bims-moremu 2026-10-11 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–10–11
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Resolvin E1 promotes the resolution of inflammation and enhances myogenic responses during aged skeletal muscle regeneration.
Perlecan regulates exercise-induced PGC-1α isoform expression and angiogenic gene program in skeletal muscle.
Inhibiting Glutaminase Reverses Senescence-Associated Mitochondrial Dysfunction and Skeletal Muscle Decline.
Rev-erb-α in Skeletal Muscle Adaptation: Integrating Circadian Control Mechanisms and Exercise Dynamic Responses.
Lactic acidosis in skeletal muscle contributes to sarcopenia.
Tomatidine Exposure During Early Myogenesis Promotes Hypertrophy of C2C12 Muscle Cells Through Increased Nuclei Accretion.
Mechanistic interactions of diet, exercise, and pharmacotherapy in skeletal muscle metabolism: evidence and translational perspectives.
Dysferlin promotes inflammatory macrophage responses and modulates Ca2+-dependent STAT1 signaling.
Evidence of a redox-dependent regulation of satellite cell activity and regeneration in human skeletal muscle following aseptic injury: a randomized controlled trial.
Microbial-derived Exerkines preserve muscle size and function during disuse in aged mice in a sex-dependent manner.
Electrical Pulse Stimulation Partially Restores Insulin Signaling in Palmitate-Induced Insulin-Resistant Skeletal Muscle Cells via Mitochondrial Remodeling and Contractile Activity-Dependent Secretome.
STING deficiency differentially affects skeletal muscle responses to high-intensity interval training and mechanical overload.
Unraveling skeletal muscle senescence in an in vitro cell culture model.
Adding Tat-Beclin1 to an endurance training program promotes additive improvements in physical function in aged male mice.
Inverse directions of association of higher physical activity and higher insulin resistance with human skeletal muscle fiber-type gene expression.
CNIH4 regulates systemic metabolism and exercise adaptations in male mice primarily through the modulation of β-adrenergic receptor trafficking.
Mitochondrial oxidative stress in skeletal muscle alters metabolic signaling responses to acute muscle contraction.
Proteomics of the skeletal muscle dystrophin complex.
Intrinsic IL-6 expression reduces rhIL-6-induced JAK/STAT activation and promotes glucose and oleic acid oxidation in cultured human myoblasts.
A nuclear role for the contractile protein troponin I/UNC-27 in regulating muscle aging in C. elegans.
Interplay between store-operated calcium entry and mitochondrial phosphate handling modulates force and fatigue during exercise.
Weight Loss or Muscle Loss? Cellular Mechanisms and Clinical Strategies for Preserving Lean Mass During GLP-1-Based Therapy.
4-Phenylbutyric acid activates an NF-κB-Egr-1 axis to control myoblast proliferation and ECM gene expression.
Use of split intein and myotropic AAV vectors enables effective preclinical gene therapy for dysferlinopathy.
Muscle oxygen saturation (SmO2): An Upstream Metabolic Link Connecting Peripheral Muscle Metabolism to Central Neurobiological Adaptations.
MyoD and Myogenin regulatory cascade is targeted by tumor signals to repress myogenesis in cancer cachexia.
Single-Nucleus Atlas of Spinal Sarcopenia Patients Reveals Disruption of Quiescent and Regenerative Satellite Cell Niches in Fatty-Infiltrated Muscle.
In silico discovery and cellular validation of PBM-342: a novel PPAR-β/δ modulator for skeletal muscle differentiation.
Identifying regulatory muscle processes in infantile and adult Pompe patients using a multi-omic and morphological approach.
Differentiated skeletal myotubes coupled with bimodal biosensing for dynamic functional evaluation of inflammatory myotube dysfunction.
More than just adipose. The impact of GLP1Ra on lean tissue.
Titin extension explains residual force enhancement in skeletal muscle.
Systemic responses to intravenous rAAV administration in boys with Duchenne muscular dystrophy.
Chemotherapy-Induced Skeletal Muscle Dysfunction and Cognitive Impairment: A Muscle-Brain Mechanistic Framework With Implications for Exercise Oncology.

Geroscience. 2026 Oct 07.

Resolvin E1 promotes the resolution of inflammation and enhances myogenic responses during aged skeletal muscle regeneration.

Ryan Arsenault, Anthony Ziadeh, Amal Assebbane, Haimen Yezihalem, Alexander Green, Junio Dort.

  Efficient muscle regeneration relies on the coordinated crosstalk between muscle stem cells (MuSCs) and their surrounding niche. Specialized pro-resolving mediators (SPMs), like resolvins, serve as critical autocrine and paracrine signals within this microenvironment, with macrophages acting as one of the primary sources of SPMs required to resolve inflammation and boost myogenesis. However, while dysregulation of endogenous SPM synthesis in aged skeletal muscle is known to drive chronic inflammation, the specific role of these lipid mediators during aged muscle regeneration remains poorly characterized. Here, we examine whether Resolvin E1 (RvE1) can accelerate the resolution of inflammation and improve the regenerative capacity of aged skeletal muscle. In vitro, RvE1 reduces pro-inflammatory gene expression and drives macrophages toward an anti-inflammatory phenotype. In aged mice, post-injury RvE1 treatment accelerates neutrophil clearance, expands the myogenic cell pool, and enhances myoblast differentiation, resulting in a trend toward improved muscle contractile function. Overall, our findings suggest that RvE1 is a therapeutic candidate that enhances aged muscle regeneration by concurrently resolving inflammation and driving myogenesis.

Keywords:  Aging; Inflammation; Muscle stem cells; Regeneration; Resolvins

DOI:  https://doi.org/10.1007/s11357-026-02566-4
Am J Physiol Cell Physiol. 2026 Oct 05.

Perlecan regulates exercise-induced PGC-1α isoform expression and angiogenic gene program in skeletal muscle.

Yuri Yamashita, Kouta Kuwahara, Miyako Nunoya, Sakurako Mihara, Toshinori Yoshihara, Satoshi Nakada, Aurelien Kerever, Manabu Funayama, Eri Arikawa-Hirasawa.

