bims-moremu 2026-09-13 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–09–13
38 papers selected by
Anna Vainshtein, Craft Science Inc.

Skeletal muscle stem cells keep their lineage options open.
Comprehensive multi-post-translational modifications profiling reveals age-associated remodeling in skeletal muscle.
MAFF is a transcription factor that regulates contraction-induced skeletal muscle transcription.
Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
Androgen receptor imprints satellite cell stemness and preserves their reservoir for lifelong regeneration and optimal repair.
CaMKIIβ Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype.
Sustained Activation of CaMKII Promotes Skeletal Muscle Contractile Dysfunction in Aging.
Hypoxia-inducible factor-1a (HIF1a) as a context-dependent integrator of metabolic stress in skeletal muscle.
Preserved mitochondrial respiration in presence of oxidative stress and reduced mitochondrial mass after 10-day bed rest in older adults.
Targeting TWEAK to enhance mitochondrial biogenesis and attenuate age-related muscle mass loss.
Transcriptional and histopathological profiling of skeletal muscle in Bla/J mice at the stage of dysferlinopathy manifestation.
miR-191 affects skeletal muscle differentiation by regulating Wwp1 in mouse myoblasts.
Targeting pyroptosis for skeletal muscle atrophy: mechanistic insights and therapeutic perspectives.
Macrophage plasticity and metabolic control in muscle repair and disease.
Strengthening muscle for healthy ageing: innovative treatments for sarcopenia.
Targeting skeletal muscle wasting: Emerging therapeutics and translational challenges.
Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2-Related Centronuclear Myopathy Mouse Model.
Biomechanical regulation of Ca2+ dynamics during muscle stem cell activation.
PIEZO1 Mediates Myoblast Proliferation Under Simulated Microgravity.
Novel Four-gene Panel for Detecting Senescence-associated Cell States in Skeletal Muscle Tissue.
Exercise as a modulator of purinergic signaling and inflammation in cancer-associated sarcopenia: a narrative review.
MicroRNA-mRNA Networks in Skeletal Muscle of Tailored Pig Models for Dystrophinopathies.
Dysfunction of caveolae in muscle disease: A cell biological perspective.
Reorientation of the SUMOylation landscape and altered L3mbtl2-mediated transcriptional activity in cancer-associated muscle contractile dysfunction.
Differential activation of TCA cycle activity and PDH flux by dichloroacetate in skeletal muscle measured by hyperpolarized [2-13C,3-2H3]pyruvate.
Dysregulated microRNA-mRNA networks in SOD1G93A mouse skeletal muscle reveal metabolic impairments in ALS.
Myotonic Muscle Activity Drives a Persistent Pain State Responsive to NaV1.8-directed Analgesics.
BE2012 a novel, REV-ERB antagonist that promotes regenerative myogenesis in vivo with substantially improved pharmacokinetics relative to SR8278.
Mitochondrial Proteostasis Links Diabetes and Sarcopenia: Cross-Scale Convergence from Experimental Models to Human Multi-Omics.
Spatiotemporal Multi-Omic Mapping Reveals Liver-Muscle Metabolic Crosstalk in Cancer Cachexia.
Engineering suppressor tRNAs for effective treatment of Duchenne muscular dystrophy.
Grip strength as a systems biomarker of aging: neuromuscular junction constraints and biomarker decoupling in gene therapy.
The Health Benefits of Exercise: Molecular and Cellular Mechanisms.
Trigonelline improves mitochondrial calcium homeostasis and reduces calpain activity after skeletal muscle ischemia-reperfusion injury in mice.
D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.
Muscle-Specific Upregulation of Timeless Mediates Exercise-Induced Amelioration of Age-Related Circadian Rhythm Disruption and Cardiac Dysfunction in Drosophila.
Lean Mass Reduction During Glucagon-like Peptide-1 Receptor Agonists-Induced Weight Loss: Rethinking Its Clinical Significance.
MitoLatentProfiler: ROI-constrained deep learning for mitochondrial phenotyping in human myotubes.

Dev Cell. 2026 Sep 09. pii: S1534-5807(26)00320-5. [Epub ahead of print]61(9): 1757-1759

Skeletal muscle stem cells keep their lineage options open.

Vittorio Sartorelli.

Expression of Pax7 has been widely used as a hallmark of muscle stem cell identity, and genetic deletion of Pax7 compromises skeletal muscle regeneration. In this issue of Developmental Cell, Gioftsidi, Hayashi et al. use lineage-tracing approaches to report that other skeletal muscle cell types also express Pax7.1.

DOI: https://doi.org/10.1016/j.devcel.2026.08.009
Zool Res. 2026 Sep 18. pii: 2095-8137(2026)05-1517-20. [Epub ahead of print]47(5): 1517-1536

Comprehensive multi-post-translational modifications profiling reveals age-associated remodeling in skeletal muscle.

Jian Li, Xinqiang Lan, Caifen Guo, Xiang Wang, Chunping Huang, Dongqin Zhang, Lin Zeng, Xiaoli Tian, Yang Xiang, Qiquan Wang.

  Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, is a major hallmark of aging. Post-translational modifications (PTMs) play essential roles in regulating protein activity and cellular homeostasis; however, how multiple PTMs are remodeled during skeletal muscle aging remains incompletely characterized. Here, we performed comprehensive multi-layered proteomic profiling of skeletal muscle from young (3-month-old) and aged (24-month-old) mice, systematically quantifying the global proteome together with five major PTMs: acetylation, phosphorylation, N-glycosylation, O-glycosylation, and ubiquitination. In total, we identified 5 337 proteins and mapped thousands of PTM sites, generating an integrated atlas of age-associated proteomic and PTM remodeling in skeletal muscle. Pathway enrichment analyses revealed distinct modification-specific patterns: acetylation and phosphorylation were predominantly associated with metabolic and mitochondrial-related pathways; N-glycosylation was enriched in immune- and secretory pathway-related processes; O-glycosylation was associated with muscle contraction-related pathways; and ubiquitination was preferentially linked to cytoskeletal organization in muscle cells. Correlation analyses further uncovered diverse association patterns among different PTMs across protein- and modification-level datasets. Phosphorylation and ubiquitination exhibited consistent positive associations, whereas acetylation and ubiquitination showed both inverse and concordant co-variation patterns across subsets of proteins. Phosphorylation and O-glycosylation displayed heterogeneous association patterns across different proteins, and acetylation and phosphorylation demonstrated positive correlations with distinct age-associated directional changes across protein subsets. Together, these results provide a comprehensive, multi-dimensional view of age-associated remodeling of the skeletal muscle proteome and multiple PTM layers, offering a valuable resource for understanding molecular alterations accompanying muscle aging and sarcopenia.

Keywords:  Acetylation; Glycosylation; Phosphorylation; Post-translational modification (PTM); Sarcopenia; Skeletal muscle aging; Ubiquitination

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2025.460
Life Sci Alliance. 2026 Dec;pii: e202603709. [Epub ahead of print]9(12):

MAFF is a transcription factor that regulates contraction-induced skeletal muscle transcription.

Taku Fukushima, Taiju Fujioka, Satoru Masubuchi, Iori Sakakibara.

Skeletal muscle adapts to exercise through rapid transcriptional remodeling, but regulators that link contractile activity to these gene programs remain unclear. Here we show that MAFF, a small MAF transcription factor, is consistently induced by acute exercise in both human and mouse skeletal muscle, with induction restricted to muscles recruited by the exercise modality. In C2C12 cells, Maff was induced by in vitro electrical pulse stimulation model. Using CRISPR/Cas9-mediated Maff knockout C2C12 cells, we found that loss of Maff reduced myogenic fusion with accumulation of unfused nuclei. RNA sequencing revealed broad reprogramming in Maff-deficient myotubes, including reduced expression of muscle structural and contractile genes and increased interferon/immune responses and extracellular matrix-related signatures. Moreover, Maff deficiency attenuated a subset of electrical pulse stimulation-responsive genes. Together, these data identify MAFF as a component of the transcriptional machinery supporting myogenic maturation and contraction-evoked gene regulation.

DOI: https://doi.org/10.26508/lsa.202603709
JCI Insight. 2026 Sep 10. pii: e210523. [Epub ahead of print]

Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.

Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning.

  Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.

Keywords:  Endocrinology; Muscle biology; Signal transduction

DOI:  https://doi.org/10.1172/jci.insight.210523
Sci Adv. 2026 Sep 11. 12(37): eaec8073

Androgen receptor imprints satellite cell stemness and preserves their reservoir for lifelong regeneration and optimal repair.

Joe G Rizk, Kamar C Ghaibour, Sirine Souali-Crespo, Emilia Calvano, Aurore Bilger, Hugues Jacobs, Nadia Messaddeq, Qingshuang Cai, Erwan Grangirard, Rajesh Sahu, Arnaud Ferry, Valentin Fourcade, Joffrey Zoll, Gianni Zanardelli, Nacho Molina, Coralie Fontaine, Jean-François Arnal, Daniel Metzger, Delphine Duteil.

Skeletal muscle stem cells (MuSC) are the guardians of muscle regeneration, sustaining tissue integrity through a delicate balance of quiescence, activation, and lineage commitment. While numerous molecular cues have been implicated in regulating these processes, the influence of androgen receptor (AR) signaling, an essential hormonal pathway for male muscle physiology, has remained largely unexplored. Here, we show that AR expression defines quiescent MuSC and acts as a safeguard of their dormancy. Integrated multiomic analyses reveal a redistribution of AR binding from quiescence-maintenance loci to regulatory elements driving activation and metabolic reprogramming during repair. Loss of AR in young adult mice disrupts this balance, precipitating premature cell-cycle entry, skewed division modalities, depletion of the stem cell reservoir, and destabilization of the niche. These defects converge with hallmarks of aging-associated androgen decline, while androgen supplementation restores regenerative competence. Together, our findings establish AR signaling as a pivotal determinant of MuSC fate and a cornerstone of skeletal muscle homeostasis.

