bims-moremu 2026-09-06 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–09–06
thirty-one papers selected by
Anna Vainshtein, Craft Science Inc.

Uncovering strategies to rescue muscle mass in ageing.
MBNL depletion drives stem cell fusion and immature myonuclear states in myotonic dystrophy type 1.
Impaired liver-muscle lactate metabolism causes sarcopenia via lactic acidosis in skeletal muscle in mice.
An integrated reference atlas of human skeletal muscle.
High-intensity interval training via electrical stimulation enhances endurance by preserving sarcoplasmic reticulum Ca2+ transients in mouse skeletal muscle.
Disuse-induced skeletal muscle IDO1 activation contributes to kynurenine-dependent muscle-liver crosstalk and hepatic oxidative injury.
Interactions Between E3 Ubiquitin Ligases and Deubiquitinases in AKT Regulation: Implications in Skeletal Muscle Homeostasis.
From gene regulation to membrane excitability: A new role for thyroid hormone in skeletal muscle.
Evidence that myoglobin PO2 is a non-invasive measure of in vivo skeletal muscle mitochondrial PO2 during exercise in humans.
Pre-conditioning against cachexia: How prior exercise enhances metabolic resilience during cancer.
Phase-transition failure in aged skeletal muscle regeneration.
Oxidative eustress is associated with AMPK and AKT activation, GLUT4 translocation and glucose uptake in skeletal muscle cells and fibres.
Myofibrillar myopathy-associated KY protein promotes muscle fibre size rescue independent of its predicted catalytic triad.
Hybrid PLGA nanoparticles outperform SLNs in intracellular delivery of an anti-inflammatory lipid mediator to skeletal muscle cells.
Endocrine Factors in Sarcopenia: Lifestyle-Based Approaches with Nutrition, Exercise, and Circadian Health.
The actomyosin cortex controls t-tubule remodeling in skeletal muscle.
The nuts and bolts of excitation-contraction coupling in skeletal muscle.
A who's who of cell types in skeletal muscle.
Endocannabinoid system dysregulation in non-communicable diseases: Implications for skeletal muscle health.
Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia.
miRNAs as cell-intrinsic epigenetic regulators in muscle in type 2 diabetes.
Engineering In Vitro Models of Skeletal Muscle With Neuromuscular Junctions Using Hierarchical Micro-Nano Biomaterials: Cooperative Effect of Adhesion Ligand Nanoclustering and Surface Anisotropy.
Peripheral Nerve Injury and Denervation-Induced Sarcopenia with a Focus on Pharmacological Dual-Target Strategies.
Autophagy Deficits in Lower Motor Neuron and Striated Muscle Diseases: From Genetics to Therapeutic Advances.
Exerkine-Mediated Inter-Organ Crosstalk and Translational Perspectives in Metabolic Diseases.
The survival motor neuron protein: structure, functions, stability, and therapeutic targeting.
A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.
Treatment updates in myotonic disorders.
Cellular and molecular mechanisms of muscle spindle development and function.
Sex-specific physical activity thresholds influencing muscle function in older adults with XX genotype of ACTN3 R577X.
Learning muscle-health trajectories in ageing: towards AI-guided organ chips.

J Physiol. 2026 Sep 02.

Uncovering strategies to rescue muscle mass in ageing.

Joelina Lienau.



Keywords:  TUDCA; ageing; bile acid; muscle atrophy; proteostasis; sarcopenia; skeletal muscle; tauroursodeoxycholic acid

DOI:  https://doi.org/10.1113/JP291783
Nat Commun. 2026 Aug 06. pii: 9476. [Epub ahead of print]17(1):

MBNL depletion drives stem cell fusion and immature myonuclear states in myotonic dystrophy type 1.

Vanessa Todorow, Xavière Lornage, Shinichiro Hayashi, Fiorella Carla Grandi, Zoé Clerc, Jeanne Lainé, Michel Ney, Mégane Lemaitre, Corentin Rouxel, Maria Kondili, Piera Smeriglio, Hanseul Oh, Mie Kato, Nobuyuki Eura, Yoshihiko Saito, Francia Victoria A De Los Reyes, Satoru Noguchi, Benedikt Schoser, Denis Furling, Ichizo Nishino, Peter Meinke, Frédérique Rau.

Myotonic dystrophy type 1 is caused by the expression of expanded CTG repeats in the DMPK gene and the resulting loss of function of MBNL protein. Affected skeletal muscle displays abundant centrally located nuclei despite limited immune-cell-associated fibre necrosis, complicating interpretation of muscle damage and remodelling mechanisms. Here we show that muscle stem cells are activated and fuse with existing muscle fibres in myotonic dystrophy type 1. Single-nucleus transcriptomics in patient's muscle identifies increased activated muscle stem cells and distinct myonuclear populations exhibiting transitional transcriptional states, including muscle stem cell associated markers and elevated DMPK expression. Myofibre-specific MBNL knockdown mouse models demonstrate that muscle stem cell fusion contributes to central nucleation, whereas their deletion does not improve myotonia or muscle strength. Together, these findings indicate that loss of MBNL function in muscle drives myonuclear accretion through stem cell-mediated fusion, giving rise to myonuclei with immature states in myotonic dystrophy type 1.

DOI: https://doi.org/10.1038/s41467-026-76476-6
Sci Adv. 2026 Sep 04. 12(36): eaeb4011

Impaired liver-muscle lactate metabolism causes sarcopenia via lactic acidosis in skeletal muscle in mice.

Takahiro Eguchi, Nozomi Hayashiji, Sho Tabata, Keiko Kabetani, Yasunori Shintani, Hideki Makinoshima, Naoki Ito.

Sarcopenia is a progressive disease characterized by age-related decline in skeletal muscle force and mass. The fundamental molecular pathogenesis of sarcopenia has not yet been elucidated. Here, we show that the accumulation of lactate and intracellular acidification, lactic acidosis, in skeletal muscle owing to impaired liver-skeletal muscle lactate metabolism is the fundamental cause of sarcopenia. Systemic lactate tolerance decreased in aged mice owing to the impaired lactate processing capacity in the liver, which caused lactic acidosis in skeletal muscle. Furthermore, pharmacological activation of hypoxia-inducible factor (HIF) or liver-specific activation of HIF1α improved age-associated impairment in lactate tolerance, lactic acidosis in skeletal muscle, and sarcopenia. Mechanistically, the decreased nicotinamide adenine dinucleotide level was the cause of dysregulated skeletal muscle functions due to lactic acidosis. Using mouse models, our results show lactic acidosis in skeletal muscle as a key molecular pathogenesis of sarcopenia and highlight HIF1α in the liver as a pharmacological target for sarcopenia.

DOI: https://doi.org/10.1126/sciadv.aeb4011
EBioMedicine. 2026 Aug 31. pii: S2352-3964(26)00349-X. [Epub ahead of print]131 106465

An integrated reference atlas of human skeletal muscle.

