bims-moremu 2026-06-21 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–06–21
thirty-six papers selected by
Anna Vainshtein, Craft Science Inc.

Impact of different exercise modalities on mitophagy in human skeletal muscle.
The nucleus as a mechanobiological hub in muscle aging.
DMD-Null mice exhibit severe muscle weakness, impaired regeneration, and deficient satellite cell function.
Short-changed: Limited short-chain fatty acid oxidative capacity in skeletal muscle mitochondria.
3D skeletal muscle model recapitulating the myostatin knockout phenotypic and mitochondrial metabolic features.
From autophagy to mitophagy: Quality control mechanisms in skeletal muscle.
Impaired skeletal muscle recovery: Immune cell dynamics across age and sex.
Senescence as a regulatory mechanism in skeletal muscle repair in young mice.
Collagen VI is a fibrosis-associated signal disrupting muscle regeneration across distinct human myopathies.
NuMA1 controls myonuclear motility in striated skeletal muscle through AMPK activity and is impaired in Duchenne muscular dystrophy.
Voltage-gated potassium channels mediate thyroid hormone control of skeletal muscle excitability.
Myostatin Signaling in Skeletal Muscle: Implications for Athletic Performance.
Modulation of satellite cell function to alleviate age-related sarcopenia: Electrical stimulation & Ca²⁺ signaling combined approach.
Myostatin Inhibitory D‑Peptides Induce Skeletal Muscle Hypertrophy along with Alteration of Bioactive Sphingolipid Metabolism.
Targeting muscle fibrosis using non-specific collagenase injections destabilizes the basal lamina and induces matrix remodeling.
Age-Dependent Effects of Adrenomedullin on Muscle Fiber Composition, Angiogenesis, and Muscle Satellite Cells Maintenance.
Skeletal muscle overuse injury: pathophysiological mechanisms, molecular pathways, and rehabilitation strategies.
Macrophage regulation of extracellular matrix remodeling in aging skeletal muscle.
Deletion of Tgf-β1 From CD206+ M2 Macrophages Ameliorates Obesity-Induced Suppression of Myogenesis and AMPK Phosphorylation in Skeletal Muscle.
Short-term high-fat feeding induces muscle-type-specific signaling adaptations in skeletal muscle of male rats.
RNF10 attenuates age-related muscle atrophy by promoting p53 degradation and alleviating oxidative stress.
Elevated MyoD1 levels expand genome-wide binding and the repertoire of regulated genes.
Vdr-Pparα-Plin5-regulated lipid droplet dynamics mediates exercise protection against HFD-induced skeletal muscle ectopic lipid deposition and insulin resistance in mice.
Prolonged heat stress induces autophagy in mouse skeletal muscle.
Exercise Training Stimulates the Release of Glutathione Peroxidase 1 (GPX1)-Enriched Extracellular Vesicles That Promote Angiogenesis.
Myosin Post-Translational Modifications Associated With Critical Illness Myopathy.
Preclinical efficacy of a gene therapy for CHKB-mediated muscular dystrophy.
Nuclear Enlargement as a Histological Hallmark of Skeletal Muscle Aging, Revealed by Deep Learning-Driven Analysis and Validated in Inflammatory Myopathies.
TRIM32 controls timely cell cycle exit in muscular differentiation through downregulation of c-Myc mRNA.
Exercise-induced myokines in metabolic regulation: mechanisms, mimetics, and translational potential.
Emerging evidence for skeletal muscle as a target of BPA exposure.
Systematic review and meta-analysis of the effects of exercise in older adults with sarcopenia.
Exercise-secreted antitumor myokines: mechanistic insights and translational potential.
Statins promote muscle metabolic danger and NLRP3-mediated myopathy via lower protein-prenylation and YAP.
Muscle Ageing and Sarcopenia Study (MASS) Lifecourse: a valuable resource for understanding skeletal muscle ageing.
GLP-1 Receptor Agonists for Obesity Management in Older Adults: A Scoping Review on the Risk of Sarcopenia and Sarcopenic Obesity.

Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00153-4. [Epub ahead of print]404 63-79

Impact of different exercise modalities on mitophagy in human skeletal muscle.

Cristóbal Muñoz-Medina, Alfonso Carriel-Nesvara, Javier Botella, Mauricio Castro-Sepulveda.

  Exercise induces profound mitochondrial adaptations in skeletal muscle, with different modalities uniquely influencing different branches of mitochondrial quality control (MQC). This review examines how endurance, resistance, and high-intensity interval training (HIIT) regulate mitophagy, the selective degradation of damaged mitochondria, in skeletal muscle (SkM). Research in rodents has shown that endurance exercise upregulates mitophagy primarily through the AMPK/PGC-1α signaling axis, promoting mitochondrial turnover and ensuring metabolic efficiency. In humans, high-intensity exercise increases mitophagy to a larger extent when compared to traditional endurance exercises. On the other hand, resistance exercise triggers alternative MQC mechanisms, including potential mitochondrial ejection. Collectively, these results suggest that mitophagy and MQC pathways are regulated in human SkM following exercise, but the specific molecular pathways seem to be specific to each exercise mode. Future studies should aim at disentangling the multiple mitophagy and MQC pathways in human SkM following exercise.

Keywords:  Aging; Exercise training; Metabolic health; Mitochondrial autophagy; Skeletal muscle plasticity

DOI:  https://doi.org/10.1016/bs.ircmb.2025.10.005
Nucleus. 2026 Dec;17(1): 2688584

The nucleus as a mechanobiological hub in muscle aging.

Osman Esen, Edmund Battey, Matthew J Stroud, Tyler J Kirby.

  Aging leads to a progressive loss of muscle mass and strength, termed sarcopenia, which is accelerated by inactivity and exacerbated by intrinsic cellular and molecular dysfunctions within the muscle fiber. Central to these changes is mechanotransduction, the process by which mechanical stimuli are converted into biochemical cues critical for protein synthesis, cytoskeletal remodeling, calcium signaling, and metabolism. Recent evidence highlights the nucleus as a key mechanosensory organelle in skeletal muscle. Forces transmitted from the extracellular matrix (ECM) through the cytoskeleton reach the nuclear envelope, where the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and nuclear lamina convert physical stress into gene-regulatory events. Aging may alter these structures, producing changes in nuclear morphology, decreased stiffness, envelope fragility, and compromised transcriptional control. This review examines how the ECM, cytoskeleton, LINC complex, and nuclear lamina change in aged skeletal muscle, proposing that impaired nuclear mechanosignaling contributes to muscle fiber dysfunction during physiological aging.

Keywords:  LINC complex; Skeletal muscle; aging; cytoskeleton; extracellular matrix; mechanotransduction; nuclear lamina; nucleus

DOI:  https://doi.org/10.1080/19491034.2026.2688584
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2606703123

DMD-Null mice exhibit severe muscle weakness, impaired regeneration, and deficient satellite cell function.

Harry Wilton-Clark, Md Nur Ahad Shah, Jamie Leckie, Sebastian Hernandez Rodriguez, Ammar Al-Aghbari, Pavel Zhabyeyev, Rika Maruyama, Yoshitsugu Aoki, Gavin Y Oudit, Toshifumi Yokota.

  Duchenne muscular dystrophy (DMD) is a debilitating and fatal X-linked disease affecting 1/5,000 males worldwide that currently has no cure [D. Duan, N. Goemans, S. Takeda, E. Mercuri, A. Aartsma-Rus, Nat. Rev. Dis. Primers 7, 1-19 (2021), 10.1038/s41572-021-00248-3]. Vast amounts of research have been conducted on DMD, and one of the most common animal models for DMD studies is the mouse muscular dystrophy (mdx) model [J. W. McGreevy, C. H. Hakim, M. A. McIntosh, D. Duan, DMM Dis. Model. Mech. 8, 195-213 (2015), 10.1242/DMM.018424/-/DC1]. Unfortunately, despite its shared genetic etiology, the mdx mouse shows a relatively mild dystrophic phenotype compared to affected humans, limiting its overall utility as a research model (G. Donen, N. Milad, P. Bernatchez, J. Neuromuscul. Dis. 10, 1003 (2023), 10.3233/JND-230126]. Notably, mdx mice have a mutation preventing the production of full-length dystrophin but are still able to produce numerous short isoforms of dystrophin. Here, we provide a comprehensive functional characterization of DMD-Null mice, which lack all dystrophin isoforms. Our studies demonstrate that DMD-Null mice show a more severe skeletal muscle phenotype than mdx mice, characterized by profound weakness, decreased exercise tolerance, and impaired muscle regeneration, while utrophin upregulation was similarly observed in DMD-Null and mdx mice. We identify a marked deficit in satellite cell proliferation and myogenic differentiation, accompanied by downregulation of regenerative gene programs. These findings suggest potential contributions of short dystrophin isoforms to muscle stem cell function, and establish DMD-Null mice as a unique model for investigating the pathogenesis of DMD and testing therapeutic interventions targeting satellite cell health and regeneration.