DOI: https://doi.org/10.1126/sciadv.aec8073
Hum Mol Genet. 2026 Sep 11. pii: ddag090. [Epub ahead of print]35(19):

CaMKIIβ Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype.

Irina Kramerova, Frieda Anastopulos, Diana Becerra, Ruby Goldstein de Salazar, Alexander R Keeble, Jeffrey S Chamberlain, Steven A Moore, Elizabeth M McNally, Melissa J Spencer.

  Calcium calmodulin kinase II (CaMKII) signaling is activated by muscle use and drives gene expression that promotes slow oxidative muscle phenotype. Previously, we showed that the calpain 3 knockout (C3KO) mouse model of limb girdle muscular dystrophy R1 (LGMDR1) exhibits impaired slow-oxidative gene expression and these deficits were associated with reduced levels of the CaMKIIβ isoform and attenuated CaMKII signaling in C3KO muscles. To investigate the contribution of CaMKIIβ signaling to the calpain 3-deficient phenotype, we generated both loss-of-function (muscle-specific conditional knockout, Camk2b cKO) and gain-of-function (muscle-specific overexpression of a constitutively active CaMK2b) models. Camk2b cKO muscles exhibited myopathic features and weakness and their muscles failed to upregulate genes that promote oxidative metabolism and stress-responses following endurance exercise, similarly to C3KO muscles. Mitochondrial respiration showed reduced activity of complex I, complex II and fatty acid oxidation. RNA sequencing of LGMDR1 patient biopsies revealed a similar reduction in genes involved in oxidative metabolism, aligning human and mouse findings. Overexpression of a constitutively active Camk2b in C3KO muscles enhanced oxidative metabolism and improved functional performance. Our results support the hypothesis that blunted CaMKIIβ signaling contributes to the failed upregulation of genes involved in oxidative metabolism and stress-responses in C3KO muscles. These studies highlight metabolic insufficiency as a central contributor to LGMDR1 pathogenesis and support the therapeutic potential of targeting CaMKII signaling to ameliorate disease features in LGMDR1.

Keywords:  disease pathways; gene expression; mouse model; muscular dystrophy

DOI:  https://doi.org/10.1093/hmg/ddag090
Aging Cell. 2026 Sep;25(9): e70704

Sustained Activation of CaMKII Promotes Skeletal Muscle Contractile Dysfunction in Aging.

Michael R Bene, Tae Chung, Elizabeth D Luczak, Gabriel Lopez-Cecetaite, William A Fountain, Giovanni Rosales-Soto, Erick Hernández-Ochoa, Corina Antonescu, Liliana Florea, Seeun J Jeong, Emily Elassal, Anne Le, Qian-Li Xue, Ahmet Hoke, Peter M Abadir, Qinchuan Wang.

  Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. Exercise engages calcium (Ca2+)- and redox-dependent signaling pathways that enhance muscle performance and adaptation, whereas aging disrupts Ca2+ and redox homeostasis. CaMKII is a key transducer of both signals, raising the possibility that sustained CaMKII signaling becomes maladaptive with aging. Here, we show that CaMKII protein abundance is increased in aged mouse skeletal muscle and that sustained CaMKII activation in young muscle is sufficient to impair contractile function before substantial atrophy develops and, with prolonged activation, to promote progressive muscle loss. Sustained CaMKII activation also disrupted mitochondrial organization and shifted the young-muscle transcriptome toward an aged profile characterized by inflammatory and stress-response pathways. Inhibiting canonical NF-κB signaling partially preserved contractile force during prolonged CaMKII activation without preserving muscle mass, and mediation analysis implicated heme/iron-related transcriptional remodeling in the muscle-mass-independent decline in force. Conversely, expression of CN19o, a peptide inhibitor of CaMKII, in aged muscle improved contractile function and shifted the transcriptome away from an aging-associated profile without inducing hypertrophy. Together, these findings identify sustained CaMKII signaling as a contributor to age-associated muscle dysfunction and support a context-dependent shift from adaptive CaMKII signaling in youth to maladaptive signaling in aging, consistent with antagonistic pleiotropy.

Keywords:  calcium signaling; calcium‐calmodulin‐dependent protein kinase type 2; muscle weakness; oxidative stress; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1111/acel.70704
J Physiol. 2026 Sep 10.

Hypoxia-inducible factor-1a (HIF1a) as a context-dependent integrator of metabolic stress in skeletal muscle.

Nicole Welch, Pugazhendhi Kannan, Seshu Vardhan Pothabathula, Annette Bellar, Abhishek A Chakraborty, Saurabh Mishra, Srinivasan Dasarathy.

  Skeletal muscle experiences large fluctuations in ATP demand and redox state during contraction, ischaemia and chronic disease, requiring rapid adaptations in substrate selection, mitochondrial workload, vascular coupling, regeneration and protein homeostasis. Hypoxia-inducible factor-1a (HIF1a) is classically viewed as an oxygen-responsive transcription factor that mediates rapid adaptation to hypoxia. Accumulating evidence across tissues, including skeletal muscle, indicates that HIF1a is also responsive to physiological and pathological inputs, such as exercise, circadian timing, redox perturbations and endogenous/exogenous cytotoxins, even when tissue hypoxia is not detectable. During hypoxia, including transient mismatches between oxygen demand and supply during muscle contraction, HIF1a activation shifts metabolism from oxidative to non-oxidative energy production, suppresses non-essential energy-consuming processes, including protein homeostasis, and promotes vascular responses that improve oxygen delivery. Under normoxic conditions, persistent HIF1a activation promotes maladaptive responses, including impaired mitochondrial remodelling, reduced anabolic responsiveness, defective regeneration, fibrosis, and atrophy- and senescence-associated reprogramming. Current evidence shows that this shift from adaptive to maladaptive signalling is determined in part by post-translational mechanisms that regulate signalling duration and target gene engagement, as well as by fibre type, circadian state and the nature of the upstream stressor. Unlike the robust responses in muscle tissue observed in preclinical models, human muscle biopsies often show modest or transient HIF1a accumulation, yet transcriptional responses indicate meaningful pathway activation, suggesting that biologically relevant signalling occurs even when total protein levels appear low. Genetic models, multiomics, and human studies support HIF1a as a context-dependent regulator of metabolic reprogramming that balances short-term adaptation with long-term energetic cost.

Keywords:  HIF1a; ammonia; context‐dependent; ethanol; hypoxia inducible factor‐1a; normoxia; skeletal muscle

DOI:  https://doi.org/10.1113/JP291159
J Physiol. 2026 Sep 11.

Preserved mitochondrial respiration in presence of oxidative stress and reduced mitochondrial mass after 10-day bed rest in older adults.

Evgeniia Motanova, Lucrezia Zuccarelli, Evgenii Lysenko, Stefano Amoretti, Marco Pirazzini, Ornella Rossetto, Lorenza Brocca, Roberto Bottinelli, Maria Antonietta Pellegrino, Giovanni Baldassarre, Clarissa Gissi, Giovanna Lippe, Mladen Gasparini, Boštjan Šimunic, Rado Pišot, Bruno Grassi, Marco V Narici.

  Ageing affects mitochondrial integrity in skeletal muscle, and physical inactivity may further exacerbate these changes. Although mitochondrial alterations are documented in ageing and disuse independently, how disuse impacts the mitochondrial phenotype in older populations remains unclear. This work aimed to characterise how physical inactivity impacts mitochondrial function, morphology and gene expression in the skeletal muscle of older adults. Ten healthy older men (65+ years) underwent 10 days of bed rest. Skeletal muscle biopsies were collected before and after bed rest to assess mitochondrial respiration (high-resolution respirometry), H2O2 emission, mitochondrial protein expression, morphology and volume density (electron microscopy) and transcriptomic profile. Ten days of inactivity increased mitochondrial reactive oxygen species (ROS) emission under non-phosphorylating conditions but did not impair oxidative phosphorylation (OXPHOS) capacity, indicating preserved respiratory efficiency. Consistently, mitochondrial respiratory complex and supercomplex protein abundance were unchanged. Mitochondrial mass decreased, as shown by reduced mitochondrial volume density. Reduced dynamin-like protein 1 (DRP1) phosphorylation at serine 637 was observed, whereas other mitochondrial fission and fusion protein levels remained unchanged. Mitochondrial morphology remained unaltered. Transcriptomic analysis revealed >3000 differentially expressed genes, characterised by downregulation of oxidative phosphorylation genes alongside altered mitophagy, antioxidant and oxidoreductase pathways. In summary, 10-day bed rest increased mitochondrial ROS emission and reduced mitochondrial mass in older skeletal muscle despite preserved respiratory function, indicating that elevated ROS production occurs upstream of respiratory dysfunction and is potentially linked to impaired antioxidant defence and ROS clearance. These findings suggest that preserving redox balance during inactivity may be a key strategy to maintain muscle health and functional independence in ageing populations. KEY POINTS: The impact of short-term physical inactivity on mitochondrial function within the context of ageing remains poorly defined. This study examined the impact of 10-day bed rest on skeletal muscle mitochondrial function, morphology and gene expression in older adults. Short-term inactivity increased mitochondrial ROS production, accompanied by a dysregulation of antioxidant and oxidoreductase genes, indicating a reduced capacity for ROS clearance. Mitochondrial respiration was preserved under both submaximal and maximal stimulation. When normalised to mitochondrial content (citrate synthase activity), respiratory capacity increased, suggesting improved intrinsic efficiency. Mitochondrial mass was reduced, supported by decreased mitochondrial volume density assessed morphologically. Transcriptomic alterations in the mitophagy pathway suggest a potential role of altered mitochondrial degradation in this reduction. These findings indicate a transient compensatory response of ageing mitochondria to short-term disuse, suggesting that functional impairments are likely driven by cardiovascular and microvascular factors rather than mitochondrial respiration itself.

