427. We demonstrated that DP71 and DP427 play important roles in cell viability during cell proliferation and fibre differentiation, respectively. Despite their different expression patterns, the absence of DP71 and DP427 resulted in a similar phenotype, including increased membrane permeability, mitochondrial aggregation, elevated ROS, and increased cyto- and genotoxicity, but induced substantially different transcriptome programs associated with impaired cell proliferation and structural reorganization of myotubes, respectively. The phenotype occurred independently of myofibre contraction, dysfunction of neuromuscular or myotendinous junctions, or other cell types. We further showed that the utrophin UP395 can partially compensate not only for DP427 but also for DP71. These results explain the observed differences in disease severity among DMD patients and suggest that individuals deficient in both DP71 and DP427 may require a different therapeutic approach than patients deficient in only DP427.
    DOI:  https://doi.org/10.1038/s41419-026-08725-x
  35. Mol Biol Rep. 2026 Apr 17. pii: 637. [Epub ahead of print]53(1):
      
    Keywords:  Akt; Cell proliferation; Renalase; Satellite cell; Self-renewal; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11033-026-11803-0
  36. Front Sports Act Living. 2026 ;8 1768179
      Skeletal muscle is increasingly recognized as an endocrine organ, and contraction-induced myokines are viewed as key mediators of the systemic benefits of exercise. This review synthesizes evidence on the roles and molecular mechanisms of major myokines-including IL-6, irisin, SPARC, oncostatin M (OSM), and decorin-in exercise-associated modulation of cancer-related inflammation and tumor progression. We propose two principal routes: direct effects on tumor cells (e.g., reduced proliferation and metastatic potential) and indirect effects mediated by remodeling of the tumor immune microenvironment. Nevertheless, the literature remains heterogeneous, and reported effects are strongly context dependent, contributing to ongoing debate. Personalized exercise prescriptions, together with deeper mechanistic studies, may accelerate the clinical translation of myokines as biomarkers and potential therapeutic targets.
    Keywords:  IL-6; OSM; SPARC; decorin; irisin; myokines
    DOI:  https://doi.org/10.3389/fspor.2026.1768179
  37. Am J Physiol Cell Physiol. 2026 Apr 16.
      Skeletal muscle wasting is a critical clinical challenge in patients with breast cancer treated with chemotherapy, given its correlation with increased mortality risk and decreased therapeutic efficacy. However, the mechanisms underlying this side effect remain poorly understood, slowing the development of effective preventive strategies. Here, we conducted a translational study using an innovative multimodal experimental design to comprehensively investigate the mechanisms driving chemotherapy-induced muscle atrophy. We analyzed 72 samples from 36 patients with breast cancer across four experimental groups at various time points during chemotherapy, complemented by in vitro experiments. Through histological, transcriptomic, targeted protein expression, and activity-based analyses, we identified NF-κB signaling and the subsequent upregulation of the ubiquitin-proteasome system as drivers of chemotherapy-induced muscle atrophy. In vitro, sulfasalazine effectively mitigated the imbalance in protein turnover and fully prevented muscle atrophy, offering promising perspectives for clinical translation and improving patient prognosis.