Christopher Nelke, Franziska Babilon, Christina B Schroeter, Anne-Katrin Güttsches, Paula Quint, Karsten Krause, Gerd Meyer Zu Hörste, Benedikt Schoser, Jörg H W Distler, Sven G Meuth, Felix Kleefeld, Tobias Ruck.

   BACKGROUND: Single-cell and single-nucleus RNA sequencing have transformed our understanding of human skeletal muscle biology, yet reproducibility and cross-study comparison remain limited by the lack of a unified reference framework and consistent cell-type annotation.
METHODS: We systematically searched for scRNA-seq and snRNA-seq datasets from adult human skeletal muscle. Seven eligible studies were retrieved and harmonised. We benchmarked multiple integration strategies to construct a joint reference atlas and derived modality-aware marker panels. Selected findings were validated by immunofluorescence in muscle biopsies.
FINDINGS: We generated a harmonised atlas comprising 122,000 cells and 630,000 nuclei from 88 healthy individuals and resolved 17 major skeletal muscle cell populations, spanning mononuclear compartments and multinucleated myofibers. Cross-modality analysis identified tissue- and modality-aware marker panels and nominated both established and previously unrecognised markers. NOVA1 emerged as a selective marker of fibro-adipogenic progenitors and was validated at the transcript and protein levels. Focusing on myonuclei, pseudotime modelling reconstructed differentiation trajectories from quiescent muscle stem cells to mature type I and type II myofibers and revealed lineage-specific programs, including transient activation of protocadherin-γ genes during type I myofiber differentiation. We further provide an interactive web application for marker-based cell-type prediction using the reference atlas.
INTERPRETATION: This integrated reference atlas and accompanying annotation tool establish a standardised framework for human muscle transcriptomics, promoting consistent cell-type assignment and providing a baseline for future studies of muscle development, ageing, and disease.
FUNDING: Else Kröner-Fresenius-Stiftung and the German Research Foundation.

Keywords:  Atlas; Muscle; Reference; Single cell; Single nucleus; Transcriptomics

DOI:  https://doi.org/10.1016/j.ebiom.2026.106465
Am J Physiol Cell Physiol. 2026 Sep 03.

High-intensity interval training via electrical stimulation enhances endurance by preserving sarcoplasmic reticulum Ca2+ transients in mouse skeletal muscle.

Luke D Flewwelling, Masih Jafari, Shahrzad Khajehzadehshoushtar, Takashi Yamada, Christopher G R Perry, Arthur J Cheng.

  This study investigated the effects of high/low-intensity interval training (HIIT/LIIT) via electrical stimulation (ES) on muscle performance, specifically focusing on fatigue resistance and cytoplasmic free calcium ([Ca2+]i) dynamics in mouse skeletal muscle. Thirty 9-week-old female C57BL6 mice underwent four weeks of involuntary IT-ES in hindlimb plantar flexor muscles in vivo, with stimulation frequencies set at either 20 Hz (LIIT) or 100 Hz (HIIT). Our results showed that IT-ES significantly enhanced fatigue resistance, particularly with HIIT, evidenced by improved muscle torque output and better preservation of tetanic [Ca2+]i levels during repeated contractions. Additionally, IT-ES led to increases in sarcoplasmic reticulum (SR) Ca2+ handling proteins, such as SR Ca2+ ATPase 1 (SERCA1) and the ryanodine receptor 1 (RyR1), as well as mitochondrial respiratory complex proteins, indicating enhanced metabolic adaptations. The results suggest that HIIT-ES is an effective intervention for improving muscle function, intracellular Ca2+ management, and mitochondrial content, providing a foundation for future consideration in rehabilitation and clinical settings.

Keywords:  High-intensity interval training; calcium; fatigue; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00795.2025
Biochim Biophys Acta Mol Basis Dis. 2026 Aug 31. pii: S0925-4439(26)00308-X. [Epub ahead of print]1873(1): 168442

Disuse-induced skeletal muscle IDO1 activation contributes to kynurenine-dependent muscle-liver crosstalk and hepatic oxidative injury.

Xiuru Li, Jinglin Peng, Yating Huang, Xuege Yang, Yanmei Niu, Li Fu.

  Physical inactivity and mechanical unloading induce skeletal muscle atrophy and are associated with systemic metabolic disorders, but the molecular basis linking muscle disuse to liver injury remains unclear. Human cohort analyses (CHARLS, NHANES), a mouse hindlimb immobilization model, and multi-level in vitro systems were used to define this mechanism. Muscle disuse activates skeletal muscle indoleamine 2,3-dioxygenase 1 (IDO1), accompanied by altered tryptophan metabolism and increased systemic kynurenine accumulation. Kynurenine functioned as a circulating pathogenic mediator that activates hepatic aryl hydrocarbon receptor (AhR) signaling, resulting in oxidative stress, hepatocyte injury, and fibrotic remodeling. Importantly, pharmacological inhibition of IDO1 in vivo and siRNA-mediated IDO1 knockdown in vitro reduced kynurenine-associated AhR signaling and attenuated hepatocyte injury-related phenotypes. These findings identify an IDO1-kynurenine-AhR axis associated with muscle atrophy-related liver pathology and suggest that skeletal muscle IDO1 activation contributes to inter-organ metabolic communication during physical inactivity. Targeting this pathway may provide a therapeutic strategy to mitigate systemic complications associated with disuse and sedentary conditions.

Keywords:  Aryl hydrocarbon receptor; IDO1; Kynurenine; Liver injury; Muscle disuse

DOI:  https://doi.org/10.1016/j.bbadis.2026.168442
Cell Biochem Funct. 2026 Sep;44(9): e70297

Interactions Between E3 Ubiquitin Ligases and Deubiquitinases in AKT Regulation: Implications in Skeletal Muscle Homeostasis.

Rajesh Dabur.

  AKT (protein kinase B, PKB) coordinates the balance between anabolic and catabolic signaling in skeletal muscle through distinct ubiquitin chain types. Some E3 ubiquitin ligases (E3s) and deubiquitinases (DUBs) form stable binary complexes via non-catalytic interfaces, adding a regulatory layer unavailable to either enzyme alone. This mechanistic synthesis review presents a systematic literature analysis (inception to May 2026; 26 eligible studies). It identified four E3-DUB pairs proposed to regulate AKT in skeletal muscle. These are TRAF6-CYLD (plasma-membrane K63-ubiquitination), MUL1-USP9X (mitochondrial K48-ubiquitination of AKT2), CHIP-UCH37 (proteasome-proximal quality control), and SCF-Skp2-USP37 (PHLPP1/2-dependent control of AKT Ser473 phosphorylation). All four interfaces are structurally separate from the catalytic sites and are regulated by upstream kinase phosphorylation. Evidence for the four pairs is markedly uneven. TRAF6-CYLD is supported by endogenous co-immunoprecipitation and functional data in muscle models. CHIP and UCH37 each act on AKT-related substrates independently and are individually well documented, but a direct CHIP-UCH37 interaction has not itself been demonstrated. SCF-Skp2-USP37 interaction data rest on a real but non-muscle direct interaction, whereas MUL1-USP9X has no reported direct interaction at all; CHIP-UCH37, SCF-Skp2-USP37, and MUL1-USP9X are therefore all presented as testable hypotheses of varying strength. In chronic atrophy, available data are consistent with disruption of these complexes contributing to AKT suppression through parallel, largely independent mechanisms. However, simultaneous disruption of all four has not been demonstrated in a single system. Available gene expression and protein datasets from sarcopenic muscle broadly support these predictions, though direct experimental validation in human tissue remains pending. This complex-centric framework recasts AKT ubiquitination as an integrated regulatory framework. Each structurally autonomous interface may represent a potentially distinct target for muscle-wasting conditions that currently lack approved therapies.