Keywords:  OXPHOS; ROS; inactivity; mitochondria; mitochondrial dynamics; oxidative metabolism

DOI:  https://doi.org/10.1113/JP291588
Sci Rep. 2026 Aug 14. pii: 28221. [Epub ahead of print]16(1):

Targeting TWEAK to enhance mitochondrial biogenesis and attenuate age-related muscle mass loss.

Zhuoya Maimaitiwusiman, Saiyare Xuekelati, Anyan Wang, Nadila Airiken, Yanbin Xu, Shuke Guo, Yining Yang, Hongmei Wang.

  Mitochondrial dysfunction is an important cause of sarcopenia, and TWEAK/Fn14, as one of the major muscle wasting cytokines, its role in the development of sarcopenia by regulating mitochondrial biogenesis remains unclear. Expression of TWEAK in old and young mice was both detected. TWEAK was silenced in C2C12 myocytes using lentiviral vectors. Immunofluorescence, western blot, real-time polymerase chain reaction (RT-PCR), and ELISA were enrolled to analyze the effects of TWEAK on myotube size, mitochondrial content, mitochondrial ROS, and inflammatory factors. Additionally, aged mice received two injections of AAV9 vectors at 15 and 17 months of age. Upon reaching 18 months of age, the effects of TWEAK knockdown on grip strength, muscle mass, and gastrocnemius muscle indices were evaluated. TWEAK/Fn14 expression was significantly increased in old mice (p < 0.001). Compared with young controls, old mice exhibited a significant decrease in grip strength (p < 0.001) and a significant increase in lean mass (p < 0.05), whereas no significant difference was observed in fat content. In DEX-treated C2C12 myotubes, TWEAK knockdown significantly increased myotube diameter, enhanced ATP content and mitochondrial quantity, upregulated protein expression of SIRT1, PGC-1α, and p-AMPK, and inhibited mitochondrial ROS, Ca2+ levels, p-p38 expression, and the secretion of inflammatory cytokines (TNF-α, IL-1β, IL-6, and iNOS). In aged mice, TWEAK knockdown did not significantly alter forelimb grip strength or lean mass, but significantly increased fat mass (p < 0.05). Mechanistically, TWEAK knockdown promoted AMPK signaling, inhibited p38 MAPK activation, enhanced mitochondrial biogenesis, and reduced serum levels of IL-1β, IL-6, and iNOS (p < 0.05), whereas serum TNF-α levels showed no significant difference. TWEAK knockdown attenuates age-related skeletal muscle mass loss and improves mitochondrial biogenesis in skeletal muscle, accompanied by modulated inflammatory factor release and altered AMPK-p38 MAPK signaling activity. However, no significant improvement in forelimb grip strength was observed in the in vivo experiment. These findings indicate that TWEAK suppression may represent a promising strategy for preserving muscle mass and metabolic homeostasis during aging, though its capacity to fully restore functional capacity requires further investigation.

Keywords:  Atrophy; Fn14; Gastrocnemius; Mitochondria; TWEAK

DOI:  https://doi.org/10.1038/s41598-026-64401-2
Biol Open. 2026 Sep 15. pii: bio062696. [Epub ahead of print]15(9):

Transcriptional and histopathological profiling of skeletal muscle in Bla/J mice at the stage of dysferlinopathy manifestation.

Igor S Limaev, Nikita S Gladyshev, Ivan A Yakovlev, Leila Kh Shigapova, Elena I Shagimardanova, Irina A Chekmareva, Alexey G Zolkin, Oleg A Gusev, Roman V Deev.

  Dysferlinopathy is a rare muscular dystrophy characterized by chronic muscle damage and ineffective regeneration. While late-stage morphological changes, such as fibroadipose replacement, are well described, the early molecular mechanisms driving muscle fiber loss and regenerative failure at the onset of the disease remain largely uncharacterized. To address this gap, we investigated the skeletal muscles of dysferlin-deficient Bla/J mice during the early manifestation stage (3 months of age). This exploratory study aimed to identify primary pathomorphogenetic events by correlating the transcriptomic profile of the tissue with its specific histopathological and ultrastructural alterations. We performed a comparative analysis of the m. gastrocnemius in 3-month-old Bla/J mice versus wild-type controls using RNA sequencing, RT-qPCR, histomorphometry and transmission electron microscopy. The results revealed atrophy and muscle fiber necrosis without the expected induction of Fbxo32 and Trim63 ubiquitin ligases, suggesting ubiquitin-proteasome system-independent muscle mass loss. Furthermore, the absence of Casp3, Bak1, and Bad induction, confirmed by the lack of active caspase-3, excluded apoptosis as the primary death mechanism. A differentiation block in satellite cells was confirmed by the lack of Myf5, Myod1, and Myog induction and a trend toward Tead4 suppression, pointing to an early failure of the reparative program. Exploratory RNA sequencing also identified a suppression of Prkn expression accompanied by LC3B-II-positive autophagosome accumulation. Immunohistochemical and immunofluorescent evaluation of the mitochondrial network (TOMM20) revealed abnormal accumulations and dense clumping, indicating impaired organelle clearance. Furthermore, ultrastructural analysis demonstrated internal organelle damage and the presence of myelin-like structures, consistent with a state of stalled mitophagy. Collectively, this exploratory study demonstrates that early muscle atrophy and myofiber necrosis in dysferlinopathy occur independently of canonical ubiquitin-proteasome and apoptotic pathways. Instead, the disease manifestation stage is structurally characterized by stalled mitochondrial clearance and a delayed regenerative response.

Keywords:   Prkn ; Tead4 ; Autophagy; Bla/J mice; Dysferlinopathy; Limb-girdle muscular dystrophy

DOI:  https://doi.org/10.1242/bio.062696
PLoS One. 2026 ;21(9): e0355370

miR-191 affects skeletal muscle differentiation by regulating Wwp1 in mouse myoblasts.

Wenhua Pu, Meimei Zhang, Siman Guo, Xiang Bao, Wenjia Cui, Chuncheng Liu.

Skeletal muscle atrophy is a key complication of various diseases, such as chronic obstructive pulmonary disease (COPD) and cancer. The mechanisms by which these diseases affect skeletal muscle metabolism need to be deeply explored. By analyzing the miRNA expression profiles in the plasma of patients with COPD, we found that miR-191 expression was significantly altered and it may influence skeletal muscle metabolism by regulating ubiquitination and the mTOR pathway. Using a mouse model of skeletal muscle injury induced by cardiotoxin, we found that miR-191 and Wwp1 showed a dynamic negative correlation in injury repair. Transfection with miR-191 mimics significantly inhibited the expression of myogenic regulatory factor Myog and differentiation markers Myh1/7/8, while downregulating key genes in the mTOR pathway. Molecular mechanism studies showed that miR-191 could directly act on the 3' untranslated region of the Wwp1 gene to inhibit its expression. This study reveals the important role of the miR-191/Wwp1 axis in skeletal muscle differentiation and provides a novel theoretical basis for research on muscle atrophy induced by COPD, cancer cachexia, and other diseases.

DOI: https://doi.org/10.1371/journal.pone.0355370
Front Immunol. 2026 ;17 1896679

Targeting pyroptosis for skeletal muscle atrophy: mechanistic insights and therapeutic perspectives.

Chen-Chen Sun, Tian-Jiao Peng, Peng Zhang, Xin-Long Fan, Chong-Tao Lu, Hui-Ling Jiang, Chang-Fa Tang.

  Skeletal muscle atrophy is a progressive syndrome characterised by the loss of skeletal muscle mass and function. It significantly impairs patients' quality of life and clinical prognosis. Current intervention strategies have limited efficacy, necessitating the identification of novel therapeutic targets. Pyroptosis, a form of programmed cell death mediated by the Gasdermin protein family and accompanied by intense inflammatory responses, has been found to play a pivotal role in skeletal muscle homeostasis. Through core signalling axes NLRP3-caspase-1-GSDMD, it triggers the release of large amounts of inflammatory cytokines, establishing and sustaining a chronic inflammatory microenvironment that drives protein degradation. This review systematically elucidates the core molecular mechanisms of pyroptosis, revealing its role in exacerbating skeletal muscle atrophy through direct damage to myofibres and the establishment of chronic inflammatory microenvironments. It summarises potential intervention strategies targeting pyroptosis, further analysing key challenges in current research and prospects for clinical translation.

Keywords:  Gasdermin D; NLRP3 inflammasome; pyroptosis; skeletal muscle atrophy; therapeutic target

DOI:  https://doi.org/10.3389/fimmu.2026.1896679
Front Immunol. 2026 ;17 1872583

Macrophage plasticity and metabolic control in muscle repair and disease.

Sarah Tiufekchiev-Grieco, James S Novak, Jyoti K Jaiswal.

  Inflammation is a tightly regulated process essential for skeletal muscle repair, and its dysregulation contributes to chronic disease and impaired regeneration. Following injury, muscle repair involves a coordinated immune response initiated by neutrophil infiltration, followed by macrophage recruitment and diversification. Rather than existing as discrete subsets, macrophages span a continuum of functional states that evolve over time in response to local environmental cues, enabling transitions from clearing debris and pro-inflammatory signaling to supporting resolution of inflammation, and remodeling and regeneration of the tissue. This functional plasticity is closely linked to intracellular metabolic programs. In this review, we examine how metabolic pathways, particularly the balance between glycolysis and oxidative phosphorylation, govern macrophage behavior through epigenetic mechanisms, thereby coupling cellular metabolism to inflammatory and regenerative gene expression. We further explore how these interconnected pathways are disrupted in chronic inflammatory muscle diseases, including muscular dystrophies. Recent transcriptomic studies highlight pathogenic macrophage populations with altered metabolic and epigenetic profiles that contribute to fibrosis and impaired regeneration. By integrating findings from both acute injury and chronic disease contexts, we provide a framework to explore macrophage function through a metabolic and epigenetic lens and discuss emerging strategies aimed at restoring macrophage plasticity and promoting the resolution of inflammation in muscle disease.