  Exercise induces diverse adaptations in skeletal muscle, and extracellular matrix remodeling plays a key role in these adaptations. Capillaries, which are essential for transporting oxygen and other molecules to maintain skeletal muscle function, are crucial for exercise adaptation. Perlecan, a heparan sulfate proteoglycan and a major basement membrane molecule in skeletal muscle, has been implicated in capillary formation and maintenance. However, its role in exercise adaptation remains unclear. Herein, we used male mice lacking perlecan expression outside of cartilage (Hspg2-/--Tg) as well as Hspg2 wild-type transgenic control mice to examine the regulatory relationship between perlecan and PGC-1α isoforms, which are key mediators of exercise-induced metabolic and angiogenic responses. Following acute treadmill exercise, Hspg2-/--Tg mice showed a significant increase in the mRNA expression of alternative promoter-driven PGC-1α isoforms (ex1b and ex1b') 3 h after exercise, whereas proximal promoter-driven isoforms showed little response. This isoform-specific response was accompanied by enhanced expression of angiogenesis-related genes, including Vegfa, Angpt1, Angpt2, and Hif1a, which peaked 3 h after exercise in perlecan-deficient muscle. In parallel with these transcriptional changes, immunofluorescent analysis revealed significantly higher baseline capillary density in Hspg2-/--Tg quadriceps muscle, a difference that became even more pronounced after 2 wk of exercise training. These findings demonstrate that perlecan deficiency enhances baseline vascular remodeling features and the angiogenic transcriptional response to exercise, suggesting that the composition of the basement membrane extracellular matrix critically regulates exercise-induced PGC-1α isoform expression and muscle-vascular crosstalk during skeletal muscle adaptation.

Keywords:  acute exercise; extracellular matrix; perlecan; skeletal muscle; vascular adaptation

DOI:  https://doi.org/10.1152/ajpcell.00956.2025
Aging Cell. 2026 Oct;25(10): e70703

Inhibiting Glutaminase Reverses Senescence-Associated Mitochondrial Dysfunction and Skeletal Muscle Decline.

Hamsa Vardini Senthil Kumar, Debanik Choudhury, Pedro Lei, Pihu Mehrotra, Shahryar Shahini, Sydney Swedick, John Toftegaard, Stelios T Andreadis.

Age-associated loss of skeletal muscle mass and function, also known as sarcopenia, is closely linked to mitochondrial dysfunction. In this study, we report that senescent skeletal muscle myoblasts exhibit elevated activity and expression of the enzyme glutaminase (GLS1), which is mediated by p38 MAPK signaling and leads to intracellular urea accumulation that impairs mitochondrial function. Pharmacological inhibition of GLS1 with CB-839 reduced urea levels, restored the expression of electron transport chain (ETC) complexes, and improved mitochondrial function. Consistent with our in vitro findings, CB-839 administration to progeroid mice similarly upregulated ETC complexes and enhanced mitochondrial respiratory capacity in skeletal muscle, leading to improved structural integrity and enhanced muscle strength. Together, these findings suggest that targeting glutamine metabolism via GLS1 inhibition may represent a promising therapeutic strategy to ameliorate age-related skeletal muscle decline by restoring mitochondrial health.

DOI: https://doi.org/10.1111/acel.70703
J Cell Physiol. 2026 Oct;241(10): e70239

Rev-erb-α in Skeletal Muscle Adaptation: Integrating Circadian Control Mechanisms and Exercise Dynamic Responses.

Ivo Vieira de Sousa Neto, Alisson Luiz da Rocha, Ana Paula Pinto, Eliézer Lucas Pires Ramos, Eduardo Rochete Ropelle, José Rodrigo Pauli, Ellen Cristini de Freitas, Adelino Sanchez Ramos da Silva.

  Circadian rhythms orchestrate a host of biological processes in a time-dependent manner to maintain homeostasis in response to exercise. Within this framework, Rev-erb-α, an intracellular nuclear receptor and transcriptional regulator, transcends its role in circadian rhythms to drive myogenesis, muscle remodeling, primary metabolism, and autophagy, underscoring its versatile, pleiotropic actions. This review consolidates experimental evidence from cell culture, genetically modified animal models, drug-based approaches and humans, highlighting the role of Rev-erb-α mechanisms in skeletal muscle and exercise adaptation. Recent frontier-of-knowledge data indicate that acute and chronic exercise elicit distinct Rev-erb-α signatures. There is bimodal regulation: Rev-erb-α is downregulated immediately post-exercise, followed by a subsequent increase, reflecting its primary role in pathway repression. In chronic conditions, the upregulation of Rev-erb-α can act as an adaptive mechanism that governs robust responses to energy demand and mitochondrial function, thereby coordinating the metabolic network, calcium homeostasis, and oxidative capacity. Also, Rev-erb-α overexpression or its pharmacological activation may reduce pathways associated with muscle atrophy, thereby preserving tissue function and muscle mass. Excitingly, higher physical activity levels increase the amplitude of Rev-erb-α over 24 h, enhancing health and performance. However, exercise timing determines the Rev-erb-α signature that affects downstream phenotypes in skeletal muscle. Thus, elucidating the mechanisms of regulation and action of the Rev-erb-α protein may offer new perspectives for improving or preserving muscle quality across different health conditions and diseases.

Keywords:  autophagy; circadian rhythms; exercise; metabolic flexibility; myogenesis

DOI:  https://doi.org/10.1002/jcp.70239
Nat Rev Rheumatol. 2026 Oct 05.

Lactic acidosis in skeletal muscle contributes to sarcopenia.

Sarah Onuora.

DOI: https://doi.org/10.1038/s41584-026-01448-5
Cell Biol Int. 2026 Oct;50(10): e70224

Tomatidine Exposure During Early Myogenesis Promotes Hypertrophy of C2C12 Muscle Cells Through Increased Nuclei Accretion.

Marissa K Caldow, Kristy Swiderski, John H V Nguyen, Emily S Haber, Kyla J H Fritz, Gordon S Lynch.