Keywords:  AKT ubiquitination; E3 ubiquitin ligase; deubiquitinase; muscle atrophy; sarcopenia; skeletal muscle; ubiquitin chain topology

DOI:  https://doi.org/10.1002/cbf.70297
J Physiol. 2026 Sep 04.

From gene regulation to membrane excitability: A new role for thyroid hormone in skeletal muscle.

Eric N Jimenez-Vazquez, David K Jones.



Keywords:  KCNH2; TWIK; ion channel; skeletal muscle; thyroid

DOI:  https://doi.org/10.1113/JP291849
Function (Oxf). 2026 Sep 03. e0222026

Evidence that myoglobin PO2 is a non-invasive measure of in vivo skeletal muscle mitochondrial PO2 during exercise in humans.

Ryan M Broxterman, Bradley A Ruple, Peter D Wagner, Russell S Richardson.

  Muscle mitochondrial partial pressure of oxygen (PmitoO2) is a key determinant of skeletal muscle oxygen consumption (V̇O2), metabolism, gene regulation, and adaptation in health and disease. Yet PmitoO2 remains difficult to measure directly in vivo in humans during exercise. Myoglobin-associated PO2 (PMbO2), measured non-invasively using proton magnetic resonance spectroscopy, may provide a measure of PmitoO2 during maximal exercise in humans because Mb is coupled to mitochondrial oxygen availability and PMbO2 falls in the low PO2 range expected for PmitoO2 in vivo. However, it remains unknown whether PMbO2 during maximal exercise varies systematically with muscle V̇O2max, as would be expected if PMbO2 reflects PmitoO2 in vivo. We analyzed data from five initially sedentary males before and after 8 weeks of single-leg knee-extensor exercise (KE) training. During maximal KE under 0.12, 0.21, and 1.00 fractions of inspired oxygen (FIO2), we measured PMbO2 using myoglobin desaturation measured by proton magnetic resonance spectroscopy and muscle V̇O2max from leg blood flow and the arterial-femoral venous O2 content difference. Across FIO2 conditions, muscle V̇O2max varied systematically with PMbO2 both before and after training, consistent with O2-dependent mitochondrial respiration. When interpreted within a canonical hyperbolic framework, the V̇O2-PMbO2 relationship yielded low apparent mitochondrial P50 values that were broadly consistent with values reported for human skeletal muscle isolated mitochondria studied in vitro. A complementary linear P50 analysis that did not assume a hyperbolic relationship supported the same interpretation. Together, these findings provide data-supported, proof-of-concept evidence that PMbO2 reflects in vivo PmitoO2 during maximal exercise in humans.

Keywords:  1H-MRS; Maximal Oxygen Uptake; Mitochondria; Skeletal Muscle.

DOI:  https://doi.org/10.1152/function.022.2026
J Physiol. 2026 Aug 31.

Pre-conditioning against cachexia: How prior exercise enhances metabolic resilience during cancer.

Swarali Paranjape, Sena Yamamoto.



Keywords:  cancer cachexia; exercise; skeletal muscle

DOI:  https://doi.org/10.1113/JP291912
Biogerontology. 2026 Sep 01. pii: 154. [Epub ahead of print]27(5):

Phase-transition failure in aged skeletal muscle regeneration.

Bo Zhang, Haijiao Shi, Xiaojing Guo, Yan Wang.

  Aged skeletal muscle is impaired at every phase of post-injury repair that has been examined, with myeloid recruitment delayed and skewed in composition, debris degradation lagging behind uptake, and muscle stem cell (MuSC) activation following a conserved trajectory at delayed kinetics. Deficits inside a phase may be differences of degree that a longer window absorbs, whereas the transition between phases offers no comparable slack. Each transition is triggered by a defined switch in signal, either the fall in damage input after debris degradation, the TNF/TGF-β balance that permits fibro-adipogenic progenitor (FAP) apoptosis, or the Ly6Chigh→Ly6Clow monocyte conversion. Because positive feedback operates beyond each switch, a compartment arriving late meets a microenvironment already committed to a self-maintaining alternative state that its later output appears unable to reverse. Retained mitochondrial lesions in postmitotic myofibers are one proposed input holding the first switch open. MuSCs face pool contraction, skewed fate allocation, and cell-autonomous defects uncorrected by a young host. FAPs resist clearance past their support phase while a stiffening matrix keeps them fibrogenic, and aged myeloid cells reach the pro-repair switch late and with attenuated output. None of these lesions need be primary for the sequence to fail. Interventions should instead be judged on whether inflammation declines, matrix remodeling closes, myogenic output yields mature fibers, and reserve survives repeated injury. Aging may therefore be read as a loss of temporal coordination, in which sub-threshold delays accumulate between compartments that must act in sequence, until a failed transition settles the tissue into an inflammatory-fibrotic endpoint.

Keywords:  Aging; Inflammation; Regeneration; Satellite cells; Skeletal muscle

DOI:  https://doi.org/10.1007/s10522-026-10500-6
Redox Rep. 2026 Dec 31. 31(1): 2721882

Oxidative eustress is associated with AMPK and AKT activation, GLUT4 translocation and glucose uptake in skeletal muscle cells and fibres.

Eva Martín-Prieto, Leonardo A Catalano-Iniesta, Escarlata Fernández-Puente, Jesús Palomero.

  Objectives: Reactive oxygen and nitrogen species (RONS) act as signalling molecules under physiological conditions; however, how oxidative eustress regulates glucose uptake in skeletal muscle remains poorly defined. We investigated the role of moderate oxidation in skeletal muscle glucose uptake, focusing on AKT/AMPK phosphorylation, GLUT4 translocation and functional glucose uptake. Methods: AKT and AMPK phosphorylation were analysed in C2C12 myoblasts/myotubes exposed to insulin and redox-modulating stimuli associated with oxidative eustress, including hydrogen peroxide, nitric oxide donors and angiotensin II. GLUT4 translocation was assessed by quantitative immunocytochemistry and confocal fluorescence microscopy in cells expressing a GLUT4 reporter. Glucose uptake was evaluated in isolated skeletal muscle fibres using 6-NBDG. Results: Oxidative eustress was associated with increased AKT and AMPK phosphorylation and enhanced GLUT4 translocation to the plasma membrane. Hydrogen peroxide, nitric oxide donors and angiotensin II increased GLUT4 presence at the plasma membrane and enhanced glucose uptake, with hydrogen peroxide showing a dose-dependent effect. Increased glucose uptake was consistent with GLUT4 translocation. Discussion: These findings support oxidative eustress as a physiological redox mechanism linking AKT/AMPK activation, GLUT4 translocation and glucose uptake in skeletal muscle. Redox signalling may therefore contribute to skeletal muscle glucose metabolism.