Keywords:  macrophage; metabolism; mitochondria; muscle; myogenesis; myopathy

DOI:  https://doi.org/10.3389/fimmu.2026.1872583
Nat Rev Drug Discov. 2026 Sep 07.

Strengthening muscle for healthy ageing: innovative treatments for sarcopenia.

Sara Ancel, Emmeran Le Moal, Yu Xin Wang, Helen M Blau.

Millions of people worldwide suffer from sarcopenia, a clinically recognized syndrome that is defined as the age-related loss of skeletal muscle mass and strength. Sarcopenia reduces mobility, leads to falls and fractures, and increases the risk of death, posing an ever-increasing health-care and economic burden to society. There are currently no approved therapies for the syndrome, partly owing to its multifactorial aetiology, highlighting the need for therapies with pleiotropic beneficial effects on muscle function. Increased understanding of the cellular, metabolic and molecular mechanisms that drive muscle wasting with ageing is informing pharmacological interventions to increase muscle strength by promoting mitochondrial function (NAD+-related molecules, urolithin A), restoring impaired autophagy (mTORC1 inhibitors), promoting anabolic signalling (myostatin inhibitors), acting as selective androgen receptor modulators, maintaining vascularization (VEGF, apelin), reducing inflammageing (inhibitors of cytokine signalling), and restoring innervation, anabolism and regeneration (inhibitors of the gerozyme 15-PGDH). The recent surge in clinical trials combining weight loss-inducing GLP1RA therapies with drugs that preserve muscle tissue suggests that treatments that promote both healthspan and lifespan, or 'healthy ageing', are on the horizon.

DOI: https://doi.org/10.1038/s41573-026-01514-3
Biochim Biophys Acta Gen Subj. 2026 Sep 10. pii: S0304-4165(26)00101-7. [Epub ahead of print] 131001

Targeting skeletal muscle wasting: Emerging therapeutics and translational challenges.

Brandon M Roberts.

  Skeletal muscle wasting is a multifactorial syndrome that contributes to weakness, reduced physical function, loss of independence, and poor clinical outcomes across aging, cancer, obesity, heart failure, disuse, and rare neuromuscular diseases. Although major advances have illuminated much of the molecular signaling for skeletal muscle, effective pharmacologic therapy remains extremely limited. This narrative review examines current and emerging drug-development strategies for muscle wasting with an emphasis on mechanistic rationale, translational evidence, and the barriers that continue to impede clinical success. The focus is on four major therapeutic areas: myostatin/activin pathway inhibition, selective androgen receptor modulators, ghrelin-related appetite-directed therapies, and mitochondria-targeted approaches. Across these classes, preclinical studies have shown that pharmacologic manipulation of anabolic or catabolic signaling, energy intake, and mitochondrial function can preserve or increase muscle mass and, in some settings, improve survival or selected functional measures. However, clinical translation has been inconsistent. A recurring theme is that favorable effects on muscle mass or muscle size do not translate into improvements in strength, mobility, fatigue, or patient-centered outcomes. Additional barriers include disease heterogeneity, limitations of preclinical models, muscle maintenance after therapy, safety concerns, regulatory demands for clinically meaningful endpoints, as well as the complexity of rare-disease development. Future progress will depend on biomarker-guided and phenotype-enriched trial design, multimodal interventions, and outcome measures that capture muscle function.

Keywords:  Molecular mechanisms; Muscle health; Obesity; Sarcopenia; cachexia

DOI:  https://doi.org/10.1016/j.bbagen.2026.131001
J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70338

Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2-Related Centronuclear Myopathy Mouse Model.

Durieux Anne-Cécile, Arnould David, Velarde Mathias, Allibert Valentine, Paret Chloé, Debelley Quentin, Kizilkilic Esra, Chambon Sidney, Girard Emmanuelle, Collin Louise, Gensel Alexandre, Castells Josiane, Pasternack Aja, Bowen Maximilien, Morel Baptiste, Hourdé Christophe, Laurent Schaeffer, Ritvos Olli, Bitoun Marc, Mounier Rémi, Freyssenet Damien.

   BACKGROUND: Autosomal dominant centronuclear myopathy (ADCNM), most commonly caused by mutations in the dynamin 2 (DNM2) gene, is a rare congenital myopathy characterized by progressive muscle weakness and atrophy. Myostatin, a key negative regulator of skeletal muscle mass, has shown therapeutic potential in several models of neuromuscular diseases. We hypothesized that inhibiting myostatin could counteract muscle deconditioning in ADCNM and evaluated the therapeutic potential of both genetic and pharmacological myostatin inhibition strategies in a mouse model of ADCNM.
METHODS: Knockin-dnm2R465W/+ (KI) mice were first crossed with knockout-myostatin mice (KO) to generate double mutant (KIKO) mice carrying both the R465W missense mutation and the myostatin gene deletion. In a second experiment, KI mice received intraperitoneal injections of a soluble activin type IIB receptor fused to IgG1 Fc fragment (sActRIIB-Fc) at 5 mg kg-1 twice weekly starting at 4 weeks of age for 4 weeks. Muscle structure, molecular pathways and functional analysis were performed in tibialis anterior muscle.
RESULTS: MRI and immunohistochemical analyses showed that KI mice exhibited impaired postnatal muscle growth between 1 and 2 months of age, resulting in persistent muscle hypotrophy (-15%, p < 0.05). This defect was associated with a significant reduction in the number of satellite cells (-53%, p < 0.001 at 1 month and -68%, p < 0.01 at 2 months), the central accumulation of dense NADH-TR staining in more than 20% of muscle fibres, an upregulation of atrophy-related E3 ligases mRNA (Trim63 + 50%, p < 0.001 and +87%, p < 0.001; Fbxo32 + 39% p < 0.05 and +95%, p < 0.001 at 1 and 2 months of age, respectively) and impaired autophagy. Genetic deletion of myostatin in KIKO mice fully restored muscle mass and normalized muscle function to wild-type conditions. Pharmacological inhibition with sActRIIB-Fc also robustly restored muscle mass to wild-type values, primarily via activation of the Akt-mTOR pathway. However, this anabolic effect was transient, as muscle mass returned to baseline 5 weeks after treatment cessation. Importantly, despite increased muscle mass, sActRIIB-Fc treatment did not improve muscle force and key pathological features, including defects in proteostasis, mitochondrial organization and excitation-contraction coupling.
CONCLUSIONS: These findings establish the proof of concept that myostatin inhibition counteracts skeletal muscle growth defect in ADCNM, which may be combined with other drugs to better address the multifactorial nature of muscle weakness in ADCNM.

Keywords:  Centronuclear myopathy; dynamin 2; muscle growth; myostatin

DOI:  https://doi.org/10.1002/jcsm.70338
J Biochem. 2026 Sep 09. pii: mvag062. [Epub ahead of print]

Biomechanical regulation of Ca2+ dynamics during muscle stem cell activation.

Kotaro Hirano, Yudai Ishikawa, Norio Motohashi, Yujiro Kobata, Hiroto Watanabe, Mao Sasaki, Takuya Yokoyama, Yuto Yamada, Yuta Aoyagi, Kanako Takakura, Akira Murakami, Masaki Tsuchiya, Yusuke Ono, Keiko Nonomura, Yoshitsugu Aoki, Yuji Hara.

  Muscle satellite cells (MuSCs) are muscle-resident stem cells that are responsible for myofiber regeneration. Although the importance of calcium ions (Ca 2+) in muscle physiology has been well established, the mechanism by which Ca 2+ mobilization governs MuSC function remains poorly understood. In this study, we aimed to systematically characterize Ca2+ dynamics in MuSCs and to define the mechanisms regulating these signals during muscle regeneration. By employing modified protocols for mouse MuSC isolation and Ca2+ measurement, we observed spontaneous Ca2+ fluctuations in MuSCs isolated from regenerating muscle after cardiotoxin-induced myofiber injury. Our detailed analysis using chemical Ca2+ indicators and a genetically encoded Ca2+ indicator revealed that the frequency and amplitude of Ca2+ fluctuations increased significantly during the activated and proliferative stages of MuSCs. This effect was more pronounced in MuSCs isolated from dystrophic and aged mice. Mechanistically, these Ca2+ fluctuations were at least partially mediated by mechanosensitive ion channels, including PIEZO1 and TRPM7, which promote MuSC migration. Collectively, our findings demonstrate that Ca2+ fluctuations through mechanosensitive ion channels act as a key regulator of MuSC activation during muscle regeneration and may provide new insights into the role of Ca2+ influx in muscle biology and the pathogenesis of muscle diseases.

Keywords:  Calcium; Channels < Calcium; Channels/Calcium < Membrane; Muscular < Diseases; Skeletal Muscle < Tissue/organ Systems

DOI:  https://doi.org/10.1093/jb/mvag062
Ann N Y Acad Sci. 2026 Sep;1563(1): e70362

PIEZO1 Mediates Myoblast Proliferation Under Simulated Microgravity.

Yizhou Liu, Xiaojian Cao, Danxia Huang, Hongmei Luo, Song Zhang, Yujie Yang, Qiuzhi Zhou, Yajie Li, Jia Xu, Hong Chen.

  Skeletal muscle atrophy is a major health risk of prolonged spaceflight, yet how microgravity reshapes muscle cells through mechanotransduction remains poorly understood. Here, we examined the mechanosensitive cation channel PIEZO1 in myoblast proliferation under simulated microgravity. Using a two-dimensional clinostat combined with Hi-C-based 3D genomics, transcriptomics, and functional assays, we found that simulated microgravity promotes C2C12 myoblast proliferation and upregulates Piezo1. Piezo1 mRNA knockdown reduced both proliferation and depolarization-induced Ca2 + influx, each partially restored under simulated microgravity, consistent with PIEZO1 being a central mediator of the response. Simulated microgravity also drove extensive 3D genome reorganization alongside changes in proliferation-related gene expression. Integrating chromatin architecture with transcriptomics, we found that PIEZO1 inhibition increased Elavl2 mRNA expression, PIEZO1 activation suppressed Elavl2 mRNA expression, and Elavl2 mRNA knockdown enhanced cell proliferation. These findings define a PIEZO1-ELAVL2 mechanotransduction axis, coupled to 3D chromatin remodeling, that regulates myoblast proliferation under simulated microgravity, and thus may be a target for countering spaceflight-associated muscle dysfunction.