Keywords:  DMD null; Duchenne muscular dystrophy; MDX; dystrophin

DOI:  https://doi.org/10.1073/pnas.2606703123
J Physiol. 2026 Jun 19.

Short-changed: Limited short-chain fatty acid oxidative capacity in skeletal muscle mitochondria.

Daniel G Sadler.



Keywords:  exercise; high‐fat diet; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1113/JP291630
Physiol Rep. 2026 Jun;14(12): e70947

3D skeletal muscle model recapitulating the myostatin knockout phenotypic and mitochondrial metabolic features.

Barbara Vernus, Elodie Jublanc, Béatrice Chabi, Laurence Pessemesse, Zacharie Cheng-Boivin, Benoit J Gentil, Anne Bonnieu, Christelle Koechlin-Ramonatxo, Bénédicte Goustard.

  3D cell culture, using a variety of bioengineering techniques, enables muscle cells to be cultured in more structural and functional biomimetic conditions than 2D cell culture. Here, we tested the ability of an engineered 3D skeletal muscle model to recapitulate in vivo metabolic muscle response. First, C2C12 myoblasts in 3D cultures showed improved myogenesis, attested by increased differentiation time, myotube formation, and gene expression of differentiated muscle markers. At the functional level, the 3D muscle culture displayed contractile properties and proper mitochondrial respiration. Second, to highlight the interest of such system we used primary myoblasts derived from myostatin knockout (Mstn-/-) mice. When compared to control wild-types 3D myotubes, 3D myotubes made from Mstn-/- myoblasts exhibit a hypertrophic phenotype associated with a decrease mitochondrial oxygen consumption, consistent with the skeletal muscle characteristics of Mstn-/- mice. Our findings show that 3D primary myotubes retain their in vivo phenotype in culture. This provides a useful framework for studying the underlying mechanisms of a various genetic muscle diseases, as well as for screening therapeutic drugs.

Keywords:  3D skeletal muscle; mitochondrial respiration; murine myoblasts/myotubes; myogenic differentiation; myostatin deficiency

DOI:  https://doi.org/10.14814/phy2.70947
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00162-5. [Epub ahead of print]404 1-61

From autophagy to mitophagy: Quality control mechanisms in skeletal muscle.

Eduardo Antuña, Nerea Menéndez-Coto, Paula Fernández-Guisasola, Ana Coto-Montes.

  Autophagy is a process which is responsible for the maintenance of cellular homeostasis. This is achieved through the orchestration of both highly selective and non-selective degradation pathways, the purpose of which is the elimination of damaged structures. Recent findings have revealed that, in addition to its intracellular function, this organelle exhibits a remarkable "social life" and forms relationships with other cellular organelles. This has led to the discovery that mitochondrial quality is maintained not only through mitophagy, but also through extracellular mechanisms between cells. This has significantly expanded our understanding of tissue integrity. In skeletal muscle, autophagy, or autophagy, is a finely tuned process that plays a crucial role in maintaining physiological performance and adaptation. Disruption of autophagy has been linked to accelerated degeneration, metabolic dysfunction, and frailty. Although therapeutic manipulation of autophagy and mitophagy shows promise in restoring muscle health, major translational barriers persist. A more profound and nuanced exploration of autophagy flux in human muscle is imperative, underpinned by novel advanced cell biology technologies and predicated on satellite cells as the primary agents in muscle regeneration. The full therapeutic potential of autophagy could be harnessed to redefine interventions against muscle ageing and associated diseases. However, this would still require critical scrutiny of the long-term effects and systemic consequences.

Keywords:  Aging; Autophagy; Mitochondria; Quality control mechanisms; Skeletal muscle

DOI:  https://doi.org/10.1016/bs.ircmb.2025.11.006
J Physiol. 2026 Jun 16.

Impaired skeletal muscle recovery: Immune cell dynamics across age and sex.

Alexandra M Winant.



Keywords:  ageing; disuse atrophy; fibrosis; immunosenescence; inflammation

DOI:  https://doi.org/10.1113/JP291594
Am J Physiol Cell Physiol. 2026 Jun 18.

Senescence as a regulatory mechanism in skeletal muscle repair in young mice.

Amanda L Johnson, Ryan T Bevington, Gianni Parise.

  Senescence is broadly considered an age-related phenomenon; however, it also been implicated in normal tissue repair and wound healing. Skeletal muscle repair is a complex process that requires the coordination of several different cell populations but the role of senescence in skeletal muscle repair has yet to be fully elucidated. We hypothesize that senescence serves as a control mechanism throughout the regenerative process and the removal of senescent cells through senolytics will negatively impact the repair process in young mice. Briefly, young mice were exposed to either (a) vehicle (VEH), receiving only a cardiotoxin (CTx) injection in one hindlimb or (b) 7 days of senolytic treatment (SEN) pre-CTx and 3x/week for 4 weeks post-CTx. Dasatinib + Quercetin (D+Q) was used to selectively eliminate senescent cells. There were no significant differences between groups in functional measures such as hindlimb grip strength and cross-sectional area. eMHC+ fibers remained elevated at D28 in the SEN group. Macrophage infiltration was twice as high in the SEN group compared to VEH at D7. Satellite cell quantity and fibrotic area were significantly increased at D14 in the SEN group compared to VEH. We conclude that reducing senescent cells during muscle repair in young mice significantly altered the kinetics of muscle repair. Therefore, senescent cells may act as a regulatory mechanism in skeletal muscle to orchestrate the activity of the different cell populations involved in repair and regeneration such as immune cells, satellite cells, and fibrotic cells.

Keywords:  Repair; Satellite cells; Senescence; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00154.2026
EMBO Rep. 2026 Jun 19.

Collagen VI is a fibrosis-associated signal disrupting muscle regeneration across distinct human myopathies.

Laura Muraine, Mona Bensalah, Stephen Gargan, Paul Dowling, Anne Bigot, Valérie Allamand, Jamila Dhiab, Maria Kondili, Sophie Perié, Jean Lacau St-Guily, Gillian Butler-oBrowne, Vincent Mouly, Kay Ohlendieck, Capucine Trollet, Elisa Negroni.

Muscle fibrosis is a major driver of progression in diverse myopathies, yet the conserved molecular mediators of this process in humans remain poorly defined. Here, we identify collagen VI as a common regeneration-impairing extracellular matrix (ECM) component across three distinct human myopathies: Duchenne Muscular Dystrophy (DMD), Oculopharyngeal Muscular Dystrophy (OPMD), and Inclusion Body Myositis (IBM). Proteomic profiling of fibrotic biopsies reveals consistent upregulation of collagen VI and laminin γ1, alongside disease-specific alterations. Fibroadipogenic progenitors (FAPs) are the predominant source of these ECM components, including collagen VI and laminin γ1. Functionally, xenotransplantation of patient-derived FAPs into regenerating mouse muscle induces localized collagen deposition, myofiber atrophy, and depletion of Pax7⁺ muscle stem cells. Mechanistic assays demonstrate that FAP-derived collagen VI is sufficient to impair myogenic fusion, while silencing COL6 in patient FAPs restores fusion capacity, directly linking pathological collagen VI deposition to regeneration failure. Our findings uncover collagen VI as a conserved effector of fibrosis and stem cell niche disruption in human myopathies, positioning it as a potential therapeutic target across genetically and clinically distinct muscle diseases.

DOI: https://doi.org/10.1038/s44319-026-00834-0
Cell Death Dis. 2026 Jun 17.

NuMA1 controls myonuclear motility in striated skeletal muscle through AMPK activity and is impaired in Duchenne muscular dystrophy.

Nathalie Couturier, Léa Castellano, Alireza Ghasemizadeh, Emilie Christin, Muriel Sébastien, Caroline E Brun, Damien Caillol, Céline Malleval, Alexandre Janin, Gaëtan Juban, Alexis Osseni, Jean-Luc Thomas, Stéphane Koenig, Jessica Brunetti, Alexandra Kraut, Yohann Couté, Nathalie Streichenberger, Rémi Mounier, Vincent Gache.

Skeletal muscle consists of a bundle of thousands of post-mitotic multinucleated cells (i.e., myofibers), in which myonuclei are evenly spaced and positioned at the periphery. This myonuclear positioning shapes myonuclear domain (MND) in myofibers, is essential for the transcriptional integrity of myofibers, is driven by the cytoskeleton and associated proteins and is required for proper myofiber functions. In numerous muscle diseases (i.e., myopathies), alteration of myonuclei localization contributes to myofiber dysfunction, supporting the need to better understand the fundamental mechanisms that regulate myonuclei dynamics in differentiated myofibers. In this study, we show that in Duchenne muscular dystrophy (DMD) myofibers, myonuclei are more dynamic and contribute to the failure in MND settings, suggesting enhanced myonuclear motility impacts myonuclear distribution. To identify new actors in MND settings, we performed a mass spectrometry (MS)-based proteomic analysis to identify microtubule-associated proteins (MAPs) in myotubes/myofibers and performed a siRNA screening on candidates. This approach highlighted NuMA1 as a new factor controlling myoblast fusion and myonuclear positioning through the control of nuclear-microtubule-organizing-center (n-MTOC) integrity and microtubule network orientation. Strikingly, while NuMA1 is restrained to myonuclei in mononucleated myoblasts, it progressively accumulates in the cytoplasm during muscle cell differentiation, preferentially with microtubule (MT) nucleation spots at the vicinity of the nuclear membrane. We identified that AMP Kinase activity has an essential role in NuMA1 nuclear/cytoplasmic accumulation through the specific phosphorylation on serine-1853 and the ability of myonuclei to accumulate NuMA1 is correlated to their motility in myofibers. Finally, we show that nuclear NuMA1 content is increased in DMD patients and mdx mouse model, contributing to more dynamic myonuclei that can be manipulated pharmacologically through the control of AMPK activity. Altogether, our data identifies a novel mechanism by which nuclear sequestration of a MAP allows to couple nuclear positioning and motion to MT organization along skeletal muscle differentiation.