Keywords:  AKT; AMPK; GLUT4 translocation; Oxidative eustress; glucose uptake; nitric oxide; reactive oxygen and nitrogen species; skeletal muscle

DOI:  https://doi.org/10.1080/13510002.2026.2721882
Hum Mol Genet. 2026 Aug 25. pii: ddag086. [Epub ahead of print]35(18):

Myofibrillar myopathy-associated KY protein promotes muscle fibre size rescue independent of its predicted catalytic triad.

Ahmed Nouh, Oscar Harrad, Andrzej M Brzozowski, William Grey, Gonzalo Blanco.

  Mutations in the Ky gene are the underlying cause of Myofibrillar Myopathy-7 (MFM-7), a rare progressive muscle weakness disease of childhood onset. A defining characteristic of the KY protein is the presence of a conserved transglutaminase-like domain, but unequivocal evidence of its enzymatic function remains to be established. To investigate the functional relevance of the predicted KY catalytic triad we use here in vitro enzymatic assays, structural modeling and in vivo rescue experiments in ky/ky mice. While structural modelling shows a striking conservation of the catalytic pocket architecture, our results show that recombinant KY proteins showed no detectable enzymatic activity under the assay conditions used. Moreover, while deletion of transglutaminase-like domain prevents phenotype rescue, replacements of the predicted catalytic residues do not impair the protein's ability to rescue fibre size in ky/ky muscle, indicating that the predicted catalytic residues are dispensable for fibre size rescue in these assays. Proteomic analyses identified KY-associated protein complexes involved in protein quality control, including core components of the Chaperone-Assisted Selective Autophagy machinery. In agreement, basal autophagic flux is significantly reduced in both KY-deficient C2C12 cells and ky/ky muscle fibres. Collectively, our data suggests that the TGN/PROT domain facilitates critical molecular associations at the sarcomeric Z-disc through a mechanism independent of catalysis and that impaired autophagic flux may contribute to the muscle phenotype.

Keywords:  Mendelian disorder; autophagy; monogenic disorders; muscular dystrophy; pproteostasis; rare disease

DOI:  https://doi.org/10.1093/hmg/ddag086
J Control Release. 2026 Sep 03. pii: S0168-3659(26)00736-4. [Epub ahead of print] 115332

Hybrid PLGA nanoparticles outperform SLNs in intracellular delivery of an anti-inflammatory lipid mediator to skeletal muscle cells.

Eleonora Maretti, Beatrice Recchia, Arianna Votta, Elena Guarnaccia, Francesca Di Cesare, Giuseppe Cannella, Cecilia Rustichelli, Dror Seliktar, Claudia Fuoco, Cesare Gargioli, Elisabetta Ferraro, Eliana Leo, Susanna Molinari.

  Chronic low-grade inflammation (CLGI) contributes to several skeletal muscle disorders as sarcopenia, still lacking disease-specific therapies. Palmitoylethanolamide (PEA) is a natural anti-inflammatory mediator with proven safety, but its high lipophilicity and poor solubility limit bioavailability and muscle delivery. The intrinsic difficulty of actively targeting skeletal muscle cells further supports the need for biomaterial-based strategies to enhance PEA delivery and therapeutic potential. Here, solid lipid nanoparticles (SLNs) and hybrid polymer-lipid PLGA nanoparticles (hyPLGA) are directly compared to identify a nanocarrier optimized for PEA delivery and bioactivity in skeletal muscle tissue. Both carriers exhibited favorable physicochemical profiles and maintained dimensional features after lyophilization, with PEA-SLNs achieving higher encapsulation efficiency. Despite this, PEA-hyPLGA nanoparticles demonstrated superior functional performance in vitro. In C2C12 myoblasts, both formulations were internalized efficiently, yet PEA-hyPLGA nanoparticles exhibited faster uptake kinetic. Notably, PEA-hyPLGA significantly reduced IL-6 and TNF-α transcript levels, enhanced PPAR-α nuclear localization, and mitigated LPS-induced cytotoxicity more effectively than Native PEA or PEA-SLNs. The efficient internalization of PEA-hyPLGA nanoparticles was also observed in human 3D muscle constructs, where the nanoparticles exhibited the ability to penetrate differentiated myofibers. Their behavior was further validated in vivo, where a prolonged retention of PEA-hyPLGA nanoparticles and their ability to reduce inflammatory markers in mouse skeletal muscle, upon intramuscular injection, was observed. Altogether, these findings indicate that hyPLGA nanoparticles represent a convenient nanostructure platform for PEA delivery and anti-inflammatory function in skeletal muscle, supporting their envisaged use as systemic administered targeted therapy toward translational strategies for sarcopenia.

Keywords:  3D myo-constructs; C2C12 cells; PEA; PPARalpha receptor; Palmitoylethanolamide; Sarcopenia

DOI:  https://doi.org/10.1016/j.jconrel.2026.115332
Aging Dis. 2026 Aug 13.

Endocrine Factors in Sarcopenia: Lifestyle-Based Approaches with Nutrition, Exercise, and Circadian Health.

Sihyung Lee, Choon Young Kim.

Sarcopenia, the age-related skeletal muscle disorder characterized by declines in muscle mass, strength, and physical performance, has significant health consequences and represents a major global public health challenge. Age-related endocrine and peripheral anabolic-catabolic dysregulation plays a central role in sarcopenia development, and lifestyle factors interact with hormonal regulation to influence skeletal muscle homeostasis. In older adults, reduced hormone secretion capacity, receptor responsiveness, and peripheral metabolism impair hormonal systems, including the somatotropic, gonadal, adrenal, and thyroid axes, as well as insulin and peripheral mediators, such as adipokines, myokines, and inflammatory cytokines. These alterations promote anabolic resistance, a catabolic environment, and metabolic dysfunction, contributing to sarcopenia. Age-related changes in appetite, nutrient utilization, and food choice impair anabolic efficiency and metabolic homeostasis. Declines in physical activity and neuromuscular efficiency disrupt multiple signaling pathways required to maintain muscle mass, and psychosocial factors may increase the risk of a vicious cycle of inactivity. Alterations in the suprachiasmatic nucleus (SCN) and inconsistent behavioral zeitgebers disrupt physiological rhythms. These lifestyle domains influence skeletal muscle homeostasis independently and interact bidirectionally through shared endocrine pathways. Current pharmacological approaches remain adjunctive, limited to confirmed endocrine deficiencies. The coordinated optimization of nutrition, exercise, and circadian health, with attention to regularity and timing, may offer complementary benefits exceeding single-domain interventions. A stage-specific and individually tailored approach supported by multidimensional monitoring and digital technologies is recommended for effective sarcopenia prevention and management.