Keywords:  Hi‐C; Piezo1; microgravity; myoblasts; skeletal muscle

DOI:  https://doi.org/10.1111/nyas.70362
Juntendo Med J. 2026 ;72(4): 377-385

Novel Four-gene Panel for Detecting Senescence-associated Cell States in Skeletal Muscle Tissue.

Taro Kunitomi, Yuri Yamashita, Eri Arikawa-Hirasawa.

Objectives: Sarcopenia, characterized by age-associated loss of skeletal muscle mass, function, and physical performance, is a major challenge in aging societies because of its association with a decreased lifespan. Existing gene expression-based diagnostic methods often rely on large gene sets, requiring high costs and analytical complexity. In this study, we developed a machine learning-driven framework to identify senescence-associated cell states in skeletal muscle tissue.
Methods: Publicly available single-cell RNA sequencing data from 2- and 24-month-old C57BL/6J male mice from single-cell and single-nucleus RNA sequencing datasets comprising over 365,000 cells from skeletal muscle were obtained from the DRYAD Repository and consolidated into 15 cell populations. Candidate genes for machine learning were selected from differential expression analysis. Multiple machine learning algorithms, including logistic regression, support vector machines, and random forest, were trained with recursive feature elimination. Model performance was evaluated using the area under the receiver operating characteristic curve.
Results: Differential expression analysis across 15 distinct cell populations yielded 30 candidate genes, to which five machine learning models were applied to select biomarkers. Using our approach, we identified a four-gene panel (Malat1, Wdr89, Zfp36, and Jund) exhibiting high predictive accuracy. This panel was validated using additional aging datasets and compared with existing models, which highlighted its potential as a reliable tool for detecting senescence-associated cells.
Conclusions: In this study, we established a four-gene biomarker panel for detecting senescence-associated cells in skeletal muscle, providing a practical tool for investigating sarcopenia pathophysiology and identifying therapeutic targets.

Keywords: cell senescence; sarcopenia; skeletal muscle
Inflamm Res. 2026 Sep 05. pii: 195. [Epub ahead of print]75(1):

Exercise as a modulator of purinergic signaling and inflammation in cancer-associated sarcopenia: a narrative review.

Emeline Moraes de Oliveira, Vitor Mariano Gonçalves Dockhorn, João Victor Garcia de Souza, Francini Franscescon, Débora Tavares de Resende E Silva.

   BACKGROUND: Sarcopenia, characterized by the progressive loss of skeletal muscle mass and strength, is highly prevalent among cancer patients and is strongly associated with poor prognosis. Increasing evidence indicates that overactivation of the purinergic system contributes to a chronic inflammatory state that promotes tumor progression and exacerbates muscle wasting.
PURPOSE: This narrative review examines how physical exercise may modulate purinergic signaling and inflammation, potentially improving the quality of life of cancer patients with sarcopenia.
METHODS: A literature search was conducted in the MEDLINE database via PubMed, including articles published between 2008 and 2025, using descriptors such as "purinergic signaling", "CD39", "CD73", "P2X7 receptor", "adenosine", "sarcopenia", "skeletal muscle metabolism", "cancer", "inflammation", and "extracellular ATP".
RESULTS: Original studies and review articles in English addressing the relationship between purinergic pathways, inflammation, muscle metabolism, and cancer were included.
CONCLUSIONS: Findings suggest that cancer-related sarcopenia is closely linked to systemic inflammation mediated by purinergic pathways, and evidence indicates that exercise may play a pivotal role in mitigating muscle loss and improving patient outcomes.

Keywords:  Cancer; Inflammation; Physical exercise; Purinergic system; Sarcopenia

DOI:  https://doi.org/10.1007/s00011-026-02331-5
J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70337

MicroRNA-mRNA Networks in Skeletal Muscle of Tailored Pig Models for Dystrophinopathies.

Sarah Reschke, Alexander Graf, Frieder Hadlich, Florian Jaudas, Thomas Fröhlich, Michael Stirm, Nikolai Klymiuk, Stefan Krebs, Eckhard Wolf, Asghar Ali.

   BACKGROUND: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked dystrophinopathies caused by mutations in the dystrophin (DMD) gene. A common DMD-causing mutation in humans is exon 52 deletion (DMDΔ52), which disrupts the reading frame and abolishes dystrophin expression. Therapeutic skipping of exon 51 or 53 can restore the reading frame, producing a truncated but functional protein and generating a BMD-like phenotype. Porcine models recapitulating DMDΔ52 (DMD) and DMDΔ51-52 (BMD-like) were used to identify molecular differences and condition-specific miRNA-mRNA networks.
METHODS: Skeletal muscle (triceps brachii) from four DMD, four BMD, and five wild-type (WT) pigs at 3.5 months of age underwent stranded total RNA-seq and small RNA-seq. Differentially expressed mRNAs (|log2FC| ≥ 1, adj. p ≤ 0.05) and miRNAs (adj. p ≤ 0.05) were identified with DESeq2. miRNA-mRNA networks were constructed using RNAhybrid predictions (MFE < -25 kcal/mol, seed pairing) filtered by inverse Pearson correlation.
RESULTS: Compared with WT, DMD muscle exhibited 1440 upregulated and 487 downregulated genes, characterized by strong repression of structural, contractile, calcium-handling and metabolic genes (e.g., MYBPC2, MYL3, MYLK2, CACNA2D3, CACNA2D4) and marked upregulation of inflammatory mediators and innate immune receptors (e.g., IL6, IL18, IL1R1, CCR1/2/5, TLR1/2/4/7/9). In contrast, BMD muscle showed partial restoration of these pathways and clustered closer to WT in global expression profiles. Distinct miRNA signatures were observed between DMD and BMD. Differential expression analysis identified 22 upregulated and 12 downregulated miRNAs in DMD versus WT and 36 upregulated and 21 downregulated miRNAs in BMD versus WT. Integration of miRNA and mRNA data yielded extensive regulatory networks (1013 unique pairs for upregulated miRNAs in DMD; 2679 pairs for downregulated miRNAs in BMD). Two condition-specific miRNAs emerged as strong biomarker candidates: ssc-miR-296-3p (upregulated exclusively in DMD, targeting 228 genes enriched in muscle structure and fatty acid metabolism) and ssc-miR-423-5p (elevated specifically in BMD, targeting 67 genes involved in calcium signalling and tissue development). Several dysregulated miRNAs, including miR-199a-5p and miR-199b, overlapped with those reported in human DMD and other muscular dystrophies.
CONCLUSIONS: Exon 51 skipping in the DMDΔ52 background partially restores key transcriptional programmes in skeletal muscle but does not fully normalize them to WT patterns. The identification of condition-specific miRNAs highlights post-transcriptional regulatory differences between DMD and BMD, positioning them as promising biomarkers and therapeutic targets. These findings underscore the translational value of porcine dystrophinopathy models for mechanistic studies and preclinical evaluation of RNA-targeted interventions.

Keywords:  Becker muscular dystrophy (BMD); Duchenne muscular dystrophy (DMD); biomarkers; enrichment analysis; exon skipping

DOI:  https://doi.org/10.1002/jcsm.70337
J Cell Biol. 2026 Oct 05. pii: e202605101. [Epub ahead of print]225(10):

Dysfunction of caveolae in muscle disease: A cell biological perspective.

Harriet P Lo, Stéphane Vassilopoulos, Nicholas Ariotti, Thomas E Hall, Robert G Parton.

Caveolae represent a prominent class of specialized membrane microdomains that are an abundant and striking feature of the sarcolemma of muscle cells. Loss or dysfunction of skeletal muscle caveolae can cause a spectrum of muscle diseases, including caveolinopathies associated with rippling muscle disease. Despite recent advances, the precise downstream mechanisms that link caveolar defects to muscle dysfunction are not resolved. In this review, we discuss the fundamental cell biology underpinning muscle diseases associated with caveolar disruption. We highlight how recent structural and functional advances in both muscle and non-muscle systems are providing crucial insights into these pathological processes. Specifically, we analyze how the loss of these abundant surface domains disrupts mechanoprotection, signal transduction, nanoscale lipid organization, and T-tubule biogenesis and function. Finally, we propose a unifying cell biological classification system for disease-associated variants of caveolin-3, with a view to providing a mechanistic framework to connect molecular defects with clinical phenotypes.

DOI: https://doi.org/10.1083/jcb.202605101
Cell Death Discov. 2026 Sep 09. pii: 360. [Epub ahead of print]12(1):

Reorientation of the SUMOylation landscape and altered L3mbtl2-mediated transcriptional activity in cancer-associated muscle contractile dysfunction.

Luis Vincens Gand, Mugeng Li, Katharina Brandt, Baoyu Zhou, Amel Nassar-Grioua, Julien Gondin, Edgar Becker, Andreas Pich, Theresia Kraft, Mamta Amrute-Nayak, Arnab Nayak.

Cachexia is a debilitating muscle-wasting disorder associated with a high mortality rate in cancer patients. However, the molecular mechanisms of muscle contractile dysfunction underlying cancer-induced cachexia (CIC) remain poorly characterized. Here, we demonstrated that CIC reorients global SUMOylation in skeletal muscle cells and alters the stability of various SUMO machinery components, particularly SUMO isopeptidases. The non-canonical polycomb repressor protein L3mbtl2 was among the predominant proteins with enhanced SUMOylation level in CIC. Surprisingly, in contrast to previous notions, we found that L3mbtl2 activates transcription of a large cohort of genes regulating muscle contraction. Mechanistically, L3mbtl2 associates with Ash2L, a component of the SET1/MLL histone methyltransferase complex. Increased SUMO modification of L3mbtl2 in CIC leads to partitioning of Ash2L from its target genes, resulting in impaired calcium handling, sarcomere disorganization and impeded muscle cell contractile properties. Our findings reveal an unprecedented connection between SUMO and CIC, a paradoxical SUMO-associated transcriptional activator function of L3MBTL2 and hold potential for developing therapeutic interventions to ameliorate CIC.