DOI: https://doi.org/10.1038/s41419-026-08987-5
J Physiol. 2026 Jun 18.

Voltage-gated potassium channels mediate thyroid hormone control of skeletal muscle excitability.

Annarita Nappi, Caterina Miro, Annunziata Gaetana Cicatiello, Ilaria Piccialli, Serena Sagliocchi, Lucia Acampora, Federica Restolfer, Rosa Sirica, Melania Murolo, Emery Di Cicco, Daniela Terracciano, Anna Pannaccione, Monica Dentice.

  Thyroid hormone (TH) is a critical regulator of skeletal muscle (SkM) physiology, influencing muscle development, metabolism and contractile function. However, the molecular mechanisms by which TH modulates muscle excitability and contraction remain incompletely defined. Here, we investigated the role of TH signalling in regulating SkM electrical activity through transcriptional control of ion channels. Using RNA sequencing of gastrocnemius muscles from wild-type (CTR), muscle-specific deiodinase type 2-deficient (mD2KO), and thyroid hormone receptor α/β-deficient (TRαKO/TRβKO) mice, we identified a shared transcriptional signature of TH deficiency characterized by the dysregulation of multiple ion channel genes. Notably, two potassium (K+) channel-related genes Kcnh2 and Kcnk1, which encode for mERG1 and TWIK-1, respectively, were downregulated, while Kcnab1 was consistently upregulated in both mD2KO and TRαKO/TRβKO muscles compared with CTR, suggesting a common TH-dependent regulatory mechanism. To investigate whether such transcriptional remodelling of K+ channels translates into functional changes, we assessed the direct effects of TH on K+ currents using patch-clamp recordings in differentiated C2C12 cells exposed to TH as a model of physiological TH signalling. Interestingly, we found that TH treatment significantly increased mERG current density in differentiated C2C12 cells, supporting a role for TH signalling in the modulation of SkM electrical activity. Collectively, these results provide a mechanistic framework through which TH contributes to the regulation of muscle electrical stability, with potential implications for thyroid-related myopathies. KEY POINTS: Thyroid hormone (TH) regulates skeletal muscle excitability through transcriptional modulation of potassium (K+) channel-related genes. RNA-seq analyses identified a TH-dependent signature with downregulation of Kcnh2 (mERG1) and Kcnk1 (TWIK-1), and upregulation of Kcnab1 under TH-deficient conditions. Chromatin immunoprecipitation demonstrates direct binding of TH receptors to regulatory regions of these channel genes. Electrophysiological recordings in differentiated C2C12 cells show that TH treatment increases mERG current density. This coordinated remodelling of K+ channel expression provides a mechanistic basis for TH-driven optimization of muscle electrical stability and contractile performance. These findings support a role for TH signalling in the regulation of skeletal muscle electrical stability, with potential implications for thyroid-related myopathies.

Keywords:  deiodinases; electrophysiology; patch clamp; thyroid hormone; voltage‐gated potassium channel

DOI:  https://doi.org/10.1113/JP291418
Compr Physiol. 2026 Jun;16(3): e70190

Myostatin Signaling in Skeletal Muscle: Implications for Athletic Performance.

Srishti Chandel, Deenathayalan Uvarajan, Mahalaxmi Iyer, Dibbanti HariKrishna Reddy, Zothan Siama, Bupesh Giridharan, Arul Narayanasamy, John M, Arvinder Wander, Balachandar Vellingiri.

  Myostatin, encoded by the MSTN gene, is a critical negative regulator of skeletal muscle growth and plays a central role in maintaining muscle homeostasis. It regulates satellite cell proliferation, differentiation, and protein synthesis through both Smad-dependent and non-Smad signaling pathways. Overexpression of myostatin promotes muscle atrophy and delays recovery, whereas reduced myostatin activity enhances protein synthesis and muscle regeneration, primarily by modulating the IGF-1/Akt/mTOR signaling pathway. Modulation of myostatin has been associated with improved metabolic function, increased insulin sensitivity, enhanced musculoskeletal adaptation, and improved performance sustainability. Genetic variations in MSTN and its receptors activin-type II receptor A (ACVR2A) and activin type II receptor B (ACVR2B) R2B contribute to inter-individual differences in muscle morphology, fiber-type distribution, and athletic performance. Specific polymorphisms, including rs1805086 and rs11333758, have been associated with variations in muscle strength, hypertrophy, and endurance capacity. Despite extensive research, a comprehensive evaluation of the relationship between MSTN signaling, skeletal muscle mass, and athletic performance remains limited. This review provides an integrated overview of myogenesis, MSTN-mediated signaling pathways, genetic polymorphisms, endocrine interactions, and therapeutic modulation strategies. We further discuss the implications of MSTN in muscle hypertrophy, inflammation, and sports performance, highlighting future research directions in precision sports genomics and translational muscle biology.

Keywords:  IGF‐1 signaling; athletic performance; genetic polymorphism; muscle hypertrophy; myostatin; skeletal muscle regulation; sports genetics; testosterone interaction

DOI:  https://doi.org/10.1002/cph4.70190
iScience. 2026 Jun 19. 29(6): 116296

Modulation of satellite cell function to alleviate age-related sarcopenia: Electrical stimulation & Ca²⁺ signaling combined approach.

Canyu Chen, Yersen Mulat, Dongsheng Jiang, Haodong Lin.

  Age-related sarcopenia is a degenerative condition characterized by loss of muscle mass and strength. Satellite cells (SCs), the stem cells of skeletal muscle, decline in number and function with age, contributing to sarcopenia. Enhancing SC function represents a promising therapeutic strategy. Neuromuscular electrical stimulation (NMES) induces passive muscle contraction and improves SC activity, partly through calcium-dependent mechanisms. Calcium signaling is essential not only for excitation-contraction coupling but also for SC proliferation and differentiation. This review summarizes age-related changes in SCs, current sarcopenia treatments, and the therapeutic potential of NMES. We propose a novel combined strategy integrating NMES with calcium signaling modulation to synergistically enhance SC function. This approach offers a promising avenue for treating age-related sarcopenia and warrants further investigation.

Keywords:  biomedical engineering; geriatrics; stem cells research

DOI:  https://doi.org/10.1016/j.isci.2026.116296
ACS Pharmacol Transl Sci. 2026 Jun 12. 9(6): 1544-1553

Myostatin Inhibitory D‑Peptides Induce Skeletal Muscle Hypertrophy along with Alteration of Bioactive Sphingolipid Metabolism.

Katsuya Morito, Natsuki Nishikawa, Keisuke Hitachi, Rina Tamaki, Minori Nishikawa, Yoshio Hayashi, Kunihiro Tsuchida, Kentaro Takayama.

  Myostatin inhibition is well-known as a promising strategy to induce skeletal muscle hypertrophy. Midsized peptides are currently noted as a new modality in broad drug development. Our previous studies identified a series of myostatin inhibitory peptides, including the 16-mer D-peptide inhibitor MID-35. However, the detailed pharmacological analysis of muscle growth provided by intramuscularly injected MID-35 has not been investigated. Additionally, since sphingosine 1-phosphate (S1P), one of the bioactive sphingolipids, is involved in the regulation of muscle mass, it is vital to explore whether MID-35 treatment affects the S1P metabolism. Here, we analyzed alterations induced by MID-35 administration in the tibialis anterior muscles of young, adult, and aged mice. Muscle differentiation-related markers (Pax7/Myod1/Myog) and atrophy-related markers (Trim63/Fbxo32) were robustly increased and decreased, respectively, within 3 days, and muscle weight gain first appeared 14 days later; intriguingly, the hypertrophy was sustained for 12 weeks. An increase in centralized nuclei and Pax7-positive signals in MID-35-treated muscles corroborated muscle regeneration associated with muscle satellite cells (mSCs). Additionally, changes in the bioactive sphingolipid metabolism were observed. In young and adult mice, the amount of S1P was significantly increased on day 3, suggesting that S1P may assist in the activation of the mSCs. Meanwhile, aging affects S1P metabolism, resulting in no significant increase in the S1P level in aged mice. This basic study using MID-35 newly proposes the interaction between myostatin signaling and bioactive sphingolipid metabolism in the muscle hypertrophic reaction and would accelerate further mechanistic evaluation, including the maintenance of the hypertrophic state.