DOI: https://doi.org/10.14336/AD.2026.0483
Sci Adv. 2026 Sep 04. 12(36): eaeb3209

The actomyosin cortex controls t-tubule remodeling in skeletal muscle.

Ana Raquel Pereira, Silvia Di Francescantonio, Ana da Rosa Soares, Tianyang Liu, Filomena A Carvalho, Josie Liane Ferreira, Graciano Leal, Inês Faleiro, Naoko Kogata, Beatrice Labella, Teresinha Evangelista, Nuno C Santos, Michael Way, Carolyn A Moores, Edgar R Gomes.

A network of plasma membrane invaginations called t-tubules plays an essential role in controlling calcium release from the endoplasmic reticulum at the triads during muscle contraction. Although the importance of t-tubules for muscle physiology is well established, and abnormalities are found in muscle disorders, the mechanisms that mediate t-tubule growth are unknown. We show that the actomyosin cortex beneath the plasma membrane, regulated by Arp2/3 complexes containing Arpc5, acts as a gatekeeper for the membrane availability during t-tubule growth. Enlarged t-tubules are formed upon disruption of Arpc5, impairing the synchronization between plasma membrane depolarization and calcium release. Knockout of Arpc5 in mouse skeletal muscle results in impaired locomotion and posture. Furthermore, we show that human triadopathy patients and Arpc5 knockout mice accumulate enlarged t-tubules. We propose that cortex-dependent membrane availability affects muscle function, offering a potential pathophysiological mechanism for muscle disorders.

DOI: https://doi.org/10.1126/sciadv.aeb3209
Eur J Appl Physiol. 2026 Sep 04.

The nuts and bolts of excitation-contraction coupling in skeletal muscle.

A F Dulhunty, M G Casarotto.

  Mobility in humans and all animals depends on the co-ordinated progress of essential steps linking electrical action potentials along the surface membrane of muscle fibres to the increased cytoplasmic Ca2+ concentrations that activate the contractile proteins. Excitation-contraction (EC) coupling is the transformation of an electrical signal into a massive release of Ca2+ from intracellular Ca2+ stores. We consider the evolution of our knowledge of the structures and proteins that underlie skeletal muscle EC coupling, unanswered questions and future developments that will reveal the fundamental molecular events of the coupling process. The deeper understanding gained with future developments will reveal the molecular basis of muscle weakness related to mutations in EC coupling proteins or result from fatigue and aging. The benefits will flow on to the rational design of therapies to increase muscle strength in the many situations where muscle weakness is related to changes in EC coupling.

Keywords:  CaV1.1; Excitation–contraction coupling; Myopathy; RyR1; STAC3; Skeletal muscle; β1a subunit

DOI:  https://doi.org/10.1007/s00421-026-06413-4
Commun Biol. 2026 Sep 03. pii: 1170. [Epub ahead of print]9(1):

A who's who of cell types in skeletal muscle.

Shubhangi Das Barman, Zofija Frimand, M Pilar J Stella, Anne-Sofie Clausen, Sierra L W Olsen, Antoine de Morree.

Cells are the basic unit of life. In multicellular organisms, cells are organized into tissues. This enables a division of labor where tissues perform complex tasks via coordinated actions of specialized cell types. Accordingly, the cellular collective determines tissue function. A comprehensive overview of which cell types exist in solid tissues is lacking. Using skeletal muscle as a model, we discuss basic principles for cell type classification, summarize 62 unified definitions of cell types in terms of lineage, molecular signatures, and function from the literature, and discuss how these cell types contribute to muscle function. For cell types for which quantitative data was available, we compare abundances in immunohistology and single cell and single-nucleus RNA sequencing data, revealing cell types that are commonly over- or underrepresented in each method. The result is a cell type resource that will serve as a benchmark for single-cell studies of skeletal muscle.

DOI: https://doi.org/10.1038/s42003-026-10803-x
Exp Gerontol. 2026 Sep 04. pii: S0531-5565(26)00291-3. [Epub ahead of print] 113312

Endocannabinoid system dysregulation in non-communicable diseases: Implications for skeletal muscle health.

Kaat Vanderbeke, Sebastiaan Dalle, Katrien Koppo.

  Non-communicable diseases (NCDs) and their associated skeletal muscle (SkM) degeneration substantially contribute to morbidity and mortality. Interestingly, the endocannabinoid system (ECS) is increasingly recognized as an important regulator of both NCD pathophysiology and SkM plasticity. This narrative review summarizes the interplay between the ECS, NCDs and SkM degeneration - a potentially interesting triad that has not yet been comprehensively described, but may stimulate future research into the role of ECS-targeted interventions in the context of disease-associated SkM wasting. Therefore, we performed a narrative synthesis of (pre)clinical studies, focusing on alterations in ECS components (endocannabinoids, enzymes, receptors), the effects of ECS modulation (e.g. receptor (ant)agonism or enzyme inhibition), and SkM degeneration symptoms, across various (models of) NCDs. Additionally, the current literature on ECS modulation and SkM degeneration in non-disease models was summarized. The main findings show that ECS composition is consistently altered in different NCDs, including obesity, cancer (cachexia), liver disease, kidney disease, cardiovascular disease and inflammatory bowel disease. Pharmacological or genetic ECS modulation has been reported to improve several disease-related outcomes, e.g. insulin resistance, liver fibrosis and renal inflammation, predominantly in preclinical models. These NCDs also exhibit hallmarks of SkM degeneration, including atrophy, impaired regeneration, inflammation, and weakness. Notably, ECS modulation could ameliorate SkM pathology in various preclinical myopathy models, raising the hypothesis of an ECS-disease-muscle axis. However, this hypothesis requires further validation, as studies directly evaluating ECS-based interventions in disease-associated SkM degeneration remain limited. Future research should directly evaluate the existence of this potential ECS-disease-muscle axis by generating more (human) data on ECS modulation in the context of disease-associated muscle wasting.

Keywords:  Cachexia; Cannabinoid receptor 1; Preclinical studies; Skeletal muscle degeneration; Skeletal muscle wasting

DOI:  https://doi.org/10.1016/j.exger.2026.113312
Cancer Discov. 2026 Sep 01. OF1-OF25

Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia.