  During myogenesis or myofiber regeneration, a proliferating muscle cell must leave the cell cycle, commit to differentiate, and fuse to neighboring myoblasts to create multinucleated myotubes, and eventually mature myofibers. These stages can be manipulated by exogenous factors including signaling molecules, mechanical cues, and nutrient supplementation. Supplementation with bioactives, such as tomatidine, can improve aspects of skeletal muscle health when evaluated using in vitro and in vivo models. In this study, a phenotypic characterization of the effects of tomatidine supplementation during proliferation, early maturation and differentiation, was undertaken in C2C12 muscle cells, cultured in growth medium, or alternatively induced to differentiate in medium supplemented with 10 µM tomatidine, for up to 4 days. Real-time impedance assays indicated tomatidine slowed C2C12 proliferation after 3 days of supplementation. Tomatidine supplementation from the onset of differentiation induced myotube hypertrophy within the first 48 h of maturation. Tomatidine-induced hypertrophy was driven by increased myonuclei fusion in developing myotubes with a concomitant increase in protein synthesis. Taken together, tomatidine's growth promoting effects on skeletal muscle cells identify its therapeutic potential for enhancing muscle regeneration and repair, by mechanisms that improve myofiber maturation and function.

Keywords:  bioactives; hypertrophy; myogenesis; skeletal muscle; tomatidine

DOI:  https://doi.org/10.1002/cbin.70224
Front Physiol. 2026 ;17 1957316

Mechanistic interactions of diet, exercise, and pharmacotherapy in skeletal muscle metabolism: evidence and translational perspectives.

Yan Wang, Mengran Qin, Xuezhi Liu, Jianxiong Ma.

  Skeletal muscle plays a central role in whole-body energy homeostasis, metabolic flexibility, and insulin sensitivity, acting as a key integrator of nutritional, mechanical, and pharmacological signals. Although diet, exercise, and pharmacotherapy are often investigated as separate interventions, they converge on shared regulatory pathways in skeletal muscle, including nutrient sensing, mechanotransduction, mitochondrial quality control, inflammatory remodeling, and anabolic-catabolic balance. Through core signaling networks such as AMPK-mTOR, SIRT1/PGC-1α, and insulin/AKT pathways, these interventions may interact in additive, complementary, synergistic, or antagonistic manners depending on physiological status, disease context, baseline metabolic condition, and intervention timing. This Review critically integrates current evidence on how diet, exercise, and pharmacotherapy regulate skeletal muscle metabolism across aging, metabolic disease, and adaptive physiological states. We propose a muscle-centered integrative framework organized around five major regulatory domains: substrate utilization and metabolic flexibility, mitochondrial remodeling, protein turnover, inflammatory control, and regenerative capacity. Within this framework, we highlight how intervention responses are shaped by key biological and clinical modulators, including age, disease state, muscle fiber composition, training status, nutritional background, and baseline metabolic health. Importantly, we distinguish findings supported by human studies from those derived primarily from preclinical or mechanistic models, thereby emphasizing differences in translational reliability. Finally, we discuss current limitations in interpreting combined interventions and outline future directions for precision-oriented strategies that integrate nutrition, exercise, and pharmacotherapy to optimize skeletal muscle function and systemic metabolic health.

Keywords:  dietary intervention; exercise; mechanism integration; pharmacotherapy; skeletal muscle metabolism

DOI:  https://doi.org/10.3389/fphys.2026.1957316
Life Sci Alliance. 2026 Dec;pii: e202603669. [Epub ahead of print]9(12):

Dysferlin promotes inflammatory macrophage responses and modulates Ca2+-dependent STAT1 signaling.

Kana Tominaga, Naoomi Tominaga.

Macrophage differentiation and activation shape tissue homeostasis and regeneration. Dysferlin (DYSF) is best known for its role in membrane repair in skeletal muscle, but its function in immune cells remains poorly understood. Here, we identify DYSF as a regulator of inflammatory macrophage-associated activation. DYSF expression increased during monocyte-to-macrophage differentiation. Gain- and loss-of-function analyses revealed that DYSF promoted inflammatory macrophage-associated responses, including cytokine production and migration. DYSF also enhanced Ca2+ influx and STAT1 Ser727-associated signaling, whereas Dysf knockdown or Ca2+ entry inhibition suppressed these responses. DYSF expression increased with aging in human CD14-positive cells and mouse monocyte/macrophage-lineage cells, and DYSF-expressing F4/80-positive macrophage-lineage cells accumulated in aged skeletal muscle. In a macrophage-myoblast co-culture system, DYSF-enriched inflammatory macrophages inhibited myogenic differentiation and myotube fusion, with this effect being partially mediated by soluble inflammatory factors, demonstrating an influence of macrophage DYSF on neighboring myogenic cells in vitro. Together, these findings support a role for DYSF in Ca2+-dependent STAT1-associated inflammatory responses in macrophages and in the suppression of myogenesis in cellular models.

DOI: https://doi.org/10.26508/lsa.202603669
Free Radic Biol Med. 2026 Oct 06. pii: S0891-5849(26)01192-5. [Epub ahead of print]

Evidence of a redox-dependent regulation of satellite cell activity and regeneration in human skeletal muscle following aseptic injury: a randomized controlled trial.

Konstantinos Papanikolaou, Athanasios Z Jamurtas, Dimitrios Draganidis, Ioannis Baloyiannis, Athanasios Poulios, Anastasia Rosvoglou, Constantinos Papadopoulos, George K Papadimas, Margarita Chrysanthou-Piterou, Sophia Havaki, Vassilis G Gorgoulis, Apostolos Sovatzidis, Panagiotis Tsimeas, Niki Syrou, Athanasios Chatzinikolaou, Nikos V Margaritelis, Michalis G Nikolaidis, Demetrios Kouretas, Ioannis G Fatouros.

  Satellite cells are essential for skeletal muscle regeneration, with their activity tightly regulated by glutathione (GSH) metabolism and redox balance. Effective regeneration requires an optimal redox hormetic range and balanced GSH levels, as both oxidative and reductive distress can impair redox signaling, satellite cell differentiation, and muscle repair. Despite its significance, redox-regulated regeneration responses in human skeletal muscle remain underexplored. Twenty-four recreationally active males provided a resting muscle biopsy and were stratified to a low or high GSH group based on their muscle glutathione levels. Participants completed two experimental trials of N-acetylcysteine (NAC) and placebo supplementation using a randomized, double-blind, crossover, repeated-measures design. NAC or placebo was administered during a 7-day loading phase before, immediately after, and daily for 8 days following an eccentric exercise injury protocol of the quadriceps muscle. Muscle biopsies, blood samples, muscle function, and soreness assessments were obtained at baseline, post-loading, and 2 and 8 days post-injury to assess cellular, morphological and functional parameters during recovery from injury. We demonstrate that restoration of intramuscular GSH balance in GSHlow individuals through NAC supplementation enhances satellite cell activity and myogenic response, promoting muscle regeneration and functional recovery. In contrast, in GSHhigh individuals, NAC supplementation propagated an aberrant Nrf2 response, resulting in compromised satellite cell kinetics and delayed skeletal muscle repair. These findings underscore the essentiality of GSH and redox balance in promoting effective muscle healing, highlighting the need for personalized antioxidant therapies that optimize skeletal muscle regeneration and recovery in humans.