Keywords:  muscle satellite cell; myostatin; peptide inhibitor; skeletal muscle hypertrophy; sphingolipid

DOI:  https://doi.org/10.1021/acsptsci.6c00124
Skelet Muscle. 2026 Jun 19.

Targeting muscle fibrosis using non-specific collagenase injections destabilizes the basal lamina and induces matrix remodeling.

Ross P Wohlgemuth, Sathvik Sriram, Sarah E Brashear, Kyle E Henricson, Jason J Howard, Lucas R Smith.

   BACKGROUND: Muscle passive and active function is dependent on the extracellular matrix (ECM). In diseases characterized by muscle fibrosis, namely Duchenne Muscular Dystrophy (DMD), the ECM contributes to deficits in muscle mechanical function and regeneration. Because fibrosis is often viewed as irreversible in DMD and other muscle diseases, there is great incentive to develop anti-fibrotic therapies to prevent or reverse fibrosis.
METHODS: In this study we tested the effectiveness of intramuscular injections of non-specific Clostridium histolyticum collagenase (CCH) on reducing ECM contents and rescuing muscle mechanical function in D2.mdx mice, models of DMD. We performed unilateral injections of collagenase into the tibialis anterior and gastrocnemius in WT and D2.mdx mice. We measured in vivo plantarflexion strength, ex vivo muscle mechanical function, immunohistochemistry, and total and cross-linked collagen content.
RESULTS: We found that crude CCH was effective at digesting the muscle ECM but did not provide a therapeutic benefit evidenced by induction of muscle weakness and bleeding within 24 h after CCH injections, and a thickened basal lamina after 7 days.
CONCLUSIONS: We conclude that future studies testing collagenase as an anti-fibrotic should use a collagenase specific to fibrillar collagens and a paired physical therapy protocol to better preserve muscle function while reducing fibrosis.

Keywords:  Collagenase; Extracellular matrix; Fibrosis; Muscular dystrophy; Skeletal muscle

DOI:  https://doi.org/10.1186/s13395-026-00432-7
Geriatr Gerontol Int. 2026 Jun;26(6): e70584

Age-Dependent Effects of Adrenomedullin on Muscle Fiber Composition, Angiogenesis, and Muscle Satellite Cells Maintenance.

Ryota Iyama, Eriko Kurogi, Takumi Yokokawa, Kazuo Kitamura, Tatsuya Hayashi, Tatsuro Egawa.

   INTRODUCTION: Sarcopenia has recently become a major public health issue. Adrenomedullin (AM) exerts diverse physiological effects, including angiogenesis, but its role in skeletal muscle is unclear. This study investigates whether AM can attenuate sarcopenic changes in aged mice compared to young adults.
METHODS: Young and old male C57BL/6J mice were randomly divided into two groups: the AM-treated group, which received subcutaneous administration of AM (50 nmol/kg body weight) 6 days a week, and the sham-treated group, which was injected with vehicle. After 3 months of treatment, we performed multi-muscle analyses (EDL, SOL, and PLA) using western blotting and immunohistochemistry.
RESULTS: AM treatment significantly increased AM levels in plasma and muscle tissue. In young mice, AM was associated with changes in muscle fiber-type composition, including a reduction in Type IIx fibers, suggesting muscle-specific functional adaptation. In aged mice, AM increased CD31-positive capillary density and Pax7-positive muscle satellite cells (MuSCs), indicating improved vascular and stem cell niches. These changes occurred without alterations in muscle mass but were accompanied by improved motor function in aged mice.
CONCLUSIONS: AM exerts age-dependent effects on skeletal muscle, with distinct responses observed in young and aged mice. These findings suggest that AM may contribute to muscle adaptation through context-dependent mechanisms involving vascular remodeling and fiber-type modulation.

Keywords:  adrenomedullin; angiogenesis; muscle fiber composition; muscle satellite cells; sarcopenia

DOI:  https://doi.org/10.1111/ggi.70584
Front Physiol. 2026 ;17 1832044

Skeletal muscle overuse injury: pathophysiological mechanisms, molecular pathways, and rehabilitation strategies.

Guoliang Wu, Na Li.

  Skeletal muscle overuse injury (OUI) is a load-related condition that develops when repeated mechanical loading exceeds the adaptive and reparative capacity of skeletal muscle. Unlike acute traumatic injury or delayed-onset muscle soreness after unaccustomed eccentric exercise, chronic skeletal muscle OUI is characterized by recurrent subthreshold loading, insufficient recovery, persistent low-grade inflammation, impaired regeneration, and maladaptive remodeling. This narrative review summarizes and critically appraises current evidence on the conceptual boundaries, pathophysiological mechanisms, molecular pathways, and rehabilitation strategies of skeletal muscle OUI. Particular emphasis is placed on distinguishing direct skeletal muscle evidence from indirect or extrapolative evidence derived from acute injury models, adjacent musculoskeletal disorders, disease models, or preclinical studies. Key mechanisms include myofiber microdamage, satellite-cell-mediated repair, extracellular matrix remodeling, inflammatory signaling, oxidative stress, mitochondrial dysfunction, protein turnover, and myogenic transcriptional regulation. Current management remains centered on individualized load modification, graded rehabilitation, correction of biomechanical contributors, and criteria-based return to activity. Pharmacological and physical modalities may provide adjunctive symptom control in selected cases, whereas regenerative, gene-based, wearable-sensor-based, and artificial-intelligence-assisted approaches remain emerging or experimental for chronic skeletal muscle OUI. By integrating mechanistic evidence with rehabilitation practice and evidence appraisal, this review provides a focused framework for understanding, preventing, and managing skeletal muscle OUI.

Keywords:  evidence hierarchy; extracellular matrix remodeling; inflammation; load management; mitochondrial dysfunction; oxidative stress; rehabilitation; satellite cells

DOI:  https://doi.org/10.3389/fphys.2026.1832044
Ageing Res Rev. 2026 Jun 16. pii: S1568-1637(26)00200-X. [Epub ahead of print] 103208

Macrophage regulation of extracellular matrix remodeling in aging skeletal muscle.

Chang-Yi Cui, Joseph C Nazario, Isabelle A Stephen, Mirko Baranzini, Yongqing Zhang, Supriyo De, Payel Sen, Luigi Ferrucci, Myriam Gorospe.

  The extracellular matrix (ECM) is a dynamic structural network that supports tissue architecture and regulates cell function. It is primarily composed of collagens, elastin, proteoglycans, and glycoproteins, which are produced by canonical and non-canonical ECM-producing cells. During aging, the ECM undergoes progressive changes in structure and composition, a process recently recognized as the 13th hallmark of aging. In skeletal muscle (SKM), age-associated ECM remodeling, largely regulated by immune system-ECM crosstalk, contributes to sarcopenia and impaired regeneration. Macrophages (MΦs), as key innate immune cells, regulate ECM dynamics both indirectly by activating canonical ECM-producing cells and directly by synthesizing ECM components. Notably, a distinct subset of ECM-producing MΦs (COL+ MΦs) has been identified across multiple tissues, although their function in SKM homeostasis and aging remains poorly understood. Here, we review current knowledge of ECM production and remodeling, with special emphasis on MΦ involvement, including COL+ MΦs, as critical regulators of fibrogenesis, especially during SKM aging and regeneration.

Keywords:  Extracellular matrix; aging; collagen; macrophages; regeneration; skeletal muscle

DOI:  https://doi.org/10.1016/j.arr.2026.103208
J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70322

Deletion of Tgf-β1 From CD206+ M2 Macrophages Ameliorates Obesity-Induced Suppression of Myogenesis and AMPK Phosphorylation in Skeletal Muscle.

Muhammad Bilal, Le Duc Anh, Nguyen Quynh Phuong, Sana Khalid, Allah Nawaz, Memoona, Muhammad Rahil Aslam, Tomonobu Kado, Yoshiyuki Watanabe, Ayumi Nishimura, Yoshiko Igarashi, Aamir Sharif, Yasuhiro Onogi, Tsutomu Wada, Ryuji Hayashi, Kenichi Hirabayashi, Seiji Yamamoto, Takashi Nakagawa, Hisashi Mori, Isao Usui, Masaru Kato, Shiho Fujisaka, Kazuyuki Tobe.