    Keywords:  cachexia; muscle biopsies; muscle wasting; skeletal muscle deconditioning; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1152/ajpcell.00148.2026
  38. Compr Physiol. 2026 Apr;16(2): e70147
      Research to date describes the suprachiasmatic nucleus (SCN) of the hypothalamus as the master pacemaker that synchronizes circadian rhythms in peripheral tissues. However, recent high-impact studies demonstrate that non-SCN tissues can also coordinate rhythms in other peripheral tissues. However, the extent to which the cardiac clock regulates peripheral clocks has not yet been tested. Therefore, we investigated the role of the cardiac clock in modulating extra-cardiac circadian function using a model of cardiac-specific deletion of the core clock protein Bmal1 (Bmal1 cKO). Bmal1 cKO mice demonstrated attenuated day-night differences in skeletal muscle core clock gene expression (Bmal1, Clock, Per1) and circadian expressed metabolic genes (Pdk4, Ppara) as well as impaired day-night muscle grip strength. In the kidney, Bmal1 cKO mice had blunted core clock gene and water balance gene expression (Avp) compared to WT mice. Proteomic analysis of serum identified fibulin 5 (Fbln5) as a potential cardiokine mediating peripheral circadian effects, with rhythmic expression of Fbln5 disrupted in the heart and serum of Bmal1 cKO mice compared to WT. Exogenous treatment of synchronized C2C12 myotubes and human renal cells with rFbln5 disrupted rhythmic clock gene expression. In vivo, supplementation of Fbln5 in the drinking water of healthy wildtype C57Bl6 mice also disrupted kidney muscle rhythms. RNA sequencing data suggested that Fbln5 alters circadian output programs via stress-activated mechanotransduction and metabolic remodeling. Importantly, these changes occur without overt SCN dysfunction. Together, we demonstrate a critical role for the heart in regulating peripheral circadian control through the novel circadian cardiokine Fbln5.
    Keywords:  BMAL1; Fbln5; cardiac; circadian rhythm
    DOI:  https://doi.org/10.1002/cph4.70147
  39. J Exp Biol. 2026 Apr 01. pii: jeb251614. [Epub ahead of print]229(7):
      Skeletal muscle is the universal biological motor, enabling a diverse range of movements throughout an animal's lifespan. Age-related changes in muscle structure differentially influence locomotor performance among individuals, but their broader impact across species and body sizes remains poorly understood. Exploring muscle ageing through a comparative lens has the potential to reveal conserved and divergent trends in muscle ageing, reflecting differences in life history, locomotor strategy and ecological context. Age-related changes manifest across structural scales - from motor units to whole musculoskeletal systems - accumulating in locomotor deficits. However, teasing apart the contributions across these scales or between biological ageing and disuse remains a major challenge, particularly when attempting to generalise across animal models or life histories. In this Review, we synthesise evidence on muscle ageing in different species across structural and size scales, overview methodologies used to quantify these changes, and highlight the potential for exercise interventions to mitigate age-related movement declines. We promote the potential for modelling approaches to complement experimental studies, enabling cause-effect relationships to unveil the properties most critical to age-related movement decline. Finally, we provide forward-looking perspectives for future studies to explore the mechanisms of muscle ageing and locomotor decline - guided by comparative, multi-scale and integrative approaches.
    Keywords:  Biomechanics; Energetics; Lifespan; Modelling; Muscle–tendon unit
    DOI:  https://doi.org/10.1242/jeb.251614
  40. J Cell Mol Med. 2026 Apr;30(8): e71133
      Sarcopenia is a muscle disorder characterized by progressive loss of muscle mass, strength and function with ageing. Non-coding RNAs have been reported to be involved in the progression of sarcopenia. The current study aimed to investigate the pathogenesis of sarcopenia. Based on the bioinformatics analyses and RT-qPCR validation, the lncRNA A430093F15Rik was selected as the potential target involved in sarcopenia progression. Its expression level was up-regulated with ageing in mice but down-regulated with myogenesis in C2C12 cells. Modulating A430093F15Rik showed that the inhibition of the lncRNA contributed to the attenuation of sarcopenia such as increased cell viability and enhanced myogenesis, while the overexpression promoted disease progression. The downstream effector of A430093F15Rik, miR-337-3p, showed opposite function to the lncRNA, while Fam168a showed similar effects. Moreover, modulating both factors also confirmed their distinct roles during sarcopenia progression. The dual luciferase and RNA pulldown assays then verified the direct binding between A430093F15Rik and miR-337-3p, and miR-337-3p and Fam168a, representing a ceRNA regulatory mechanism between A430093F15Rik, miR-337-3p and Fam168a. The current study identified a novel lncRNA, A430093F15Rik, that is involved in the progression of sarcopenia by acting as a competitive endogenous RNA (ceRNA) to sponge miR-337-3p and regulate the expression of Fam168a.