Keywords:  antioxidants; glutathione; muscle function; muscle stem cells; redox eustress; regeneration

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.10.010
Physiol Rep. 2026 Oct;14(19): e71137

Microbial-derived Exerkines preserve muscle size and function during disuse in aged mice in a sex-dependent manner.

Jainil Daredia, Taylor R Valentino, Ahmed Ismaeel, Yuan Wen, John J McCarthy, Benjamin I Burke.

  Disuse-induced muscle atrophy is a critical clinical challenge in older adults. Existing countermeasures have largely failed to preserve muscle size and function, underscoring the need for novel therapeutic strategies. We recently identified pipecolic acid and succinate (PAS) as microbial-derived exerkines that prevent disuse-induced atrophy and preserve muscle function in adult mice. Here, we tested whether PAS similarly protects aged muscle. Aged male and female mice received vehicle (VEH) or PAS via drinking water during 10 days of unilateral hindlimb casting. PAS did not preserve soleus or plantaris mass, but casted gastrocnemius mass was greater in PAS- than VEH-treated mice irrespective of sex. PAS attenuated the loss of soleus and plantaris fiber cross-sectional area, with the largest effect in the female soleus. PAS enhanced soleus contractile function in a sex-specific manner: females exhibited greater absolute force and rate of force development, and males greater fatigue resistance. Gastrocnemius citrate synthase activity was greater in PAS- than VEH-treated females but not males, mirroring the female-specific preservation of soleus fiber size and function. These sexually dimorphic responses highlight microbial-derived metabolites as a novel therapeutic avenue for preserving muscle function during disuse in aging and underscore the importance of considering sex as a biological variable.

Keywords:  aging; disuse atrophy; muscle function; pipecolic acid; succinate

DOI:  https://doi.org/10.14814/phy2.71137
J Cell Physiol. 2026 Oct;241(10): e70240

Electrical Pulse Stimulation Partially Restores Insulin Signaling in Palmitate-Induced Insulin-Resistant Skeletal Muscle Cells via Mitochondrial Remodeling and Contractile Activity-Dependent Secretome.

Falcone Alessandro, Yilmaz Sevgican, Hendlinger Mona, Schrauwen Patrick, Lipaeva Polina, Piribauer Marlene, Heilmann Geronimo, Trenkamp Sandra, Roden Michael, Mastrototaro Lucia.

  Lipid oversupply induces insulin resistance in skeletal muscle (SkM), partly by altering mitochondrial function and dynamics. Although electrical pulse stimulation (EPS) improves insulin signaling in myotubes, the mechanisms contributing to this effect under lipotoxic conditions remain unclear. Thus, we investigated whether EPS restores lipid-induced insulin resistance in association with changes in mitochondrial respiration and dynamics, lipotoxic intermediates and evaluated the contribution of contraction-induced secreted factors, including small extracellular vesicles (sEV). Murine C2C12 myotubes were treated with palmitate (PA, 0.3 mmol/l) and subjected to EPS (1 Hz, 11.5 V) for 24 h. Insulin signaling, mitochondrial dynamics, respiratory capacity and lipotoxic intermediates were assessed by Western blotting, high-resolution respirometry and liquid chromatography-tandem mass spectrometry in control (CON) and PA-treated cells before and after EPS. Additionally, CON and PA-treated cells were incubated for 24 h with conditioned media and sEV from unstimulated or EPS-stimulated CON and PA-treated cells to evaluate the effect of the myocellular secretome on AKT signaling. PA reduced insulin-stimulated AKT(Ser473) and (Thr308) phosphorylation, which was partially rescued by EPS. In PA cells, EPS decreased the fusion proteins mitofusin 1 and 2 (MFN1, MFN2) and increased the fission marker dynamin-related protein 1 (DRP1). However, mitochondrial respiration and lipid accumulation were unaffected by EPS. Furthermore, conditioned media and sEV from EPS-stimulated cells enhanced AKT phosphorylation in PA-treated cells. These findings demonstrate that attenuation of lipid-induced insulin resistance is independent of mitochondrial respiratory capacity and lipid accumulation, but it is associated with alterations in proteins involved in mitochondrial dynamics and is likely mediated by exercise-derived sEV.

Keywords:  exercise; insulin resistance; mitochondrial dynamics; myokines; skeletal muscle cells

DOI:  https://doi.org/10.1002/jcp.70240
J Physiol Sci. 2026 Oct 03. pii: S1880-6546(26)00051-X. [Epub ahead of print] 100105

STING deficiency differentially affects skeletal muscle responses to high-intensity interval training and mechanical overload.

Haiyu Zhao, Reima Onishi, Mayuko Oba, Ryota Iyama, Takumi Yokokawa, Ai Takemura, Tatsuya Hayashi, Tatsuro Egawa.

  Skeletal muscle adapts to mechanical stress through inflammatory, mitochondrial and translational responses, but upstream sensors remain unclear. Stimulator of interferon genes (STING) links cytosolic DNA sensing to inflammatory signaling. We examined its role using STING-knockout (KO) mice. The STING agonist diamidobenzimidazole (diABZI) elicited a genotype-dependent Tnfα response. During four-week high-intensity interval training (HIIT), KO mice showed lower absolute running performance, but changes from baseline did not differ between genotypes. Overload increased plantaris mass across genotypes without an interaction. Phosphorylated 4E-BP1 abundance showed a significant genotype × overload interaction, whereas the p-4E-BP1/total 4E-BP1 ratio showed an overall genotype difference without a significant interaction. The ratio was lower overall in KO muscle, while overload-induced p70S6K responses were preserved. Tnfα, Il-6 and TBK1 responses to HIIT and overload were stimulus dependent. These findings suggest that STING contributes selectively, rather than uniformly, to metabolic, translational and inflammatory regulation during skeletal muscle adaptation.