   BACKGROUNDS: Obesity and diabetes impair the ability of the muscle to regenerate, repair and remodel, resulting in a gradual decrease in muscle mass and function. However, the underlying mechanisms and effective therapeutic strategies remain poorly understood. M2 macrophages within skeletal muscle play an important role in tissue recovery following injury. This study aims to investigate the role of M2 macrophages derived transforming growth factor-beta 1 (Tgf-β1) in regulation of skeletal muscle function under diet-induced obese conditions.
METHODS: An CD206+ M2 macrophage-specific Tgf-β1 gene knockout (Tgf-β1 KO) mouse model was generated by crossing CD206-CreERT2 mice with Tgf-β1f/f mice, followed by tamoxifen administration to induce Tgf-β1 gene deletion. Mice were then placed on a high-fat diet (HFD) for 12 weeks to develop obesity-induced skeletal muscle dysfunction. The study used multiple physiological and molecular analyses, including exercise tolerance, hanging time, grip strength, glucose and insulin tolerance tests, western blotting, RT-qPCR and others.
RESULTS: The present findings demonstrated improved exercise performance, as evidenced by increased running distance twice (p = 0.0008) in Tgf-β1 KO mice. Deletion of CD206+ M2 macrophage-specific Tgf-β1 stimulates fibro-adipogenic progenitors (FAPs), inducing Follistatin (Fst) expression by 1.70-fold (p = 0.04) and follistatin-like protein 1 (Fstl1) by 2.60-fold (p = 0.01) in tibialis anterior (TA), thus enhancing myogenesis. The Tgf-β1 KO mice showed increased muscle fibre type I (Myh7 by 2.40-fold, p = 0.005), muscle fibre type IIa (Myh2 by 1.50-fold, p = 0.003), type IIx (Myh1 by 2.35-fold, p = 0.002) in soleus and type II (Myh4 by 1.76-fold, p = 0.02) in TA. In Tgf-β1 KO mice, insulin-stimulated Akt phosphorylation was significantly increased in adipose tissue by 2.14-fold (p = 0.0003) and in the liver by 1.62-fold (p = 0.01). Besides, the Tgf-β1 KO mice showed increased circulating adiponectin by 1.23 fold (p = 0.003), thereby activating the AMPK/SIRT1/PGC-1α pathway with the phosphorylation level of AMPKα increased by 1.5-fold (p = 0.02), and PGC1α protein level increased by 2.2-fold (p = 0.02) via increased AdipoR1 mRNA expression by 1.8-fold in TA, p = 0.0001 and by 1.8-fold in soleus, p = 0.01 in skeletal muscle, leading to improved mitochondrial function in skeletal muscle.
CONCLUSIONS: The CD206+ M2 macrophage-specific Tgf-β1 deletion ameliorates obesity-induced muscle dysfunction, potentially via two distinct mechanisms. Firstly, it enhances myogenesis by promoting FAP-mediated expression of Fst and Fstl1, thereby augmenting myogenesis-related gene expression in skeletal muscle. Secondly, it also induces adipocytes to produce and secrete adiponectin into the bloodstream, thereby enhancing mitochondrial function via the AMPK/SIRT1/PGC-1α pathway.

Keywords:  M2 macrophage‐derived Tgf‐β1; mitochondrial function; muscle dysfunction; sarcopenic obesity

DOI:  https://doi.org/10.1002/jcsm.70322
Physiol Rep. 2026 Jun;14(12): e70904

Short-term high-fat feeding induces muscle-type-specific signaling adaptations in skeletal muscle of male rats.

Arata Tsutaki, Hidetaka Imagita, Asumi Yoshida.

  Short-term high-fat diet (HFD) feeding is used to study metabolic dysregulation, yet many rodent models use extreme fat contents that may not reflect physiological conditions. Skeletal muscle responses to short-term HFD also vary by muscle type. We tested whether a physiologically relevant HFD induces muscle-type-specific changes in skeletal muscle signaling and mitochondrial-related proteins. Male Wistar rats were fed a low-fat diet (LFD; 10% energy from fat) or HFD (40% energy from fat) for 4 weeks (n = 5/group). Soleus and extensor digitorum longus (EDL) muscles were analyzed for OXPHOS complexes, mitochondrial dynamics proteins, and ERK1/2 signaling. HFD increased energy intake and visceral adiposity without changing body weight or muscle mass. In soleus, OXPHOS complex II was reduced, whereas other complexes were preserved. In EDL, phosphorylation of ERK1/2 (Thr202/Tyr204) and Drp1 (Ser616) was reduced without changes in total protein abundance. Thus, short-term, physiologically relevant HFD feeding induces muscle-type-specific molecular and signaling adaptations before overt changes in body weight or muscle mass.

Keywords:  ERK signaling; high‐fat diet; mitochondrial dynamics; muscle‐type specificity; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70904
Free Radic Biol Med. 2026 Jun 17. pii: S0891-5849(26)00887-7. [Epub ahead of print]254 168-180

RNF10 attenuates age-related muscle atrophy by promoting p53 degradation and alleviating oxidative stress.

Hong Yang, Yingxiao Zhang, Li Zhang, Xin Dai, Jing Yu, Yuxing Zhao, Donglin Fu, Yue Shu, Min Zhou, Pan Cheng, Yongxin Wu, Ying Xiang, Hailin Yang, Qian Xiao.

  Evidence identifies proteostasis imbalance and oxidative stress serve as fundamental pathological hallmarks of muscular atrophy, yet ring finger protein 10 (RNF10), a novel E3 ubiquitin ligase, in age-related muscular atrophy remains poorly characterized. Employing a natural aging mouse model and D-galactose-induced senescent C2C12 myotubes, we performed loss- and gain-of-function approaches for RNF10 with the aim of elucidating its downstream regulatory mechanisms. Aged mice showed significant declines in skeletal muscle mass and exercise capacity. Histological analysis revealed a significant reduction in gastrocnemius muscle (GAS) fiber cross-sectional area (CSA). Both in vivo and in vitro experiments showed elevated aging markers, increased inflammatory factors, decreased protein synthesis, enhanced proteolysis, and upregulated muscle atrophy indicators accompanied by nearly 50% reduction of RNF10 expression. AAV-mediated restoration of RNF10 in aged mice improved skeletal muscle mass and function, while reducing inflammatory levels and enhancing systemic antioxidant capacity. Mechanistically, RNF10 directly interacted with p53 to promote its ubiquitin-dependent degradation, which in turn reduced oxidative stress and improved mitochondrial function. In senescent myotubes, RNF10 deficiency elevated mitochondrial oxidative stress and disrupted proteostasis, effects that were rescued by p53 inhibition. TIGAR expression increased upon p53 degradation, and TIGAR silencing abolished the protective effects against myotube atrophy and oxidative stress, indicating that TIGAR is required for these beneficial outcomes. Our findings demonstrate that promoting RNF10-mediated p53 degradation represents a promising therapeutic strategy for sarcopenia intervention.

Keywords:  Muscle atrophy; Oxidative stress; Proteostasis; RNF10; Sarcopenia

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.032
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2605749123

Elevated MyoD1 levels expand genome-wide binding and the repertoire of regulated genes.

Oscar N Whitney, Gina M Dailey, Joseph K McKenna, Xavier Darzacq, Robert Tjian.

  Transcription factor (TF) upregulation accompanies many cellular state transitions, yet how increased TF abundance impacts gene regulation remains unclear. Two broad models are often invoked, whereby higher TF levels amplify the expression of preexisting target genes, or, by mass-action binding, expand genome engagement and regulation to lower-affinity sites. We sought to elucidate how these two regulatory modes contribute to cell differentiation in a well-characterized myogenic system by upregulating the expression of the myogenic TF MyoD1 in C2C12 myoblasts. Unexpectedly, elevated MyoD1 levels impaired myoblast fusion (a hallmark of myogenic differentiation), yet enabled robust contraction in myotubes that did form. Live-cell single-molecule imaging and CUT and RUN profiling revealed that elevated MyoD1 dosage increased total genome-wide chromatin binding and broadened genome occupancy by preferentially engaging lower-affinity sites. Integrating CUT and RUN with RNA sequencing (RNA-seq) experiments linked expanded MyoD1 binding to upregulation of cell adhesion genes. Cell mixing and fractionated RNA-seq experiments supported a two-population model in which an adhesion-gene-upregulated, unfused myoblast population supported contraction of myotubes formed by fusion-competent cells. Ectopic expression of several individual MyoD1-upregulated cell adhesion genes was sufficient to recapitulate the "off script" myotube contraction phenotype. Together, these results support a MyoD1 dose-dependent "spillover" model, in which increased TF abundance broadens cis-regulatory engagement and produces distinct cell differentiation outcomes.

Keywords:  MyoD1; transcription factor dosage; transcription regulation

DOI:  https://doi.org/10.1073/pnas.2605749123
Pharmacol Res. 2026 Jun 13. pii: S1043-6618(26)00215-X. [Epub ahead of print] 108300

Vdr-Pparα-Plin5-regulated lipid droplet dynamics mediates exercise protection against HFD-induced skeletal muscle ectopic lipid deposition and insulin resistance in mice.

ZhenBo Cao, Yanjun Niu, Jingjing Liu, Jinghua Zhang, Shiqi Lu, Ke Wang, Xiaoning Cui, Zheng Zhu.