DOI: https://doi.org/10.1038/s41420-026-03337-y
iScience. 2026 Sep 18. 29(9): 117325

Differential activation of TCA cycle activity and PDH flux by dichloroacetate in skeletal muscle measured by hyperpolarized [2-13C,3-2H3]pyruvate.

Sung-Han Lin, Andrew Cho, Mai T Huynh, Zohreh Erfani, Blanka Kucejova, Sasanka Wathukara Dewage, Thomas Jue, Xiaorong Fu, Zoltán Kovács, Shawn C Burgess, Jae Mo Park.

  Despite the central role of skeletal muscle bioenergetics in whole-body metabolic health, assessing mitochondrial oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity in vivo remains a major challenge. While hyperpolarized [1-13C]pyruvate has been used to probe pyruvate dehydrogenase (PDH) flux to approximate TCA cycle activity, this approach relies on the unreliable assumption that PDH and TCA cycle fluxes are tightly coupled. Here, we demonstrate that hyperpolarized [2-13C,3-2H3]pyruvate can track label-incorporation into TCA cycle-derived glutamate in rat skeletal muscle. Following intravenous dichloroacetate administration, we observed a greater increase in hyperpolarized [1-13C]acetyl-L-carnitine relative to [5-13C]glutamate, suggesting disproportionately increased PDH flux relative to TCA cycle flux. A similar trend was also observed in ex vivo GC-MS analysis of skeletal muscle tissue collected from rats injected with [U-13C3]pyruvate. Together, these findings highlight the complex interplay between PDH and TCA cycle fluxes and establish hyperpolarized [2-13C,3-2H3]pyruvate as a robust agent for assessing mitochondrial metabolism in skeletal muscle.

Keywords:  TCA cycle; acetyl-L-carnitine; dichloroacetate; hyperpolarized; oxidative phosphorylation; pyruvate; pyruvate dehydrogenase; skeletal muscle

DOI:  https://doi.org/10.1016/j.isci.2026.117325
Dis Model Mech. 2026 Sep 10. pii: dmm.052963. [Epub ahead of print]

Dysregulated microRNA-mRNA networks in SOD1G93A mouse skeletal muscle reveal metabolic impairments in ALS.

Libby Moody, Eleni Christoforidou, Greig Joilin, Andrew Dilley, Majid Hafezparast.

  Amyotrophic lateral sclerosis (ALS) is a multi-system disease in which skeletal muscle actively contributes to pathology, yet the regulatory circuits that drive muscle dysfunction remain unclear. We examined microRNA (miRNA)-messenger RNA (mRNA) interactions in the gastrocnemius of hSOD1G93A mice across presymptomatic, early- and late-symptomatic stages, using RNA-seq, bioinformatics, and RT-qPCR. Compared with hSOD1WT and non-transgenic controls, hSOD1G93A muscle showed mutation-specific transcriptome reprogramming: 48 dysregulated miRNAs and 558 mRNAs at presymptomatic, and 64 miRNAs and 685 mRNAs at late-symptomatic stages. Functional enrichment pinpointed carbohydrate-handling pathways (glycolysis/gluconeogenesis, pentose-phosphate, fructose-mannose metabolism) as the dominant downregulated gene sets. Network analysis revealed clusters in which upregulated miRNAs converged on, and showed inverse expression patterns relative to metabolic transcripts. RT-qPCR confirmed inverse expression of 10 candidate miRNAs and 11 metabolic mRNAs, substantiating miRNA-guided repression of glycolytic enzymes and energy-sensing nodes. Collectively, we show that SOD1G93A drives an early, sustained miRNA signature that dampens glycolysis gene expression, which could promote the fast-to-slow fibre-type transition and exacerbate energy deficit in ALS muscle. Targeting these circuits offers a strategy to restore metabolic balance and slow disease progression.

Keywords:  Amyotrophic Lateral Sclerosis; Metabolism; Motor Neurone Disease; Muscle; SOD1; microRNA

DOI:  https://doi.org/10.1242/dmm.052963
J Clin Invest. 2026 Sep 08. pii: e198055. [Epub ahead of print]

Myotonic Muscle Activity Drives a Persistent Pain State Responsive to NaV1.8-directed Analgesics.

Tyler S Nelson, Aida Calderon-Rivera, Heather N Allen, Alaina L Waters, Emanuel Loeza-Alcocer, Jorge B Pineda-Farias, Narges Pachenari, Santiago Loya-Lopez, Kimberly Gomez, Erick J Rodriguez-Palma, Paz Duran, Michael S Gold, Rajesh Khanna.

  Pain is a common and disabling feature of myotonic disorders, yet its biological basis remains poorly understood and no targeted analgesic therapies currently exist. Here, we demonstrate that skeletal muscle hyperexcitability is sufficient to initiate a persistent pain state independent of inflammation, nerve injury, or overt tissue damage. Using complementary pharmacological and genetic models of myotonia resulting from loss of the voltage-gated skeletal muscle chloride channel ClC-1 function, we show that transient and chronic myotonia produce robust mechanical, thermal, and cold hypersensitivity, as well as spontaneous pain-like behavior. Notably, pain-like behaviors induced by transient myotonia persist long after overt motor symptoms have resolved, suggesting that a transient episode of muscle hyperexcitability is sufficient to trigger prolonged alterations in nociceptive processing. Physiological recordings revealed altered excitability of dorsal root ganglion and superficial dorsal horn neurons and enhanced sensory-evoked activity in the parabrachial nucleus, indicating altered nociceptive processing across multiple levels of the pain neuraxis. Transient myotonia increased total sodium current density in sensory neurons, with a shift toward a greater tetrodotoxin-resistant current fraction. Pharmacological inhibition with the NaV1.8-directed analgesic Suzetrigine markedly attenuated pain-like behaviors in both models of myotonia. Together, these findings establish a link between myotonia and persistent alterations in nociceptive processing and identify NaV1.8-directed analgesia as a promising therapeutic strategy for myotonia-associated pain.

Keywords:  Muscle biology; Neuromuscular disease; Neuroscience; Pain; Sodium channels

DOI:  https://doi.org/10.1172/JCI198055
J Pharmacol Exp Ther. 2026 Aug 17. pii: S0022-3565(26)01211-5. [Epub ahead of print]393(9): 105011

BE2012 a novel, REV-ERB antagonist that promotes regenerative myogenesis in vivo with substantially improved pharmacokinetics relative to SR8278.

Isabelle Cote, Aurore C Valfort, Ryan K Sanders, Sheryl L Burris, Matthew E Hayes, Rhea Arya, Lingaiah Maram, Bahaa Elgendy, Feng Yue, Thomas P Burris.

  Pharmacological inhibition of REV-ERBs has emerged as a potential therapeutic strategy for several diseases with unmet medical needs. Indeed, chronic treatment with SR8278, a synthetic REV-ERB antagonist, has mitigated pathology in various preclinical models of human musculoskeletal and neurological diseases, including Duchenne muscular dystrophy, epilepsy, Alzheimer disease, Parkinson disease, and frontotemporal dementia. However, SR8278, the first and most widely used REV-ERB antagonist, has poor pharmacokinetic properties, which limits its utility. The REV-ERBs (α and β) are widely expressed nuclear receptors that function as ligand-dependent transcriptional repressors, and the therapeutic potential for inhibition of these receptors remains unclear because of the lack of adequate pharmacological tools. Here, we report BE2012, a significantly improved REV-ERB antagonist with >22-fold longer half-life than SR8278. In a cell-based reporter assay, BE2012 exhibited greater potency toward REV-ERBα (EC50 = 0.38 μM) and REV-ERBβ (EC50 = 0.57 μM) compared with SR8278. Notably, in primary myoblast differentiation assays, BE2012 outperformed SR8278 in increasing the proportion of MyoG+ cells as well as differentiation and fusion indices. In a cardiotoxin-induced muscle injury model, both BE2012 and SR8278 led to increased myofiber cross-sectional area (22%-34% higher than controls). Lastly, transcriptomic profiling revealed remarkable overlap of differentially expressed genes between the 2 compounds, with oxidative phosphorylation and mitochondrial protein complex emerging as the most significantly enriched pathways for both ligands, which have been shown to accelerate regenerative myogenesis. These results establish BE2012 as a refined REV-ERB antagonist for in vivo applications and a valuable tool for deeper exploration of the therapeutic potential of inhibiting REV-ERB activity. SIGNIFICANCE STATEMENT: This study establishes BE2012 as a novel REV-ERBα/β antagonist with a 22-fold longer half-life and improved potency compared with SR8278, the only available REV-ERB antagonist whose poor bioavailability has limited its utility for in vivo use. In an acute muscle injury model in mice, BE2012 promoted regenerative myogenesis and induced a broad transcriptomic reprogramming that was highly concordant with that of SR8278, suggesting it could serve as a new gold-standard REV-ERB antagonist tool compound in the field.

Keywords:  Nuclear receptor; Pharmacokinetics; REV-ERB antagonist; Regenerative myogenesis; Skeletal muscle; Transcriptomics

DOI:  https://doi.org/10.1016/j.jpet.2026.105011
Diabetes Metab J. 2026 Sep;50(5): 825-843

Mitochondrial Proteostasis Links Diabetes and Sarcopenia: Cross-Scale Convergence from Experimental Models to Human Multi-Omics.

Shibo Wei, Soyeon Shin, Dongryeol Ryu, Chang-Myung Oh.