    Keywords:  A430093F15Rik; Fam168a; ceRNA; miR‐337‐3p; sarcopenia
    DOI:  https://doi.org/10.1111/jcmm.71133
  41. Front Cell Dev Biol. 2026 ;14 1792645
      Aging is intimately associated with multisystem functional decline and an increased risk of chronic diseases. A pivotal cytological basis underlying this process is the progressive dysregulation of the mitochondrial quality control (MQC) network. Emerging evidence suggests that MQC is not a singular process but rather a multitiered synergistic system encompassing mitochondrial biogenesis, dynamic remodeling, selective autophagy (mitophagy), proteostasis maintenance, and coordinated mitochondrial-organelle communication. This integrated network is critical for preserving cellular energy homeostasis, redox balance, and stress tolerance. During aging, impairments in mitochondrial genomic coordination, network topology, autophagic flux, and protein import and folding collectively contribute to bioenergetic decline, chronic low-grade inflammation, and metabolic imbalance. As a safe and sustainable nonpharmacological intervention, regular exercise systematically remodels MQC structure and function by integrating signaling axes such as AMPK, SIRT1, and p38 MAPK, thereby promoting coordinated mitochondrial renewal and partially reversing aging-associated mitochondrial dysfunction. On the basis of a systematic elucidation of the core mechanisms of MQC and its dysregulation during aging, this review highlights the differential regulatory effects of distinct exercise modalities-specifically endurance training, high-intensity interval training (HIIT), and resistance training-on mitochondrial dynamics, autophagic flux, proteostasis, and mitochondrial turnover. Furthermore, the intrinsic associations among exercise-MQC coupling, inflammatory responses, metabolic imbalances, and emerging peripheral biomarkers are explored. Finally, current research limitations and challenges in clinical translation are analyzed, and future research directions regarding dose-response relationships, multimodal exercise prescriptions, personalized strategies, and systemic integrated regulation are proposed. This review aims to provide a refined theoretical basis for optimizing exercise-based anti-aging interventions.
    Keywords:  age; aging; exercise; mitochondrial quality control; physical training
    DOI:  https://doi.org/10.3389/fcell.2026.1792645
  42. Cells. 2026 Apr 06. pii: 650. [Epub ahead of print]15(7):
      Skeletal muscle differentiation is tightly regulated by membrane potential dynamics and voltage-dependent ion channel activity. Potassium (K+) and calcium (Ca2+) currents cooperate to orchestrate the transition of myoblasts into fusion-competent myotubes, and alterations in this process are associated with dystrophic phenotypes. Here, we investigated the electrophysiological remodeling accompanying C2C12 myogenesis and the modulatory effects of the polyphenol resveratrol (RES) on calcium voltage-gated channel subunit alpha 1 S (CACNA1S, Cav1.1, L-type) currents. Whole-cell patch-clamp recordings were performed in proliferating and differentiating C2C12 cells to characterize the temporal expression of K+ currents and voltage-dependent Ca2+ channels (VDCCs). During differentiation, three electrophysiological subpopulations were identified according to K+ current profiles: SK4+/EAG-/Kir-, SK4-/EAG+/Kir-, and SK4-/EAG+/Kir+. This sequence paralleled a progressive membrane hyperpolarization from -20 mV to -70 mV, consistent with the physiological maturation of myogenic cells. In C2C12 myocytes, nimodipine-sensitive L-type currents were the only Ca2+ conductance observed. Their activation threshold (~-30 mV) and half-activation voltage (V/2 ≈ -12 mV) indicated the co-expression of embryonic and adult Cav1.1 isoforms. Exposure to RES (30 µM, 48 h) produced a depolarizing shift in activation (ΔV/2 ≈ +9 mV) and a reduction in current amplitude across all voltages, consistent with a transition toward the adult splice variant of Cav1.1. These findings suggest that RES promotes electrophysiological maturation of skeletal muscle cells by modulating calcium channel expression and gating behavior. Given its known ability to correct splicing abnormalities in CACNA1S and related genes, resveratrol emerges as a promising pharmacological agent for restoring calcium homeostasis in neuromuscular disorders such as myotonic dystrophy type 1 (DM1).