Keywords:  Compensatory overload; Exercise; HIIT; Inflammation; STING; Skeletal muscle

DOI:  https://doi.org/10.1016/j.jphyss.2026.100105
Front Aging. 2026 ;7 1866906

Unraveling skeletal muscle senescence in an in vitro cell culture model.

Kayo Moreira Bagri, Morgana Teixeira Lima Castelo-Branco, Claudia Mermelstein.

   Introduction: Skeletal muscles are crucial for voluntary movement, posture, breathing, joint stability, and therefore are essential for maintaining overall health and quality of life. Aging, sarcopenia, cancer, immobilization, and several muscle pathologies can have an impact on muscle function, and muscle cell senescence is associated with these conditions.
Methods: Here we aimed to develop a primary cell culture model to study skeletal muscle cell senescence. We induced cell cycle arrest in cultured embryonic chick muscle cells using a low concentration of cytosine arabinoside (Ara-C) for 9 days.
Results: Our results show that Ara-C was able to induce several cellular senescence-associated bone fide characteristics, including reduced cell proliferation, increased β-galactosidase expression, increased reactive oxygen species production (ROS), increased p53 and p21 expression, increased muscle fibroblast cell size and nuclei numbers, increased lysosomal activity, decreased muscle differentiation (decreased muscle fiber size and decreased desmin expression), and increased secretion of IL-6, TNFα and TGFβ. Interestingly, inhibition of fibroblast growth factor receptor recovers the AraC-induced senescent phenotype in myogenic cells.
Conclusion: This new experimental model could be used to deepen our understanding of the molecules and signaling pathways associated with the initiation and establishment of skeletal muscle senescence. Furthermore, this model could be used to test new drugs and therapeutic interventions aiming the amelioration of senescence-associated conditions.

Keywords:  FGF; ROS; cytosine arabinoside; desmin; lysosomes; muscle; p53; senescence

DOI:  https://doi.org/10.3389/fragi.2026.1866906
Physiol Rep. 2026 Oct;14(19): e71128

Adding Tat-Beclin1 to an endurance training program promotes additive improvements in physical function in aged male mice.

Thuan Thien Tchen, Shakibur Rahman, Thaysa Ghiarone, Lynn A Spruce, Hossein Fazelinia, Elizabeth M Brown, Charalampos Papachristou, Sue C Bodine, Vitor A Lira, Kleiton A S Silva.

  Autophagy is a hallmark of aging, but it has not been exclusively targeted to attenuate aging-related physical dysfunction. Here, we combined Tat-Beclin1 and endurance training to determine its effect on physical function domains in aged male mice. Mice were randomly divided into Control (N = 5), Tat-Beclin1 (TB, 15 mg/kg, 2×/week, N = 9), Exercise (Exe, 70%-maximal-running-speed, 3×/week, N = 9), and TB+Exe (N = 8) for 1 month in 23-month-old male C57BL/6J mice. Animals were assessed for grip strength (GS), endurance capacity (EC) on a treadmill, and balance and coordination on a rotarod. Gastrocnemius/plantaris (G/P) and tibialis anterior muscles were harvested for western blotting, myofiber typing, and proteomic profiling (G/P only). Although no significant interaction was observed, the TB+Exe group showed improvements in GS, EC, and balance and coordination performance, an outcome comparable with additive effects of both therapies. Limited changes were observed in myofiber typing and autophagy markers among groups. A proteomic analysis revealed that TB upregulated biological processes involved in muscle contraction, whereas TB+Exe surprisingly upregulated acute inflammatory responses, including proteins such as haptoglobin and orosomucoid-1. Altogether, combining TB and endurance training elicits additive effects on physical functions of aged male mice and may represent a new approach to attenuate aging-related physical dysfunction.

Keywords:  Tat‐Beclin1; autophagy; exercise; physical function; proteomics

DOI:  https://doi.org/10.14814/phy2.71128
iScience. 2026 Oct 16. 29(10): 117293

Inverse directions of association of higher physical activity and higher insulin resistance with human skeletal muscle fiber-type gene expression.

Dan L Ciotlos, Sarah C Hanks, Arushi Varshney, Michael R Erdos, Nandini Manickam, Heather M Stringham, Peter Orchard, Erin M Hill-Burns, Narisu Narisu, Lori L Bonnycastle, Michael D Sweeney, Jouko Saramies, Markku Laakso, Jaakko Tuomilehto, Timo A Lakka, Karen L Mohlke, Michael Boehnke, Francis S Collins, Heikki A Koistinen, Stephen C J Parker, Laura J Scott.

  To investigate the interplay between physical activity and cardiometabolic traits in human skeletal muscle, we characterized gene expression and chromatin accessibility across skeletal muscle cell types in 263 Finnish individuals from the FUSION Tissue Biopsy Study. We analyzed single-nucleus RNA-seq data (168,309 nuclei), single-nucleus ATAC-seq data (242,069 nuclei), and bulk RNA-seq data. Lower insulin resistance (HOMA-IR) and higher total physical activity were both associated with higher proportions of Type 1 nuclei and lower proportions of Type 2x nuclei. Traits typically associated with better health-lower trait values of cardiometabolic traits such as HOMA-IR and higher physical activity levels-were associated with higher expression of energy metabolism genes and lower expression of signaling pathway genes across muscle fiber types, total pseudobulk, and to some extent in bulk tissue. HOMA-IR and physical activity appeared to have inverse and partially independent directions of association when adjusting for both traits in the same model.

Keywords:  chromatin accessibility; gene expression; insulin resistance; physical activity; single nucleus; skeletal muscle; snATAC-seq; snRNA-Seq; type 2 diabetes

DOI:  https://doi.org/10.1016/j.isci.2026.117293
Nat Commun. 2026 Sep 08. pii: 10632. [Epub ahead of print]17(1):

CNIH4 regulates systemic metabolism and exercise adaptations in male mice primarily through the modulation of β-adrenergic receptor trafficking.

Xu Liu, Zhihong Wang, Shuya Chen, Runqi Wang, Tao Bo, Zhiwei Liu, Zhihao Jia, Yong Zhang.