  Aerobic exercise serves as an effective non-pharmacological strategy for alleviating high-fat diet (HFD)-induced ectopic lipid deposition and insulin resistance (IR) in skeletal muscle. Vitamin D receptor (Vdr) is involved in the alleviation of ectopic lipid deposition in skeletal muscle by exercise, yet the underlying mechanisms remain to be further elucidated. In our study, twenty-four C57BL/6J male mice were fed with vitamin D (VD) - deficient diet to establish a VD deficiency model and conduct aerobic exercise; lentivirus transfection was used to knockdown Vdr in C2C12 cells; skeletal muscle-specific knockout of Vdr (Vdr-MKO) male mice were fed a HFD to establish a model of ectopic lipid deposition in skeletal muscle and IR, followed by aerobic exercise intervention. We evaluated the blood, energy metabolism of mice, and conducted histological analysis, immunofluorescence staining, RT-qPCR, Western blotting and Co-Immunoprecipitation on the muscle of mice. We found that the decrease in Vdr weakened the beneficial effects of exercise on lipid metabolism in skeletal muscles. Vdr-MKO aggravates HFD-induced ectopic lipid deposition and IR in skeletal muscle, and impairs the protective effects of aerobic exercise on lipid metabolism and insulin sensitivity. Mechanistically, Vdr ablation leads to downregulated of Pparα and Plin5, reduced interaction between Plin5 and Cgi-58, as well as impaired lipid droplet protection and mitochondrial oxidative capacity in myocytes. The lipid droplet dynamics regulated by Vdr exerts a protective effect in aerobic exercise-mediate alleviation of HFD-induced ectopic lipid deposition and IR in skeletal muscle of mice.

Keywords:  ectopic lipid deposition; exercise; lipid droplet dynamics; perilipin 5; vitamin D receptor

DOI:  https://doi.org/10.1016/j.phrs.2026.108300
Am J Physiol Regul Integr Comp Physiol. 2026 Jun 15.

Prolonged heat stress induces autophagy in mouse skeletal muscle.

Sau Qwan Yap, Melissa Roths, Swathy Krishna, Tori E Rudolph, Joshua T Selsby.

  Environment-induced heat stress (HS) is a significant and expanding threat to human health and efficient agricultural production. In this investigation, we aimed to determine the extent to which HS impacted skeletal muscle health. We hypothesized that HS would decrease autophagosome degradation and autophagic flux in mouse skeletal muscle. To test this hypothesis, female C57 mice were exposed to thermoneutral (TN; 30 °C) or heat stress (HS; 37.5 °C) conditions for 24 h, and the gastrocnemius, soleus, and diaphragm muscles were immediately collected. A subset of mice was treated with colchicine to assess autophagic flux. Environment-induced HS increased rectal and subcutaneous temperatures by ~2.0 °C and decreased feed intake by 75% and body mass by 14%, without a change in muscle mass. In all muscles, 24 h of HS increased phosphorylated HSP 27 by 1.47-fold to 4.5-fold compared to TN; however, HSPs 27, 60, 72, and 90 were similar between groups. We discovered HS increased autophagic flux in the gastrocnemius and diaphragm, but not soleus, without changes in most key autophagy regulatory proteins. Markers of mitophagy, regulators of mitochondrial architecture, and mitochondrial abundance were largely similar between groups for all muscles. Environment-induced HS increased ER stress regulators, BIP by 1.7-fold to 2.9-fold and p-IRE1α by 1.84-fold to 2.75-fold in all muscles, and p-eIF2α was increased 3.6-fold in soleus. Counter to our hypothesis, these data demonstrate that 24 h of HS did not decrease autophagosome degradation or flux across a range of muscles in a mouse HS model.

Keywords:  Colchicine; Heat Stroke; Heat shock proteins; Hyperthermia; Unfolded protein response

DOI:  https://doi.org/10.1152/ajpregu.00190.2025
FASEB J. 2026 Jun 30. 40(12): e72052

Exercise Training Stimulates the Release of Glutathione Peroxidase 1 (GPX1)-Enriched Extracellular Vesicles That Promote Angiogenesis.

Alexander M Fliflet, Ray A Spradlin, Yanqi Tan, Ane Nishitha Vijayan, Sung Jun Choi, Wei-Chun Kao, Edita Aksamitiene, Michael Nelappana, Shengzhe Ding, Kai-Yu Huang, Aryaman Joshi, Nurila Kambar, Tom Bludgen, Madeleine Meehan, Jayna L Boss, Michael Knipp, Hongming Fan, Cecilia Leal, Roger A Sunde, Lawrence W Dobrucki, Stephen A Boppart, Hyun Joon Kong, Jonathan V Sweedler, Marni D Boppart.

  An acute bout of high intensity exercise can transiently increase circulating extracellular vesicles (EVs) that possess beneficial molecular cargo. However, no studies to date have comprehensively evaluated plasma quantity, protein content, and function of EVs collected from blood after multiple bouts of endurance exercise. Here we demonstrate that 4 weeks of voluntary wheel running increases plasma EV quantity when collected immediately after the last bout of training in mice. These EVs (ExerVs) are enriched in oxidoreductases, including the antioxidant glutathione peroxidase 1 (GPX1). Repeated, systemic injections of ExerVs into sedentary recipient mice twice per week for 4 weeks did not alter mitochondrial content or function, fiber size, or fiber type, but increased capillary density and perfusion in skeletal muscle. ExerVs also stimulated tube formation and branch lengthening in vitro and improved the recovery of capillary content after a period of disuse in vivo. ExerVs isolated from GPX1-/- mice lacked the ability to stimulate vessel formation, whereas GPX1-encapsulated liposomes robustly increased capillary growth, both in vitro and in vivo. The results from this study suggest that circulating ExerVs positively impact vascular structure and function in skeletal muscle in a manner that may be dependent on GPX1.

Keywords:  angiogenesis; antioxidants; exercise; extracellular vesicles; glutathione peroxidase 1

DOI:  https://doi.org/10.1096/fj.202505096RR
Acta Physiol (Oxf). 2026 Jul;242(7): e70240

Myosin Post-Translational Modifications Associated With Critical Illness Myopathy.

Fernando Ribeiro, Bruno Di Geronimo, Nicola Cacciani, Anna Widgren, Yvette Hedström, Anselmo S Moriscot, Peter M Kasson, Shina C L Kamerlin, Jonas Bergquist, Lars Larsson.

   BACKGROUND: Critical illness myopathy is a common and devastating consequence of critical care, causing dramatic loss of muscle mass and function in intensive care unit patients. Functional deficits often exceed the loss in muscle mass and myosin content. However, the mechanisms underlying the loss of force and emergence of myosin-expressing non-force-generating fibers remain elusive.
METHODS: Myosin dysfunction was investigated in six intensive care unit patients exposed to a 12-day mechanical ventilation and immobilization period using mass spectrometry-based proteomics and molecular dynamics simulations.
RESULTS: Previous single muscle fiber analyses revealed decreased fiber size and specific force from the 1st to the 12th days in all patients. A subset of myosin-expressing fibers exhibiting a complete loss of contractile function was identified in three of the patients despite similar atrophy levels (~30%, p < 0.05) after 12 days. All fibers had decreased specific force after 12 days of mechanical ventilation, but 9% to 21% of the fibers were non-force generating. The decline in specific force was linked to 27 post-translational myosin modifications, including oxidation, ubiquitination, acetylation, and methylation. Molecular dynamics simulations indicated oxidation-induced rigidity of the myosin head, predicted to compromise the flexibility of the actin-binding and converter domains. Non-force-generating fibers exhibited a unique proteomic signature predicted to enhance myosin motor domain exposure and rigidity.
CONCLUSION: In addition to muscle wasting and myosin loss, abnormal myosin post-translational modifications contribute to muscle weakness in ICU patients with CIM, including the development of muscle fibers incapable of generating contractile force.

Keywords:  critical care; liquid chromatography–tandem mass spectrometry; mechanical ventilation; muscle contraction; skeletal muscle

DOI:  https://doi.org/10.1111/apha.70240
Mol Ther Adv. 2026 Sep 10. 34(3): 201766

Preclinical efficacy of a gene therapy for CHKB-mediated muscular dystrophy.

Mahtab Tavasoli, Mariam Alkandari, Gabriel Dorighello, Jennifer Devitt, Laura Hagerty, Jesse Damsker, Eric P Hoffman, Christopher R McMaster.

  Loss-of-function variants of the CHKB gene cause an autosomal recessive disease described as an early onset congenital megaconial (large peripheral mitochondria) muscular dystrophy. CHKB encodes choline kinase β, the first enzyme in the biochemical pathway for synthesis of the major membrane phospholipid phosphatidylcholine. Chkb -/- mice recapitulate the human disease with affected skeletal muscle displaying a decrease in strength, myofiber atrophy, megaconial mitochondria, fat accumulation within muscle cells, and an increase in muscle injury. Here, we assessed the therapeutic potential of an AAV therapy for the treatment of CHKB-mediated muscular dystrophy. Chkb -/- mice were injected once suborbitally with three different doses of recombinant AAV9 (rAAV9) encoding human CHKB under control of a constitutive and ubiquitous promoter (AAV9-CHKB). The AAV9-CHKB-treated mice were biochemically and phenotypically indistinguishable from the wild type mice. In the Chkb -/- mouse model, all doses resulted in expression of the CHKB protein and restored choline kinase β enzyme activity, body and muscle weight, and normal muscle cell physiology, and they prevented lipid metabolism imbalance and increased the capacity to walk. These findings point to AAV9-mediated gene therapy as a potential treatment for CHKB-mediated disease.