    Keywords:  calcium channel; myocyte; myogenesis; potassium channel; resveratrol
    DOI:  https://doi.org/10.3390/cells15070650
  43. Adv Sci (Weinh). 2026 Apr 17. e75355
      Disuse-induced muscle atrophy remains a therapeutic challenge due to its complex etiology. Osteocalcin (OCN) is a bone-derived hormone with metabolic functions, while its role in muscle atrophy remains poorly understood. Here, we identified a mechanosensitive Piezo1/osteocalcin/Irisin axis linking bone mechanotransduction to muscle homeostasis. We showed that bilateral hindlimb immobilization (IMM) markedly reduced circulating undercarboxylated OCN. OCN deficiency exacerbated IMM-induced muscle atrophy, whereas exogenous OCN attenuated muscle atrophy and promoted recovery. Mechanistically, Piezo1 acted as an upstream regulator of OCN, as pharmacological Piezo1 activation attenuated muscle atrophy in an OCN-dependent manner, whereas bone-specific Piezo1 knockdown abolished these protective effects. Furthermore, OCN exerted protective effects through the muscle receptor Gprc6a and the downstream effector Fndc5/Irisin, muscle-specific knockdown of either Gprc6a or Fndc5 abolished OCN-mediated protective effects. Notably, pair-feeding experiments demonstrated that OCN directly protects against muscle atrophy independent of increased food intake. Finally, we demonstrated functional conservation of this axis in porcine myotubes. Notably, only animal models were used in the current study, and future studies are needed to test if the signaling axis has relevance to humans. Collectively, this work establishes that the Piezo1/Osteocalcin/Irisin axis mediates mechanical unloading-induced muscle atrophy and highlights this axis as a promising therapeutic target for disuse-induced muscle atrophy.
    Keywords:  Fndc5/Irisin; Piezo1; muscle atrophy; osteocalcin
    DOI:  https://doi.org/10.1002/advs.75355
  44. bioRxiv. 2026 Apr 08. pii: 2026.04.06.716693. [Epub ahead of print]
      Myostatin (MSTN) is a TGFβ family ligand that restricts muscle growth. Genetic loss-of-function in MSTN increases muscle mass, reduces fat accumulation, and improves metabolic health in mice and humans, with no known adverse phenotypes. Thus, depleting MSTN has therapeutic potential for obesity, sarcopenia, and other muscle wasting conditions. Recently developed monoclonal antibodies (mAbs) targeting MSTN or its receptors are expensive, require frequent injections/infusions, and risk a loss of efficacy from the development of anti-drug antibodies. Here, we report a comparatively inexpensive and durable alternative to mAbs, a virus-like particle (VLP)-based active immunotherapy, termed "MS2.87-97", that elicits an antibody response against a discrete and unique epitope in mature MSTN protein, with no cross-reactivity to GDF11. Compared to controls, MS2.87-97-treated mice had less age-associated weight gain and exhibited significantly reduced body fat by DEXA scan. MS2.87-97-treated mice also had significantly improved bodyweight-adjusted grip strength, and upon dissection, they were found to have increased muscle mass. No major safety concerns were identified. Echocardiography revealed no evidence of functional impairment of the heart, and histological analysis showed no change in myocardial collagen deposition (fibrosis). These initial findings support the continued preclinical development of MS2.87-97 as an immunotherapeutic for treating obesity, sarcopenia, and muscle wasting.
    DOI:  https://doi.org/10.64898/2026.04.06.716693