Exercise improves glucose and lipid metabolism by remodeling skeletal muscle and adipose tissue, processes that depend on beta-adrenergic receptor signaling. How receptor trafficking and activation are coordinated across tissues remains unclear. Here we show that Cornichon homolog 4 controls beta-adrenergic receptor localization and activity in metabolic tissues. Cornichon homolog 4 expression increases in human and mouse skeletal muscle after resistance training. Loss of Cornichon homolog 4 in all tissues or skeletal muscle impairs beta2-adrenergic receptor trafficking and causes exercise-induced hyperglycemia and defective glucose use. Its loss also worsens diet-induced obesity. In adipose tissue, loss of Cornichon homolog 4 weakens beta3-adrenergic receptor signaling, thermogenesis and exercise-induced lipolysis. Pharmacological activation of beta2- or beta3-adrenergic receptors partially restores glucose or adipose defects. Mechanistically, Cornichon homolog 4 links adrenergic receptor signaling to extracellular matrix gene expression and Smad signaling. These findings identify Cornichon homolog 4 as a coordinator of metabolic adaptation.

DOI: https://doi.org/10.1038/s41467-026-77408-0
Free Radic Biol Med. 2026 Oct 07. pii: S0891-5849(26)01182-2. [Epub ahead of print]257 224-240

Mitochondrial oxidative stress in skeletal muscle alters metabolic signaling responses to acute muscle contraction.

Ethan L Ostrom, Aurora Mattson-Hughes, James MacDonald, Theo Bammler, Nicholas J Day, Matthew J Gaffrey, Jesse B Trejo, Wei-Jun Qian, Bo Hagy, Jennifer R Giorgione, Kenneth M Humphries, Holly Van Remmen, Ricard Rodriguez-Mias, Judit Villen, David J Marcinek.

Activation of redox-sensitive signal transduction cascades is an increasingly appreciated mechanism of exercise adaptation in skeletal muscle. Aging and disease are associated with altered redox homeostasis, potentially altering redox responses to muscle contraction, and adaptations to exercise. It is unclear how chronic steady-state changes in redox homeostasis affect contraction-induced signaling cascades. Here we use a novel model of inducible superoxide dismutase 2 knockdown (iSOD2 KD) in skeletal muscle to test how chronic mitochondrial redox perturbations affect subsequent signaling responses to acute fatiguing muscle contraction. After a 12-week doxycycline treatment to knock down SOD2, littermate controls (CON) and iSOD2 KD animals underwent a single acute fatiguing contractile stimulus of the right hindlimb. Muscle tissue was collected immediately after or 3 h after completion of the stimulus followed by redox proteomic and transcriptomic analysis, respectively, and compared to naïve unstimulated controls of each genotype. iSOD2 KD led to decreased protein expression of several key iron-sulfur cluster biosynthesis proteins and increased reversible thiol oxidation of proteins in the mitochondrial compartment in response to muscle contraction. The transcriptomic response to contraction in KD shows activation of apoptosis, oxidative stress, and inflammatory pathways and no significant perturbation in controls. Controls show pathway activation of insulin signaling and glucose metabolism, calcium signaling, and energy stress signaling processes compared to no activation in KD muscle. These results indicate that chronic mitochondrial redox stress shifts acute signaling responses away from metabolic signaling pathways and toward oxidative stress and apoptotic signaling processes which may lead to pathological or maladaptive signaling responses over time.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.10.001
Adv Clin Chem. 2026 ;pii: S0065-2423(26)00077-6. [Epub ahead of print]135 75-115

Proteomics of the skeletal muscle dystrophin complex.

Paul Dowling, Dieter Swandulla, Kay Ohlendieck.

  Proteomics is a widely applied analysis pipeline in biomedical research and clinical chemistry. In skeletal muscle biology, proteomics has been extensively used to identify and characterize individual proteoforms in normal and diseased contractile tissue. This article outlines mass spectrometric approaches to study the proteome of myofibers and associated cell types. We highlight sample preparation and protein digestion for bottom-up proteomics, as well as mass analyzers and bioinformatic data handling. As an illustrative example, the identification and characterization of the sarcolemmal dystrophin-glycoprotein complex, which is primarily involved in the progressive muscle wasting disorder Duchenne muscular dystrophy, are explored.

Keywords:  Biochemical analysis; Biochemistry methods; Cytoskeleton; Dp427; Dystrobrevin; Dystroglycan; Dystrophin; Mass spectrometry; Musculoskeletal disorder; Proteomics; Sarcoglycan; Sarcospan; Syntrophin

DOI:  https://doi.org/10.1016/bs.acc.2026.08.001
Am J Physiol Cell Physiol. 2026 Oct 06.

Intrinsic IL-6 expression reduces rhIL-6-induced JAK/STAT activation and promotes glucose and oleic acid oxidation in cultured human myoblasts.

Anja Srpčič, Katarina Miš, Barbara Žvar Baškovič Gantar, Klemen Dolinar, Ulrik Nygaard Mjaaseth, Arild Rustan, Eili T Kase, Katja Lakota, Katja Perdan Pirkmajer, Sergej Pirkmajer.

  Interleukin-6 (IL-6), produced by skeletal muscle and extramuscular tissues, regulates skeletal muscle function through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. However, the interaction between intrinsic (locally produced) IL-6 and extrinsic (circulating) IL-6 in skeletal muscle remains unclear. We investigated whether and how intrinsic expression of IL-6 in cultured primary human myoblasts influences their response to extrinsic stimulation with recombinant human IL-6 (rhIL-6). Using gene silencing, we found that suppression of intrinsic IL-6 enhanced rhIL-6-induced phosphorylation of STAT1 and STAT3. Silencing STAT3 also increased rhIL-6-induced STAT1 phosphorylation, but silencing STAT1 had no effect on STAT3 phosphorylation. Pretreatment of myoblasts with neutralizing anti-IL-6 antibodies increased phosphorylation of STAT1 and STAT3 induced by 50 ng/mL rhIL-6, whereas pretreatment with 5 ng/mL rhIL-6 reduced this response. Despite increased JAK/STAT signaling, IL-6 silencing decreased glucose and oleic acid uptake and oxidation under both basal and rhIL-6-stimulated conditions. Collectively, our results imply that intrinsic IL-6 restrains activation of the JAK/STAT pathway by extrinsic IL-6, but acts synergistically with it to promote myoblast energy metabolism.