Juliano Machado, Vignesh Karthikaisamy, Hermine Mohr, Doris Kaltenecker, Pia Benedikt, Pauline Morigny, Amit Mhamane, Julia Geppert, Amy Rose Fumo, Kerstin Haase, Estefania Simoes, Joanna D C C Lima, Anastasia Georgiadi, Achim Krüger, José Pinhata Otoch, Marc E Martignoni, Vickie E Baracos, Mariam Jamal-Hanjani, Marilia C L Seelaender, Olga Prokopchuk, Julia Szendrödi, Maria Rohm, Stephan Herzig, Mauricio Berriel Diaz.

Cancer cachexia is a devastating wasting syndrome with no approved therapies. In this study, we identify the tumor-derived glycoprotein ADAMTSL4 as a circulating factor associated with body weight loss in preclinical cachexia models and patients with colorectal and lung cancers. In mice, Adamtsl4 overexpression converted non-cachexia-inducing tumors into cachexia-inducing tumors, whereas its deletion in cachexia-inducing tumors spared fat and muscle, blunted muscle atrophy signatures, and reduced cachexia severity. ADAMTSL4 engages the latency-associated peptide (LAP) of TGFβ1, promoting local activation of TGFβ1 at muscle cell membranes. Genetic blockade of proTGFβ1 or pharmacologic inhibition of TGFβ signaling reduced ADAMTSL4-dependent wasting in adipocytes and muscle cells. Suppression of tumor-derived ADAMTSL4 attenuated skeletal muscle fibrosis in mice. Together, the association between increased circulating ADAMTSL4 levels and TGFβ-driven muscle atrophy and fibrosis gene signatures in patients with cachectic cancer identifies ADAMTSL4 as an upstream regulator of TGFβ1 and a potential therapeutic target in cancer cachexia.
SIGNIFICANCE: Cancer cachexia lacks effective therapies and remains a major cause of cancer-related morbidity and mortality. We identify tumor-derived ADAMTSL4 as an upstream regulator of latent TGFβ activation via LAP engagement that promotes multiorgan wasting and fibrosis-related remodeling. Targeting ADAMTSL4 may provide a selective therapeutic strategy without systemic TGFβ pathway blockade.

DOI: https://doi.org/10.1158/2159-8290.CD-26-0045
Signal Transduct Target Ther. 2026 Sep 02. pii: 359. [Epub ahead of print]11(1):

miRNAs as cell-intrinsic epigenetic regulators in muscle in type 2 diabetes.

Allah Nawaz, Marsel Lino, Nida Haider, Antonio S Gomes, Anindya Ghosh, Eiichiro Satake, Arijeet K Gattu, C Ronald Kahn.

miRNAs are important metabolic regulators and are altered at both the cellular and secreted levels in diseases, including type 2 diabetes (T2D). However, to what extent these alterations are in response to factors in the in vivo milieu or are cell-intrinsic remains unclear. Here we used a disease-in-a-dish model in which iPSCs from T2D patients and controls were differentiated into myoblasts (iMyos), and their cellular and secreted miRNAs were profiled. We found that iMyos from T2D donors exhibit cell-intrinsic alterations in miRNA expression and secretion in small extracellular vesicles (sEVs)/exosomes. Integrating miRNA-predicted targets with transcriptomic and proteomic data revealed that miRNAs altered in T2D iMyos were associated with coordinated changes in their predicted targets, but with a much greater impact on protein than on mRNA levels. This effect was validated by miRNA overexpression in control iMyos. The upregulated miRNAs targeted pathways related to aerobic respiration, membrane trafficking, and RNA metabolism. Even more marked changes were observed in sEV-associated miRNAs secreted by T2D iMyos, indicative of T2D-associated effects on miRNA sorting and release. Target genes of secreted miRNAs altered in T2D iMyos were enriched in metabolic pathways including insulin signaling and mitochondrial metabolism. Consistent with this, sEVs derived from control iMyos increased glucose uptake and mitochondrial function in recipient human white adipocytes, whereas sEVs from T2D iMyos did not. Thus, in T2D, muscle exhibits cell-intrinsic alterations in expression and secretion of miRNAs, which function as epigenetic regulators of protein expression locally, as well as potentially in distal tissues.

DOI: https://doi.org/10.1038/s41392-026-02846-7
Small. 2026 Sep 03. e75566

Engineering In Vitro Models of Skeletal Muscle With Neuromuscular Junctions Using Hierarchical Micro-Nano Biomaterials: Cooperative Effect of Adhesion Ligand Nanoclustering and Surface Anisotropy.

Shirin Nour, Kristy Swiderski, Sahar Salehi, Gordon S Lynch, Andrea J O'Connor, Greg G Qiao, Daniel E Heath.

  The development of high-fidelity in vitro contractile skeletal muscle containing neuromuscular junctions (NMJs) is an unmet challenge, largely because current systems cannot accurately reproduce hierarchical micro- to nano-scale biointerfacial cues of the native extracellular matrix. This limitation impairs tissue regeneration and limits the clinical relevance of existing models for drug screening and studies of disease pathophysiology. Herein, we present hierarchical, anisotropic biomaterials that induced early maturation of myotubes and NMJ development during co-culture with motor neurons. We accomplished this by creating micro-nano biomaterial interfaces that presented nanoclusters of integrin-binding ligands to promote mechanotransduction on the surface of aligned electrospun microfibers. Controlling surface topography and nanoscale ligand clustering led to 1.5- to 2.5-fold increases in myoblast proliferation, myotube formation, elongation, and alignment, resulting in spontaneous twitching and enhanced myotube-neuron connections, including increased acetylcholine receptor clustering, neurite branching, and myotube contraction compared to control surfaces without the requirement for exogenous neurotrophic factors or electrical stimulation. These findings highlight the importance of tailoring the distribution and presentation of adhesive ligands for in vitro development of NMJs and synaptic organization. Our approach offers a scalable, high-resolution platform for advancing skeletal muscle tissue engineering, studying muscle development and neuromuscular diseases, and shaping therapeutic screening strategies.

Keywords:  biointerface; micropattern; motor neuron; neuromuscular junction; peptide functionalized biomaterials; skeletal muscle tissue engineering; tissue model

DOI:  https://doi.org/10.1002/smll.75566
Biomol Ther (Seoul). 2026 Sep 01. 34(5): 1087-1102

Peripheral Nerve Injury and Denervation-Induced Sarcopenia with a Focus on Pharmacological Dual-Target Strategies.

Chawon Yun, Jun Hong Won, So Young Lee, Tae Hwan Kim, Ga Hee Kim, Jung Il Lee.