  Sarcopenia in type 2 diabetes mellitus is increasingly recognized as a mechanistic consequence of chronic metabolic stress rather than mere age-related comorbidity. This review synthesizes evidence demonstrating how insulin resistance, hyperglycemia, lipotoxicity, and inflammation converge on skeletal muscle mitochondrial proteostasis to drive progressive decline. We evaluate seven pathway modules-mitochondrial dynamics, mitophagy, biogenesis, oxidative phosphorylation, nicotinamide adenine dinucleotide (NAD+)/sirtuin (SIRT)-linked regulation, protein import, and the mitochondrial unfolded protein response (UPRmt)-across an evidence map encompassing basic, clinical, and multi-omics studies. Dynamics and mitophagy represent mechanistically central quality-control nodes; their impairment permits dysfunctional organelle accumulation and promotes atrophic cascades. Direct evidence density, however, remains weighted toward oxidative phosphorylation and mitochondrial biogenesis. NAD+/SIRT-linked regulation, protein import fidelity, and UPRmt represent mechanistically upstream but comparatively underinvestigated signals. We propose a diabetes-centered framework where mitochondrial proteostasis failure mediates atrophy and reinforces insulin resistance via a self-amplifying feed-forward loop, supported by pathway responsiveness to coherent interventions. Human multi-omics data highlight network-level dysregulation rather than isolated defects, underscoring module-based biomarker strategies. Translationally, exercise remains the mechanistic cornerstone, while pathway-directed adjuncts-NAD+ precursor repletion, mitophagy modulators, and emerging pharmacotherapeutics-are warranted for patients with identifiable module-specific failure patterns.

Keywords:  Diabetes mellitus, type 2; Mitophagy; Multiomics; Muscle, skeletal; Proteostasis; Sarcopenia

DOI:  https://doi.org/10.4093/dmj.2026.0310
Adv Sci (Weinh). 2026 Sep 08. e77489

Spatiotemporal Multi-Omic Mapping Reveals Liver-Muscle Metabolic Crosstalk in Cancer Cachexia.

Zihan Tian, Qianyu Wang, Wenyan Gao, Xianfeng Li, Jiawen Fan, Xiaoliang Wu, Siqi Liu, Xiangdong Ming, Danna Yeerken, Mutian Shen, Qingjie Min, Qimin Zhan, Yan Wang.

  Tumor and host interaction contributes to cancer cachexia, a systemic wasting syndrome characterized by tissue loss (adipose and skeletal muscle), anorexia, fatigue, and metabolic reprogramming. Nevertheless, the spatio-temporal molecular dynamics of multiple tissues during cancer cachexia development remain elusive. Here, we present a comprehensive overview of the biological alterations and metabolic reprogramming of cancer cachexia across two species, 25 organs, and 3230 samples, by integrating transcriptomic, proteomic, and metabolomic profiles spanning different cachectic stages and sexual dimorphism. Using this cancer cachexia atlas (CCAtlas), we identified dysregulated tissues of cancer cachexia, including skeletal muscle, liver, and blood. We revealed coordinated metabolic reprogramming across tissues, including dysregulated amino acid metabolism and one-carbon metabolism. Temporal profiling illustrated dynamic molecular signatures during cancer cachexia progression. The exacerbated inflammatory status in males potentially contributed to a more severe whole-body wasting phenotype. The liver-muscle crosstalk potentiated skeletal muscle atrophy through creatine deficiency via hepatic Gamt downregulation in the LLC model. Creatine supplementation and hepatic Gamt overexpression in the LLC model attenuated skeletal muscle wasting. Together, CCAtlas provides fundamental and systemic insights into multi-omic molecular dynamics and metabolic rewiring of cancer cachexia from the perspective of tumor and/or inter-organ crosstalk across species.

Keywords:  Gamt; cancer cachexia; creatine; inter‐organ crosstalk; metabolism reprogramming; spatiotemporal dynamics

DOI:  https://doi.org/10.1002/advs.77489
Sci Adv. 2026 Sep 11. 12(37): eaeg3466

Engineering suppressor tRNAs for effective treatment of Duchenne muscular dystrophy.

Julien Oury, Ying-Hsin Chen, Sean McFarland, Delilah Jewel, Joel Wen, Teerithveen Pasricha, Steffany Villaseñor, William Mannheim, Victoria Rose, Sophia Zheng, Gokul Sriman Thanigai Arasu, Michael Calhoun, Alexis Dilts, McKenna Montminy, Nathan Strozewski, Nitusingh Thakur, Paul L Kaplan, Peter M Eimon, Jeff Coller, Harvey Lodish.

Duchenne muscular dystrophy (DMD) is a fatal disorder caused by loss of dystrophin, a protein essential for muscle cell integrity. To date, no therapeutic has restored full-length dystrophin. Suppressor transfer RNAs (sup-tRNAs) have the potential to treat the ∼15% of patients with DMD and nonsense mutations. We have evolved highly potent UAA sup-tRNAs through an extensive mutagenesis screening campaign, optimized our adeno-associated virus (AAV) expression vectors, and developed efficient RNA polymerase III promoters. We show that systemic delivery of these sup-tRNAs restores full-length dystrophin and recovers muscle strength and motor function in mice at lower doses than AAV microdystrophin therapies. We see no adverse toxicology and observe proteome-wide reversion of molecular pathophysiology. These data establish sup-tRNAs as a promising therapeutic platform for DMD and other disorders.

DOI: https://doi.org/10.1126/sciadv.aeg3466
Front Aging. 2026 ;7 1908078

Grip strength as a systems biomarker of aging: neuromuscular junction constraints and biomarker decoupling in gene therapy.

Patrick E Sewell, Christopher Jensen.

  Grip strength has emerged as one of the most robust predictors of mortality, disability and healthspan across populations. Yet its predictive validity rests on an often-unstated assumption: that grip strength serves as a passive readout of systemic biological integrity rather than an isolated measure of forearm function. Here we propose that grip strength derives its prognostic power from its position as a convergent output of multiple aging-sensitive physiological systems-including neuromuscular, vascular, metabolic, endocrine and inflammatory networks. We highlight the neuromuscular junction (NMJ) as a particularly critical and often-overlooked rate-limiting factor, noting that age-related strength loss (∼2.5-4% annually) outpaces mass loss (∼0.6-1% annually) by two-to fivefold-a disparity attributable in large part to NMJ deterioration. We introduce the concept of biomarker decoupling and apply it to the emerging landscape of longevity gene therapies being explored in early translational and compassionate-use settings-including follistatin, klotho, FOXO3, hTERT, SIRT1, PGC-1α, VEGF and FGF21. Critically, we argue that follistatin's anabolic efficacy is contingent on intact NMJ integrity, with denervated muscle fibers exhibiting a blunted net anabolic response despite elevated follistatin expression-creating a therapeutic paradox wherein mass gains can occur without proportional functional improvement. We provide a conceptual analysis of how each therapy may influence grip strength, predict decoupling risk based on the breadth of systems affected, outline plausible timing windows for intervention, and propose a heuristic framework for clinical interpretation. The decoupling categories and any numeric ranges presented here are conceptual and hypothesis-generating rather than empirically validated.

Keywords:  biological aging; biomarker; dynapenia; follistatin; gene therapy; grip strength; neuromuscular junction; sarcopenia

DOI:  https://doi.org/10.3389/fragi.2026.1908078
MedComm (2020). 2026 Sep;7(9): e70926

The Health Benefits of Exercise: Molecular and Cellular Mechanisms.

Peifeng Ying, Huilin Wang, Xiu Lu, Wenjuan Zhang, Zhehao Lin, Kai Wang, Shangxuan Li, Lu Chen, Mingchao Jiang, Sarkawt Hamad, Yi Wang, Jianmin Wu, Shukuan Ling.

  Exercise is a low-cost lifestyle intervention that can prevent and alleviate various diseases. It is a potent physiological stimulus that activates conserved molecular signaling pathways. Through the coordinated integration of multiple molecules, pathways, and systems, it leads to systemic health benefits. However, most studies focus on individual systems or molecular mechanisms, lacking systematic integration of the cross-system regulation induced by exercise. We summarize the molecular mechanisms of exercise in the musculoskeletal, cardiovascular, nervous systems, among others. Exercise induces the release of exerkines (e.g., irisin, interleukin-6, and brain-derived neurotrophic factor) and extracellular vesicles, which activate key signaling pathways to enhance mitochondrial function, metabolism and physiological adaptation, while suppressing inflammation and oxidative stress, thereby alleviating diseases and delaying aging through cross-system coordination. We further explore exercise-induced adaptive regulation in extreme environments, including microgravity, hyperbaria, and hypoxia, offering a multifaceted perspective on organismal health regulation. Finally, we outline the prospects and challenges of multiomics, artificial intelligence-driven precision medicine, personalized exercise prescriptions, and exercise mimetics. Overall, this review provides a more integrated perspective on the molecular basis of exercise and offers directions for future mechanistic and translational studies.

Keywords:  exercise; extreme environments; metabolic–immune network; multisystem regulation; personalized exercise; signaling pathways

DOI:  https://doi.org/10.1002/mco2.70926
Biomol Biomed. 2026 Sep 07.

Trigonelline improves mitochondrial calcium homeostasis and reduces calpain activity after skeletal muscle ischemia-reperfusion injury in mice.

Anastasia E Stepanova, Anna S Ustinova, Anastasia D Igoshkina, Shravani Prashant Utture, Svetlana O Rakhmaeva, Ekaterina I Khoroshavina, Tatyana A Baranovskaya, Konstantin N Belosludtsev, Mikhail V Dubinin.