Keywords:  JAK/STAT signaling pathway; glucose metabolism; human myoblasts; interleukin-6; oleic acid metabolism

DOI:  https://doi.org/10.1152/ajpcell.00264.2026
bioRxiv. 2026 Aug 10. pii: 2026.08.08.743652. [Epub ahead of print]

A nuclear role for the contractile protein troponin I/UNC-27 in regulating muscle aging in C. elegans.

Allan Alcolei, Manon Froment, Laurent Molin, Charline Roy, Romain Bulteau, Jean-Louis Bessereau, Florence Solari.

Muscle ageing is characterized by evolutionarily conserved subcellular alterations across diverse organisms. In Caenorhabditis elegans , the decline in sarcomeric gene expression is among the earliest detectable ageing-associated changes, emerging at the onset of adulthood. To identify causal regulators of muscle ageing in an unbiased manner, we developed a genetic screening strategy that enables visual monitoring of muscle ageing at both cellular and organismal scales. Using this approach, we identified a mutation that delays the age-associated loss of sarcomeric transcripts. Unexpectedly, the mutation maps to the troponin I gene unc-27 , which encodes a conserved regulator of muscle contraction not previously implicated in gene regulation. The mutation alters a single amino acid within a predicted nuclear localization signal (NLS). We found that multiple NLS motifs mediate the active transport of UNC-27 into muscle nuclei from early adulthood onward. Disruption of UNC-27 nuclear localization preserves sarcomeric gene expression during ageing and delays early hallmarks of muscle decline, including proteostatic imbalance and mitochondrial fragmentation. Transcriptomic analyses further revealed that nuclear UNC-27 selectively regulates the expression of genes encoding structural components of the muscle apparatus in adult animals. These results support the existence of a homeostatic sarcomere surveillance pathway, in which a structural protein unexpectedly acquires a transcriptional regulatory role in response to age-associated physiological state. The conservation of NLS motifs in mammalian UNC-27 orthologues suggests that this mechanism may be evolutionarily conserved, with potential relevance to human muscle physiology and disease.

DOI: https://doi.org/10.64898/2026.08.08.743652
J Physiol. 2026 Oct 09.

Interplay between store-operated calcium entry and mitochondrial phosphate handling modulates force and fatigue during exercise.

Emmet A Francis, Juliette Hamid, Anusha Kumar, Padmini Rangamani.

  The dynamics of calcium ions ( Ca2+ ) in skeletal muscles link electrochemical activation and contractile force generation. Recent experimental data suggest that store-operated Ca2+ entry (SOCE), the process of extracellular Ca2+ influx upon the depletion of Ca2+ from the sarcoplasmic reticulum (SR), helps delay the onset of muscle fatigue during exercise. We hypothesize that SOCE regulates force generation during prolonged muscle activity by allowing for sustained Ca2+ release from the SR. We test this hypothesis with a quantitative biophysical model that simulates the biochemical events of muscle contraction, from depolarization at the T-tubules to Ca2+ release from the SR to Ca2+ binding and force generation throughout the myoplasm. We also consider the balance between Ca2+ removal from the myoplasm and SOCE through the T-tubule membrane, along with mitochondrial uptake of free Ca2+ and phosphate. We use the model to test the effects of SOCE inhibition on force production. The magnitude of myoplasmic Ca2+ and force is lower in SOCE knockout cells, especially when SOCE reduction is combined with impaired uptake of phosphate by mitochondria. We then test the effects of SOCE during resistance exercise or high-intensity interval training. These simulations predict a context-dependent relationship between force generation and SOCE - increased SOCE is associated with greater force production during resistance exercise but worsens the effects of fatigue in certain cases of high-intensity training. Such SOCE-induced fatigue is attributed to phosphate accumulation in the myoplasm and can be mitigated by increased rates of mitochondrial phosphate uptake. KEY POINTS: Store-operated calcium entry (SOCE) provides a mechanism for calcium ion ( Ca2+ ) influx following the depletion of Ca2+ from intracellular stores such as the sarcoplasmic reticulum (SR). Recent experiments suggest that SOCE is an important modulator of contractile force generation in skeletal muscle. Here we develop a computational model of Ca2+ handling in the myoplasm, SR, and mitochondria and the resulting effects on force generation in skeletal muscle fibres to examine the role of SOCE during extended periods of activity. Our model predicts that increasing SOCE leads to enhanced force over periods of repeated stimuli during resistance exercise due to sustained Ca2+ release. Our simulations show a complex relationship between SOCE and force production during high-intensity interval training, with exacerbated phosphate accumulation in the myoplasm leading to force reduction for very high levels of SOCE. This effect can be mitigated by enhanced mitochondrial phosphate uptake.

Keywords:  calcium release; excitation‐contraction coupling; exercise physiology; mitochondria; phosphate transport; skeletal muscle; store‐operated calcium entry; systems biophysics

DOI:  https://doi.org/10.1113/JP289463
Diabetes Obes Metab. 2026 Oct 07.

Weight Loss or Muscle Loss? Cellular Mechanisms and Clinical Strategies for Preserving Lean Mass During GLP-1-Based Therapy.

Esma Sukurica, Goksemin F Sengul, Fatma Uysal Cinar.

  Glucagon-like peptide-1 receptor agonists and newer dual- and triple-incretin receptor agonists have transformed obesity treatment by producing substantial and sustained weight loss. However, reported reductions in lean body mass have raised concerns about potential skeletal muscle loss and sarcopenia, particularly in older adults and individuals with limited muscle reserves. This review examines the cellular and tissue-level mechanisms that may contribute to lean mass changes during GLP-1-based therapy and evaluates strategies for preserving skeletal muscle. Reductions in fat-free or lean body mass should not be interpreted as equivalent to loss of contractile skeletal muscle, as these compartments also include body water, organs, connective tissue, and the fat-free component of adipose tissue. Incretin-based therapies predominantly reduce fat mass, while preclinical studies and limited human evidence suggest possible improvements in skeletal muscle quality through enhanced insulin sensitivity, reduced myosteatosis and inflammation, and favourable mitochondrial adaptations. Nevertheless, the proportion of lean mass reduction attributable to true skeletal muscle loss and its long-term functional significance remain uncertain. Rapid weight loss and inadequate nutrient intake may increase the risk of clinically relevant muscle loss in susceptible populations. Individualized protein intake, progressive resistance exercise, management of gastrointestinal adverse effects, and functional monitoring therefore represent the reasonable strategies for skeletal muscle preservation. Emerging anabolic combination therapies remain investigational and should be evaluated using strength and physical performance outcomes in addition to body composition. Accordingly, this review explores the potential mechanisms underlying skeletal muscle changes during GLP-1-based therapy and discusses strategies to support muscle preservation during therapy-induced weight loss. Ultimately, the success of GLP-1-based therapy should be defined not only by the magnitude of weight loss, but also by the extent of that weight loss and the preservation of skeletal muscle mass and function.