  Peripheral nerve injury (PNI) causes rapid disruption of neuromuscular connectivity, leading to sarcopenia characterized by muscle wasting, mitochondrial dysfunction, and metabolic imbalance. Although calcium dysregulation and aberrant AMPK/mTOR signaling are known contributors, the molecular cascade linking nerve injury to muscle degeneration remains incompletely understood. This review explores pharmacological and molecular strategies to restore neuromuscular integrity after PNI. We focus on agents such as 4-aminopyridine (4-AP), a potassium channel blocker that enhances nerve conduction, and clemastine, an antihistamine that promotes Schwann cell-mediated remyelination. These compounds represent a potential dual approach to accelerating nerve repair while maintaining muscle viability. We also explore muscle-centered molecular strategies, focusing on pathways such as Forkhead box protein O (FOXO), Glycogen synthase kinase 3 beta (GSK-3β), signal transducer and activator of transcription 3 (STAT3), and TGF-β/Smad, which govern the balance between protein synthesis and degradation. Of note, most current studies suggest that phytochemicals derived from marine sources, including seaweed, may attenuate denervation-induced catabolism by modulating FOXO signaling and suppressing E3 ubiquitin ligase activity. Additionally, we highlight the critical crosstalk between motor neurons and skeletal muscle, mediated by neurotrophic factors such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and Neurotrophin-3 (NT-3), which support both neuromuscular junction stability and axonal regrowth. By integrating insights from nerve biology and muscle physiology, this review outlines a therapeutic framework that targets both nerve regeneration and muscle preservation, an approach that effectively addresses nerve injury-induced sarcopenia effectively.

Keywords:  Denervation; Dual target approach; Nerve regeneration; Peripheral nerve; Sarcopenia; Schwann cell

DOI:  https://doi.org/10.4062/biomolther.2026.047
Annu Rev Pathol. 2026 Sep 03.

Autophagy Deficits in Lower Motor Neuron and Striated Muscle Diseases: From Genetics to Therapeutic Advances.

Angela Sisto, Freke Mertens, Mélissa Lallier, Rani Robeyns, Alexander L N van Nuijs, Pieter Van der Veken, Wim Martinet, Vincent Timmerman.

The degradation and recycling of damaged proteins and organelles through autophagy is a vital process to maintain terminally differentiated cells under energy-demanding physiological conditions and mechanical stress. Clinical and molecular studies of numerous congenital disorders of striated muscle and inherited neuropathies have reported severe autophagy defects as an underlying pathological mechanism. In this review, we investigate the genetic mutations underlying lower motor neuron diseases, skeletal muscle dystrophies, and (cardio)myopathies and how these mutations disrupt autophagy pathways. Through an in-depth analysis of the defective step of the autophagy pathway, we propose pharmacological targets that are able to correct the autophagy defects, thereby improving disease pathology. Finally, we discuss the current limitations in the development of autophagy-modulating drugs and propose novel technologies to support this growing field. By outlining key mechanisms and targets, this review supports the development of more effective autophagy modulators for rare diseases.

DOI: https://doi.org/10.1146/annurev-pathmechdis-032125-020448
Curr Obes Rep. 2026 Sep 03. pii: 75. [Epub ahead of print]15(1):

Exerkine-Mediated Inter-Organ Crosstalk and Translational Perspectives in Metabolic Diseases.

Bojun Zhou, Shiyan Zhang, Zhanbo Zhang, Shuman Ran, Haining Guo, Siqi Wang, Hua Meng.

   PURPOSE OF REVIEW: Exercise is a cornerstone intervention for obesity and related metabolic diseases. However, its systemic benefits cannot be fully explained by increased energy expenditure, enhanced skeletal muscle glucose uptake, reduced adiposity, or improved peripheral insulin sensitivity alone. We review recent advances in exercise-responsive exerkines, with a focus on how these factors coordinate inter-organ crosstalk among major metabolic organs, including skeletal muscle, adipose tissue, liver, pancreas, and intestine.
RECENT FINDINGS: Both acute exercise and chronic training change the secretory profiles of multiple organs, giving rise to a broad spectrum of exercise-responsive factors, including proteins, metabolites, lipids, nucleic acids, and extracellular vesicle-associated cargo. Collectively, these exerkines coordinate inter-organ communication and regulate systemic energy homeostasis, inflammation, and tissue function, thereby promoting metabolic adaptation and mitigating lipotoxicity and insulin resistance. Among the candidates identified to date, IL-6, FGF21, GDF15, and myostatin have undergone relatively advanced translational investigation. Their development highlights both the therapeutic promise and the limitations of exerkine-based strategies, as illustrated by FGF21 analogues for metabolic diseases and the limited efficacy or tolerability reported for some GDF15-targeted interventions. Exerkines provide a molecular framework for understanding how exercise produces coordinated metabolic adaptations across organs. However, most candidate exerkines still require stronger human validation, clearer tissue-source attribution, defined receptor pathways, dose-response characterization, and long-term safety assessment. Exerkine-based strategies should therefore be viewed not as replacements for exercise, but as potential complementary approaches for populations with limited exercise capacity, including frail older adults, patients with cardiopulmonary disease, individuals with severe obesity or neuromuscular disorders, and those recovering from surgery or prolonged bed rest.

Keywords:  Exerkines; Inter-organ crosstalk; Metabolic diseases; Metabolism; Physical activity

DOI:  https://doi.org/10.1007/s13679-026-00752-1
Front Cell Neurosci. 2026 ;20 1894100

The survival motor neuron protein: structure, functions, stability, and therapeutic targeting.

Bradley R Smith, Rachel Massalee, Mason Mayer, Brendan M Melvin, Arianna Valeri, Cecelia C Mangione, Barrington G Burnett.

  The survival motor neuron (SMN) protein is an essential and highly versatile assembly factor that coordinates RNA metabolism and ribonucleoprotein (RNP) complex formation across multiple cellular compartments. Although SMN is required for the survival of virtually all cell types, its deficiency disproportionately affects α-motor neurons, causing their selective degeneration and giving rise to spinal muscular atrophy (SMA). Once viewed primarily as a motor neuron disease, SMA is now understood to be a multi-systemic disorder in which cell-intrinsic dysfunction extends to skeletal muscle, inflammatory glial cells, and metabolic organs. This review examines the regulatory mechanisms that control SMN protein stability, collectively termed proteostasis, with a focus on how post-translational modifications coordinate with the ubiquitin-proteasome system and the autophagy-lysosomal pathway to govern protein turnover and clearance. We also address the emerging concept of gene dosage sensitivity, including the underappreciated paradox that therapeutic SMN overexpression can be as harmful as deficiency, producing distinct toxicities in both neuromuscular and peripheral tissues. Finally, we highlight the need for next-generation combination therapies that integrate genetic modifiers, targeted degradation strategies, and post-translational regulators to maintain SMN levels within the narrow physiological range required for safety and efficacy.

Keywords:  neurodegeneration; post-translational modifications; proteostasis; spinal muscular atrophy; survival motor neuron; ubiquitin-proteasome system

DOI:  https://doi.org/10.3389/fncel.2026.1894100
Hum Mol Genet. 2026 Aug 25. pii: ddag084. [Epub ahead of print]35(18):

A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.

Timothy J Hines, Jonathan R Funke, Samia L Pratt, Alaura D Rice, Jeffery L Twiss, Robert W Burgess.

  Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6 J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36Y1003N) and alpha-tubulin 4A (Tuba4aQ176P) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6 J mice, which confirmed the Tuba4aQ176P variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have overt ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.