Keywords:  CHKB; choline kinase; dystrophy; gene therapy; muscle; myopathy; phosphatidylcholine; phospholipid

DOI:  https://doi.org/10.1016/j.omta.2026.201766
Aging Cell. 2026 Jun;25(6): e70577

Nuclear Enlargement as a Histological Hallmark of Skeletal Muscle Aging, Revealed by Deep Learning-Driven Analysis and Validated in Inflammatory Myopathies.

Tam Dao, Thanh T Nguyen, Gia Minh Hoang, Junhyeon Park, Yunju Jo, Thach Hoang Ngoc, Diep Hong Pho, Dien Tran Minh, Emma Anh Ton, Sunjae Lee, Hyun Jin Kim, Vu Chi Dung, Jae Gwan Kim, Dongryeol Ryu.

  Aging reshapes the architecture of human skeletal muscle, yet objective tissue-level markers that capture this process remain limited. We combined large-scale histology with deep learning to identify reproducible features of muscle aging and to test their biological relevance. We analyzed 974 hematoxylin-eosin whole-slide images from a population resource using a dual-attention convolutional neural network and an independent Mask R-CNN model to quantify nuclear size and density, verified by manual review. The classifier distinguished young from aged muscle with high accuracy (AUC 0.91; accuracy 86.2%), and attention maps consistently highlighted nuclear enlargement and spatial disorganization as salient features. Nuclear diameter increased with age (Spearman's ρ = 0.71, p < 0.0001) across automated and manual measurements. Transcriptomes matched to the same donors showed that samples with larger nuclei were enriched for pathways related to chromatin remodeling, proteostasis, cellular senescence, mitochondrial activity, and telomere regulation, whereas smaller nuclei aligned with anti-inflammatory and DNA repair programs. External pediatric inflammatory myopathies exhibited nuclear enlargement comparable to aged muscle, suggesting inflammation-related premature histologic aging. These findings identify nuclear enlargement as a robust, quantifiable feature that integrates structural and molecular signatures of muscle aging. The proposed deep learning-based nuclear morphometry provides a scalable framework for tissue-level aging biomarkers and suggests a potential "muscle aging clock" applicable to both physiological aging and disease states.

Keywords:  cellular senescence; deep learning; nuclear enlargement; skeletal muscle aging; transcriptomics

DOI:  https://doi.org/10.1111/acel.70577
FEBS J. 2026 Jun 16.

TRIM32 controls timely cell cycle exit in muscular differentiation through downregulation of c-Myc mRNA.

Lu Xiong, Elisa Lazzari, Sabrina Pacor, Simeone Dal Monego, Erica Piovesan, Danilo Licastro, Germana Meroni.

  Mutations in TRIM32 cause limb-girdle muscular dystrophy recessive 8 (LGMDR8), a neuromuscular disorder primarily affecting the proximal muscles of hips and shoulders. However, the precise pathogenic mechanism remains unclear. In this study, we used Trim32 knock-out C2C12 murine myoblasts to investigate the impact of full Trim32 loss along the myogenesis process. We found that Trim32 deficiency alters global transcriptomics already in the early phases of the differentiation process leading to impaired myogenic signaling, ultimately resulting in delayed and abnormal myotube formation. Following this up, we discovered that lack of Trim32 disrupts the transition from proliferation to differentiation by limiting the necessary downregulation of the proto-oncogene c-Myc, thus delaying and altering the immediate early onset of differentiation. Interestingly, unlike previous reports that emphasized protein-level regulation, our data reveal that, at this precise stage of differentiation, Trim32 regulates the stability of c-Myc at mRNA level. Attenuating c-Myc expression level is able to partially recover the myogenesis defects observed in the absence of Trim32, suggesting that the Trim32-c-Myc axis may represent an essential hub, although likely not the exclusive mechanism, in muscle regeneration within LGMDR8 pathogenesis.

Keywords:  LGMDR8; TRIM32; c‐Myc; muscular dystrophy; myogenesis

DOI:  https://doi.org/10.1111/febs.70619
Arch Pharm Res. 2026 Jun 19.

Exercise-induced myokines in metabolic regulation: mechanisms, mimetics, and translational potential.

Muhammad Arif Aslam, Jongmin Lee, T Scott Bowen, Joo Young Huh.

  Skeletal muscle, once regarded solely as a contractile tissue, is now recognized as a dynamic endocrine organ that secretes exercise-induced myokines-bioactive peptides with autocrine, paracrine, and endocrine functions. These myokines coordinate systemic energy homeostasis by regulating glucose and lipid metabolism, mitochondrial function, inflammation, and interorgan communication. Building on our previous review published in 2018, this review synthesizes major advances in exercise-induced myokines within an evidence-based framework considering mechanistic support and translational relevance. We highlight both well-established and emerging myokines, including interleukin-6 (IL-6), irisin, myostatin, growth differentiation factor 11 (GDF11), IL-15, brain-derived neurotrophic factor (BDNF), meteorin-like (METRNL), secreted protein acidic and rich in cysteine (SPARC), fibroblast growth factor 21 (FGF21), β-aminoisobutyric acid (BAIBA), leukemia inhibitory factor (LIF), apelin, and musclin, and discuss their roles across major target tissues including skeletal muscle, liver, adipose tissue, and bone. We also summarize natural and synthetic compounds reported to modulate myokine expression, secretion, or activity, and discuss the opportunities and current limitations of targeting myokine pathways. Although several myokine axes show therapeutic promise, the current literature indicates substantial heterogeneity in causal evidence, receptor or target certainty, and translational readiness. These insights support a more selective view of myokines as biologically heterogeneous mediators of muscle-organ crosstalk and provide a framework for mechanism-based therapeutic development in metabolic disease.

Keywords:  Exercise; Metabolism; Muscle–organ crosstalk; Myokines; Skeletal muscle

DOI:  https://doi.org/10.1007/s12272-026-01624-x
BMC Endocr Disord. 2026 Jun 16.

Emerging evidence for skeletal muscle as a target of BPA exposure.

Muneebah Vaid, Hilda Dahbur, Hadi Dahbour, Isabel Martinez-Pena Y Valenzuela.

  Endocrine disruptors are exogenous chemicals that interfere with hormonal signaling, and among them, bisphenol-A (BPA) is one of the most widely used and globally prevalent. Human exposure to BPA occurs through multiple routes, and measurable levels are detected in the majority of biological samples worldwide. At the molecular level, BPA interacts with several nuclear and membrane receptors, conferring estrogenic and anti-androgenic properties that disrupt endocrine, metabolic, and cardiovascular systems. Although the biological effects of BPA have been extensively studied in reproductive, neural, hepatic, and adipose tissues, its impact on skeletal muscle has been comparatively understudied, despite the central role of this tissue in glucose homeostasis and energy metabolism. In addition, direct human evidence specifically linking BPA exposure to skeletal muscle structure or function remains limited. This review summarizes current evidence regarding the effects of BPA on skeletal muscle structure and function. Experimental studies indicate that BPA disrupts insulin signaling in skeletal muscle by impairing insulin receptor-dependent pathways, reducing Akt phosphorylation and GLUT4 translocation, and promoting inflammatory responses, ultimately leading to insulin resistance and glucose intolerance. Developmental exposure to BPA further alters muscle fiber composition, gene expression, calcium signaling, and excitation-contraction coupling, with persistent effects on muscle phenotype and function. Collectively, the findings reviewed here identify skeletal muscle as a critical, yet underrecognized, target of BPA toxicity and underscore the need for future studies addressing chronic low-dose exposure and long-term outcomes, particularly in human populations.

Keywords:  Bisphenol-A; Endocrine disruptors; Inflammation; Insulin signaling; Skeletal muscle

DOI:  https://doi.org/10.1186/s12902-026-02355-2
Sci Rep. 2026 Jun 17.

Systematic review and meta-analysis of the effects of exercise in older adults with sarcopenia.

Maria Clara Fagundes Lucio, Raphael Gonçalves de Oliveira, Laura Isabel Martins de Almeida, Laís Campos de Oliveira.