Skeletal muscle ischemia-reperfusion injury (IRI) causes persistent tissue damage and functional impairment, partly through mitochondrial calcium dysregulation and calpain-mediated proteolysis. This study investigated whether trigonelline (TG), a natural alkaloid, improves skeletal muscle recovery and mitochondrial homeostasis after IRI. Male C57BL/10 mice were randomly assigned to sham control, untreated IRI, or IRI plus TG groups. After 2 h of bilateral hindlimb ischemia, mice received a single intraperitoneal dose of TG (150 mg/kg) immediately before tourniquet release and were evaluated after 7 days of reperfusion. Functional performance, serum creatine kinase (CK) activity, quadriceps mass and histology, mitochondrial respiration and calcium handling, 4-hydroxynonenal (4-HNE) levels, and calpain activity were assessed. TG did not reduce CK activity, prevent quadriceps mass loss, restore grip strength, or significantly improve mitochondrial respiration. Exploratory wheel-running data suggested faster recovery of spontaneous activity. TG increased the number of regenerating fibers and shifted the fiber-diameter distribution toward larger fibers. It also reduced alamethicin-induced mitochondrial calcium release, restored calcium retention capacity to near-control levels, and decreased calpain activity. Although 4-HNE was elevated in both ischemic groups at 2 h, it remained elevated at day 7 only after TG treatment. Thus, a single post-ischemic dose of TG selectively improved mitochondrial calcium handling and reduced calpain activity and was associated with histological features consistent with muscle repair, but did not prevent muscle loss or restore strength. These preliminary findings support further investigation of TG as a potential strategy for recovery after ischemic muscle injury.

DOI: https://doi.org/10.17305/bb.2026.14854
Mol Ther. 2026 Sep 11. pii: S1525-0016(26)00777-X. [Epub ahead of print]

D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.

Jae Ho Shim, Ji Yeon Lee, Byung Kook Ahn, Sang Woo Woo, Jihye Han, Hyeon Soo Kim.

Sarcopenia, the age-related loss of skeletal muscle mass and function, lacks FDA-approved pharmacotherapy. The mechanistic target of rapamycin complex 1 (mTORC1), activated by leucine via Sestrin2, is the master regulator of muscle protein synthesis, but L-leucine suffers from rapid catabolism and poor bioavailability. Here, we report D-leucine methyl ester hydrochloride (DLMEH), a metabolically stabilized prodrug incorporating D-stereoisomer conversion, methyl esterification, and hydrochloride salt formation. Three orthogonal biophysical methods demonstrate that DLMEH directly binds Sestrin2 (Kd 28.3 μM), equivalent to L-leucine. Sestrin2 siRNA knockdown and rapamycin co-treatment confirm Sestrin2-dependent, mTORC1-specific activation. In human primary myotubes, DLMEH (100 μM) restores dexamethasone-suppressed protein synthesis by 58.2%, significantly exceeding L-leucine (800 μM, 28.5%). In a rat dexamethasone-induced atrophy model, intravenous DLMEH (100 mg/kg/day, 14 days) preserves gastrocnemius mass (19.3% rescue), grip strength (90% of normal), and treadmill endurance (85% of normal), all superior to oral L-leucine. RNA-seq reveals 41.7% reversal of dexamethasone-induced transcriptomic changes with enrichment in mTOR signaling, ribosome biogenesis, and oxidative phosphorylation. Safety profiling establishes NOAEL at 2000 mg/kg with therapeutic index greater than 30. DLMEH represents a first-in-class Sestrin2-targeting mTORC1 activator for sarcopenia.

DOI: https://doi.org/10.1016/j.ymthe.2026.09.007
Aging Cell. 2026 Sep;25(9): e70708

Muscle-Specific Upregulation of Timeless Mediates Exercise-Induced Amelioration of Age-Related Circadian Rhythm Disruption and Cardiac Dysfunction in Drosophila.

Deng-Tai Wen, Shouzhi Lv, Jing-Yao Sun, Ying-Qi Chen, Ying Lin, Zhong-Rui Du, Gang-Bin Sun, Tian-Shuo Yuan, Deyu Shu, Wen-Qi Hou.

  The core genes of the circadian pathway, such as Timeless(Tim), not only participate in the regulation of biological rhythms, but also play significant roles in DNA damage repair, chronic inflammation, and cellular metabolism. However, it remains unclear whether exercise can delay the age-related phenotypic degeneration by regulating the muscle Tim gene. In here, we first carried out the expression regulation of the muscle Tim gene in the Drosophila by constructing the Mhc-gal4/Tim-UAS system, and then subjected the flies to a 4-week endurance exercise intervention. The results showed that the knockdown of the muscle Tim gene accelerated aging-related phenotypic deterioration in Drosophila, manifesting as increased nighttime activity, decreased climbing speed, elevated heart rate and reduced stroke volume, shortened time to hypoxic heart failure, and shortened lifespan. This is accompanied by reductions in muscle tissue levels of the Clk gene, Sir2 gene, PGC-1α gene, Mhc gene, MRCC-I protein, and SOD protein, along with a significant increase in ROS. Conversely, overexpression of the muscle Tim gene delayed aging-related phenotypic changes in aged Drosophila. Exercise not only effectively counteracts the acceleration of aging-related phenotypic deterioration caused by muscle Tim gene knockdown but also further delayed aging-related phenotypic changes in aged Drosophila on the basis of muscle Tim gene overexpression. In summary, this study highlights the role of the muscle Tim gene in the aging of skeletal muscles and the heart, as well as the relationship between exercise and the muscle Tim gene, providing strategies for the prevention and treatment of age-related diseases.

Keywords:   Timeless ; aging; circadian rhythm; exercise; mitochondrial; oxidative stress

DOI:  https://doi.org/10.1111/acel.70708
High Blood Press Cardiovasc Prev. 2026 Sep 06.

Lean Mass Reduction During Glucagon-like Peptide-1 Receptor Agonists-Induced Weight Loss: Rethinking Its Clinical Significance.

Federica Moscucci, Giuliano Tocci, Giulia Nardoianni, Carmine Savoia, Vincenzo Contino, Gaetano Leo, Raffaella Bocale, Giovambattista Desideri, Francesco Baratta.

  The substantial weight loss achieved with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin agonists has transformed the management of obesity and cardiometabolic risk. However, the accompanying reduction in lean mass has raised concerns regarding potential sarcopenia and impaired physical function, particularly in older adults. These concerns have become increasingly relevant as incretin-based therapies assume a central role in cardiovascular prevention. Importantly, reductions in lean mass measured by dual-energy X-ray absorptiometry and other body-composition techniques do not necessarily reflect deterioration in muscle quality, strength, or functional capacity. We propose that a substantial proportion of the observed decline in lean mass represents a physiological adaptation to the reduced mechanical loading associated with marked weight loss. Obesity imposes chronic biomechanical overload on weight-bearing musculature, promoting compensatory increases in muscle mass. Conversely, successful weight reduction lowers mechanical demands and may induce adaptive remodeling of antigravity muscles toward a new equilibrium appropriate for a lighter body. This interpretation is supported by established principles of unloading physiology derived from studies of immobilization, bed rest, and microgravity, as well as by emerging concepts linking body-weight sensing to musculoskeletal adaptation. We present a conceptual framework in which energy deficit, improvements in tissue composition, and mechanical unloading act as complementary contributors to lean mass reduction during GLP-1 RAs therapy. We also propose testable predictions that may help distinguish adaptive remodeling from pathological muscle loss (Fig. 1). From a cardiovascular prevention perspective, the key question may not be whether lean mass decreases during successful obesity treatment, but whether these changes impair physical function or diminish the substantial cardiometabolic benefits of weight reduction. Recognizing mechanical unloading as an underappreciated explanatory framework for interpreting lean mass loss during incretin-based therapy may improve risk-benefit assessment and redirect attention toward clinically meaningful outcomes, including muscle strength, physical performance, mobility, and cardiovascular health.

Keywords:  Cardiovascular prevention; GLP-1 receptor agonists; Lean mass; Mechanical loading; Muscle function; Obesity

DOI:  https://doi.org/10.1007/s40292-026-00819-z
SLAS Discov. 2026 Sep 09. pii: S2472-5552(26)00040-7. [Epub ahead of print] 100334

MitoLatentProfiler: ROI-constrained deep learning for mitochondrial phenotyping in human myotubes.

Antoine Martin-Tissier, Fahym Bounazou, Aniela Zablocki, Roman Lambert, Guillaume Fargier, Caroline Roelants, Marine Foray, Giulio Morozzi, Marc Liberatore, Erwann Ventre, Joanne Young, Mélanie Flaender, Bianca Freytag.

  Mitochondrial network organization in skeletal muscle reflects metabolic health and is disrupted in primary mitochondrial myopathies, type 2 diabetes/insulin resistance, and age-related functional decline. Studying these disruptions in vitro using mature human myotubes is, however, complicated by the dense, anisotropic architecture of mitochondria, which poses fundamental challenges for automated segmentation and phenotypic classification. Here we present MitoLatentProfiler, a deep learning framework that combines images of micropatterned primary human myotubes with a topology-preserving U-Net and a Classifier U-Net that jointly optimizes segmentation and phenotype classification, structuring the encoder latent space for downstream analysis. Constraining analysis to troponin-positive myotubes excludes confounding signals from neighboring cells. The resulting embeddings organize along two main axes: a morphological axis (fusion/fission balance, shared by TOMM20 and MitoTracker) and a marker-specific axis (associated with bioenergetic insult, MitoTracker only), enabling hierarchical marker-adaptive classification. The segmentation model achieves Dice =0.82 and clDice =0.86. A hierarchical support vector machine classifier reaches macro F1 up to 0.93, outperforming classical morphological descriptors across donors (n=2), markers, and plates not seen during training. Fragmentation, Hypertubulation, and two Damaged phenotype-scores (induced by oligomycin/antimycin and carbonyl cyanide m-chlorophenyl hydrazone) yield Z' factors of 0.54, 0.38, 0.87, and 0.96 respectively, confirming screening applicability for damage and fragmentation readouts. The modular design allows the encoder to serve as a fixed feature extractor: adapting to new phenotypes requires only retraining the lightweight classifier. This pipeline provides a scalable tool for mechanistic studies and compound screening targeting mitochondrial dysfunction in muscle disease.

Keywords:  Deep learning segmentation; High-content screening; Image-based phenotyping; Latent space representation; Mitochondrial morphology; Skeletal muscle myotubes

DOI:  https://doi.org/10.1016/j.slasd.2026.100334