Keywords:  Neurogenetics; mouse model; rare disease

DOI:  https://doi.org/10.1093/hmg/ddag084
J Neurol. 2026 Sep 04. pii: 562. [Epub ahead of print]273(10):

Treatment updates in myotonic disorders.

Emma Matthews, Mark J Specterman, Karlien Mul.

  Myotonia is delayed muscle relaxation after forceful contraction. It is due to hyperexcitability of the skeletal muscle membrane. It can arise from primary skeletal muscle ion channel dysfunction, involving chloride or sodium channels, but is also a prominent clinical feature in myotonic dystrophies where altered RNA splicing leads to secondary ion channel dysregulation amongst other systemic manifestations. Clinically, myotonia can range from delayed eye opening to a disabling symptom causing impaired mobility, functional difficulty and sometimes pain. It can also be a "hidden disability" with many patients feeling socially embarrassed by "looking healthy", yet being unable to do everyday physical tasks or to do them as effortlessly as their peers. It is a symptom that almost always indicates a genetic diagnosis, although it can occur in acquired conditions, including metabolic and drug-induced causes. To experience myotonia without knowing what it is can be baffling. To receive a genetic diagnosis associated with it can be life changing. Although there is no cure, there are many effective and available symptomatic treatments for myotonia and currently we are in an exciting era of clinical trials for new molecular disease-modifying therapies for myotonic dystrophy type 1. In this review, we consider recent developments in the treatment of myotonic disorders and how they may change clinical practice.

Keywords:  Disease modifying; Genomics; Myotonic disorders; Sodium channel blockers; Therapy development

DOI:  https://doi.org/10.1007/s00415-026-14073-9
Physiology (Bethesda). 2026 Sep 02.

Cellular and molecular mechanisms of muscle spindle development and function.

Cyrrus M Espino, Theanne N Griffith.

  An organism's external environment is dynamic and ever-changing. Survival depends on an animal's ability to engage with its surroundings through adaptive and purpose driven movement. Organisms that rely on such movement are endowed with an internal sensory system, known as proprioception, which enables the precise detection and awareness of the body and its limbs in space. The principal receptors that give rise to this system are known as "proprioceptors", a unique population of peripheral sensory neurons embedded within skeletal muscle and tendons, referred to as muscle spindles and Golgi tendon organs, respectively. Over the years, advancements in cellular, molecular, and electrophysiological techniques have provided fundamental insight into the signaling pathways that regulate proprioceptor development. These same approaches have also facilitated the discovery of the ionic and neuromodulator mechanisms that regulate proprioceptor activity. In more recent years, emerging evidence suggests that proprioceptive feedback may engage in non-cell autonomous regulation of other physiological systems, potentially expanding their role beyond detectors of movement and force. In this review, we will examine the cellular and molecular mechanisms that govern the development and function of muscle spindle afferents. Furthermore, we will highlight their emerging influence on neurological and musculoskeletal disease.

Keywords:  Ion Channels; Proprioception; Sensory Neurons

DOI:  https://doi.org/10.1152/physiol.00017.2026
Sci Rep. 2026 Sep 03. pii: 27560. [Epub ahead of print]16(1):

Sex-specific physical activity thresholds influencing muscle function in older adults with XX genotype of ACTN3 R577X.

Hsiu-Ching Hsu, Wen-Hui Fang, Meng-Chang Lee, Wei-Teing Chen, Yu-Hsuan Chen, Hsiao-Ting Lin, Chih-Chien Wang, Syu-Bi Lin, Cheng-Jung Chen, Mei-Jung Chen, Sui-Lung Su.

  Physical activity is widely recommended to maintain muscle health in older adults, yet its effects may vary depending on genetic background. The ACTN3 R577X polymorphism leads to α-actinin-3 deficiency in XX homozygotes and may influence skeletal muscle performance. We examined the association between physical activity and muscle mass and function in 682 community-dwelling adults aged ≥ 65 years who participated in annual health examinations between 2021 and 2024. Skeletal muscle mass index was assessed using dual-energy X-ray absorptiometry, while grip strength, gait speed, and five-time chair stand performance were evaluated according to Asian Working Group for Sarcopenia criteria. Physical activity was quantified using metabolic equivalents derived from the International Physical Activity Questionnaire. No significant association was observed between ACTN3 R577X genotype and sarcopenia components. However, in women with ACTN3 XX, physical activity exceeding 441 MET-min/week was significantly associated with poorer chair stand performance (β: 4.19, 95% CI: 0.98 ~ 7.40), revealing a U-shaped relationship between physical activity and physical performance. Sex-specific physical activity thresholds may exist in older adults with the ACTN3 XX genotype, with physical activity above 441 MET-min/week being associated with poorer muscle function in women. This specific MET value is an exploratory finding, requiring more external validation.

Keywords:   ACTN3 R577X polymorphism; Aging; Muscle function; Physical activity; Sex differences

DOI:  https://doi.org/10.1038/s41598-026-57340-5
Ageing Res Rev. 2026 Sep 02. pii: S1568-1637(26)00338-7. [Epub ahead of print] 103346

Learning muscle-health trajectories in ageing: towards AI-guided organ chips.

Liu Yu, Zhuosheng Lin, Lanlan Hu, Xiong Zhou, Qiuyou Xie, Ling Wang, Jaking Tang, Yaobin Wu.

  Age-related decline in muscle health is commonly defined using cut-offs for strength, muscle quantity or quality, and physical performance. These measures are essential for diagnosis, but prevention and recovery require an understanding of how muscle responds to stress over time. A central question is when recovery remains possible and why older adults with similar clinical measurements follow different trajectories. Clinical cohorts, animal studies and static cell models each address part of this problem. None readily combines human-tissue relevance with controlled perturbation, repeated functional measurement and experimentally testable recovery cues. We propose a clinically anchored workflow that treats sarcopenia as a model problem for studying age-related muscle change as a dynamic process. The sequence begins with a clinical or biological question, applies a standardised perturbation, uses repeated functional readouts, matches analysis to the question and data structure, and validates the resulting interpretation against independent evidence. Human muscle organ chips, particularly when integrated with adipose, immune, vascular or neuromuscular modules, can expose engineered muscle to defined inflammatory, metabolic, unloading or denervation-like stress while tracking functional and molecular responses. Current evidence remains largely proof of concept and does not support prediction of patient-specific recovery windows, responder status or long-term sarcopenia progression. AI should support this experimental sequence by organising time-course data, quantifying donor-, platform- and measurement-related uncertainty, prioritising informative readouts, and suggesting follow-up experiments. Within these limits, AI-assisted organ-chip studies could help investigate reversible decline, tissue crosstalk and divergent recovery in ageing.

Keywords:  ageing; artificial intelligence; muscle health; organ chips; sarcopenia

DOI:  https://doi.org/10.1016/j.arr.2026.103346