  Aging is associated with progressive physiological changes that impair physical functioning and quality of life (QoL), as exemplified by sarcopenia, a condition characterized by the loss of skeletal muscle mass and strength that increases the risk of falls, dependency, and mortality. Although physical exercise is widely recognized as an effective intervention, the literature remains heterogeneous with respect to the most appropriate modalities for this population. This study aimed to synthesize evidence from randomized controlled trials investigating the effects of physical exercise on skeletal muscle mass, muscle strength, physical performance, QoL, and mortality in older adults with sarcopenia. A systematic search was conducted in PubMed, Embase, CENTRAL, Web of Science, CINAHL, PEDro, SPORTDiscus, and LILACS databases, with no restrictions on language or publication date, up to May 26, 2025. The methodological quality of included studies was assessed using the PEDro scale. Meta-analyses were performed using standardized mean difference or mean difference for post-intervention data, and the certainty of evidence was graded according to the GRADE approach. Sensitivity analyses evaluated the impact of studies with a high risk of bias, and subgroup analyses compared different exercise modalities and diagnostic criteria for sarcopenia. Following systematic screening, 72 studies were included, of which 36 were classified as having a low risk of bias. Physical exercise was superior to control conditions in improving skeletal muscle mass (small effect size), muscle strength, and physical performance (moderate effect size), with no significant effects on QoL. Resistance exercise was more effective than aerobic exercise for increasing skeletal muscle mass (large effect size). The combination of physical exercise and nutritional supplementation yielded greater benefits than either intervention alone for muscle mass and strength and, in sensitivity analyses, also for physical performance. A meta-analysis for mortality was not performed, as only one RCT reported this outcome, representing very limited evidence that precludes any meaningful pooled estimate or definitive conclusions regarding the effects of exercise on mortality in this population. Subgroup analyses stratified by diagnostic criteria demonstrated overall consistent effects across the different sarcopenia definitions. The certainty of evidence ranged from very low to moderate. Physical exercise should be considered a first-line intervention for older adults with sarcopenia, given its potential to improve skeletal muscle mass, muscle strength, and physical performance, supported by moderate-certainty evidence. The effects of exercise combined with nutritional supplementation and the comparative effectiveness of different exercise modalities remain uncertain, as the certainty of evidence for these analyses was low to very low, and future studies are likely to modify these conclusions.

Keywords:  Aging; Older adults; Physical exercise; Sarcopenia

DOI:  https://doi.org/10.1038/s41598-026-55850-w
Front Sports Act Living. 2026 ;8 1830759

Exercise-secreted antitumor myokines: mechanistic insights and translational potential.

Songyang Han, Cuiyao Du, Chenqiong Zhao, Qi Zhang, Meiling Wu, Cheng Yang, Xia Liu.

   Background: Cancer remains a major threat to human health. Exercise has been shown to reduce cancer risk, inhibit tumor progression, and improve patient prognosis and quality of life; however, its precise molecular underpinnings are not yet fully understood.
Objective: To synthesize current evidence and identify critical knowledge gaps, this review focuses on exercise-induced myokines secreted by skeletal muscle and examines their potential direct and indirect roles in tumorigenesis and malignant progression.
Findings: We systematically reviewed the molecular mechanisms by which several key exercise-responsive myokines exert tumor-suppressive effects, including interleukin-6 (IL-6), Secreted Protein Acidic and Rich in Cysteine (SPARC), irisin, and other prominent myokines.
Results: Significant progress has been made in elucidating the antitumor mechanisms of major myokines. Nevertheless, their intracellular signaling pathways remain incompletely defined. The majority of existing studies rely on in vitro cell models and lack validation in physiologically relevant in vivo settings or clinical contexts. Notably, several myokines exhibit functional duality, capable of exerting either tumor-suppressive or tumor-promoting effects depending on the specific microenvironmental context.
Conclusion: Future research must urgently delineate the interaction networks of myokines with their upstream regulators and downstream effectors. It is essential to validate their true in vivo mechanisms using standardized animal models and well-characterized clinical samples. Furthermore, systematic evaluation of their pharmacokinetics, delivery strategies, and potential off-target effects is required to advance the clinical translation of myokine-based therapeutic interventions.

Keywords:  cancer suppression; exercise; molecular mechanism; myokines; skeletal muscle

DOI:  https://doi.org/10.3389/fspor.2026.1830759
Sci Adv. 2026 Jun 19. 12(25): eadz3612

Statins promote muscle metabolic danger and NLRP3-mediated myopathy via lower protein-prenylation and YAP.

Nazli Robin, Nicole G Barra, Kevin P Foley, Yujin E Li, Akhilesh K Tamrakar, Danish Patoli, Irena A Rebalka, Tabitha Cree, Kaitlyn Bibby, Khang Nguyen, Rhianna Davis, Darryl Y Chan, Brittany M Duggan, Brandyn D Henriksbo, Megan E Borges, Dana Kukje Zada, Han Fang, Daniel M Marko, Paul Gregorevic, Kevin I Watt, Richard J Mills, Gary Sweeney, Thomas J Hawke, Bénédicte F Py, Jonathan D Schertzer.

Statin intolerance and side effects such as low-level myopathy limit statin use and the dose for optimal cholesterol lowering. We found that priming the NLRP3 inflammasome with bacterial components like lipopolysaccharide lowered the dose of statins that caused side effects in muscle cells. We then built models of low-level statin myopathy and found that muscle cell-autonomous statin-induced myopathy occurs through the NLRP3 inflammasome in vitro and in mice. Statin-induced muscle cell death and higher Atrogin-1 were prevented by blocking NLRP3 or restoring isoprenoids but not cholesterol. Statins reduced glycolysis in muscle cells, which required lower protein prenylation. Statins lowered YAP effector genes and promoted nuclear accumulation of FOXO. Activating YAP, restoring isoprenoids, or blocking NLRP3 mitigated nuclear FOXO accumulation, statin-induced muscle atrophy, and statin-mediated lowering of protein synthesis. These results define a statin-induced myopathy pathway where metabolic danger engages the NLRP3 inflammasome and YAP via lower prenylation independent of cholesterol.

DOI: https://doi.org/10.1126/sciadv.adz3612
Geroscience. 2026 Jun 13.

Muscle Ageing and Sarcopenia Study (MASS) Lifecourse: a valuable resource for understanding skeletal muscle ageing.

Rachel Cooper, Christopher Hurst, Holly Syddall, Helen Atkinson, Jonathan G Bunn, Daniela Carpinelli, Antoneta Granic, Susan J Hillman, Emma Grace Lewis, Claire McDonald, Katie Sloan, Karen Suetterlin, Miles D Witham, Avan A Sayer.

  Advances in our understanding of the biology of skeletal muscle ageing are being made at pace, with great potential for these findings to inform the identification of novel treatments for sarcopenia. However, translation of findings from animal models to humans has been hampered by limitations of existing human muscle biopsy studies. Devised to directly address this challenge, the Muscle Ageing and Sarcopenia Study (MASS) Lifecourse is a novel resource for the study of human muscle ageing. This deep-phenotyped observational study of 260 community-dwelling men and women aged 18 to 85 years living in North East England includes muscle biopsy samples and detailed characterisation of physical function, health status and sociodemographic and behavioural risk factors. Few human observational studies, with muscle tissue sample collection, have the breadth and depth of data on such a wide range of other relevant characteristics across the full adult age range as MASS Lifecourse. This study therefore presents new opportunities to catalyse translational research on ageing muscle across the life course, identify novel treatment targets and deliver benefits for patients and the public.

Keywords:  Ageing; Deep phenotyping; Interdisciplinary translational research; Life course; Muscle; Sarcopenia

DOI:  https://doi.org/10.1007/s11357-026-02341-5
Curr Nutr Rep. 2026 Jun 17. pii: 55. [Epub ahead of print]15(1):

GLP-1 Receptor Agonists for Obesity Management in Older Adults: A Scoping Review on the Risk of Sarcopenia and Sarcopenic Obesity.

Hilal Simsek, Asli Ucar.

   PURPOSE OF REVIEW: Obesity pharmacotherapy has become increasingly relevant in older adults due to challenges in lifestyle modification and the burden of non-communicable diseases. Despite the expanding use of anti-obesity medications (AOMs), sarcopenia and sarcopenic obesity (SO) remain major concerns in this population. This review synthesizes current evidence on glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a well-studied AOMs, focusing on their effects on sarcopenia through mechanistic insights and clinical considerations in older adults.
RECENT FINDINGS: GLP-1 RAs effectively induce weight loss; however, concomitant muscle mass loss is common, raising concerns about sarcopenia. Weight cycling introduces uncertainty regarding skeletal muscle health and SO risk. Although data on muscle mass indices and physical performance remain limited and inconsistent, evidence suggests favorable effects on muscle metabolism and composition. Mechanistically, these effects are linked to GLP-1 RA-mediated suppression of inflammatory pathways, modulation of skeletal muscle metabolism, and preservation of mitochondrial function, thereby influencing insulin resistance. The most common adverse events are mild to moderate gastrointestinal symptoms, which may be mitigated through dietary counseling during dose escalation. Integrating GLP-1 RA therapy with tailored resistance exercise and caloric restriction with dietary counseling, including adequate protein intake (1.2-1.6 g/kg/day), may help preserve muscle mass and function in older adults. Implementation of GLP-1 RA-specific medical nutrition therapy protocols, with dietitian involvement to optimize dietary recommendations and manage adverse events, is recommended. Studies addressing skeletal muscle quantity, quality, and functional capacity are needed to clarify the effects of GLP-1 RAs on sarcopenic obesity in older adults.

Keywords:  Anti-obesity medications; Glucagon-like peptide receptor agonists (GLP-1RAs); Sarcopenia; Sarcopenic obesity

DOI:  https://doi.org/10.1007/s13668-026-00777-x