Keywords:  GLP‐1 receptor agonists; body composition; lean body mass; obesity; resistance exercise; sarcopenia; skeletal muscle; skeletal muscle loss; weight loss

DOI:  https://doi.org/10.1111/dom.71422
iScience. 2026 Oct 16. 29(10): 117620

4-Phenylbutyric acid activates an NF-κB-Egr-1 axis to control myoblast proliferation and ECM gene expression.

Kana Tominaga, Naoomi Tominaga.

  Myogenic progression is tightly controlled by epigenetic mechanisms. Here, we demonstrate that the histone deacetylase inhibitor 4-phenylbutyric acid (4-PBA) selectively promotes myoblast proliferation without inducing myotube differentiation. Mechanistically, 4-PBA increases histone H3 acetylation at lysines 18 and 27 through HDAC5 suppression, resulting in activation of NF-κB p65. HDAC5 overexpression attenuates 4-PBA-induced histone H3 acetylation, NF-κB/early growth response 1 (Egr-1) activation, and myoblast proliferation, supporting a causal role for HDAC5 suppression. Chromatin immunoprecipitation identifies Egr-1 as a direct transcriptional target of NF-κB p65. Transcriptomic analyses reveal that Egr-1 regulates extracellular matrix- and myogenesis-associated gene programs, including nonfibrillar collagen genes. Together, these findings define an epigenetic mechanism by which 4-PBA modulates myoblast proliferation through HDAC5-dependent histone acetylation and NF-κB p65-Egr-1-driven transcriptional programs, providing insight into how epigenetic therapeutics influence skeletal muscle cell behavior.

Keywords:  4-phenylbutyric acid; HDAC5; NF-κB/Egr-1 signaling; extracellular matrix remodeling; myoblast proliferation

DOI:  https://doi.org/10.1016/j.isci.2026.117620
Sci Transl Med. 2026 Oct 07. 18(870): eaei5938

Use of split intein and myotropic AAV vectors enables effective preclinical gene therapy for dysferlinopathy.

Nikki M McCormack, Stephanie Lee-Diaz, Theodore R Reyes, Marshall W Hogarth, Jada L Covington, Camryn A Bragg, Zarek O Harper, Thomas Diehn, James S Novak, Christine L Halbert, Jeffrey S Chamberlain, David L Mack, Martin K Childers, Jyoti K Jaiswal, Hichem Tasfaout.

Limb-girdle muscular dystrophy type R2 (LGMDR2) is a genetic disorder characterized by progressive skeletal muscle weakness and degeneration. It is caused by mutations in the DYSF gene, which prevent dysferlin expression. Dysferlin protein is essential for muscle cell membrane repair. Gene therapy using adeno-associated viral (AAV) vectors to restore full-length dysferlin expression is a promising therapeutic approach for LGMDR2. However, the large size of the dysferlin cDNA (6.2 kilobases) exceeds the ∼4.7-kilobase packaging capacity of AAV vectors, posing a challenge to effective delivery of the full-length protein. Here, we describe the use of split inteins and myotropic AAV vectors for efficient systemic gene delivery and expression of full-length dysferlin in the muscles of an LGMDR2 mouse model. We generated and validated a potent split-intein version of dysferlin that enables reconstitution of scarless full-length dysferlin protein. In vitro assessment of these constructs demonstrated a high capacity of the reconstituted dysferlin to restore membrane repair defects in dysferlinopathic mouse myoblasts. Systemic administration of split-intein and dysferlin dual AAVMYO1 vectors improved muscle strength, increased contractile force, and reduced histopathological abnormalities in the LGMDR2 mouse model at both the presymptomatic stage and late stage of the disease. Compared with the homologous recombination dual-AAV vector strategy, the split-intein technology demonstrated superior efficiency in restoring the full-length dysferlin protein and resulted in greater functional improvements. These findings demonstrate the curative potential of this split intein-based gene therapy approach for LGMDR2.

DOI: https://doi.org/10.1126/scitranslmed.aei5938
Neurosci Biobehav Rev. 2026 Oct 05. pii: S0149-7634(26)00480-X. [Epub ahead of print] 107022

Muscle oxygen saturation (SmO2): An Upstream Metabolic Link Connecting Peripheral Muscle Metabolism to Central Neurobiological Adaptations.

Karuna Regmi, Ekta Kohli.

  Physical activity (PA) and neuropsychology have been associated, although the peripheral mechanisms that connect skeletal muscle activity to central nervous system remain unclear. Various muscle derived signaling molecules, including myokines and metabolites, are released due to PA. Lactate is one of the signaling molecules released via muscle during PA and it may serve as an intermediatory metabolite which links peripheral muscle metabolism to central neurobiological adaptations. Along with it, PA also induces alterations in muscle oxygen saturation (SmO2), reflecting changes in local metabolic stress and mitochondrial demand. SmO2 plays a vital role in exercise physiology but still how it impacts neuropsychology has not received attention. Reductions in muscle oxygenation due to PA has been associated with elevated lactate production, while lactate itself acts as an energy substrate, signaling molecules, and epigenetic modulators within the brain, promoting BDNF expression and neuroplastic processes. In this review, we propose that SmO2 can act as an upstream physiological signal within a SmO2-lactate-brain axis, translating peripheral metabolic stress into positive neuropsychological outcomes. Establishment of SmO2 as a non-invasive biomarker of neuropsychology could act as a novel model to understand the interactions between PA and brain. This can help to optimize interventions based on PA aiming to enhance cognition, emotional resilience and neurological health.

Keywords:  Lactate; Muscle Oxygen saturation; Neuropsychology; Physical Activity; SmO(2)

DOI:  https://doi.org/10.1016/j.neubiorev.2026.107022
Biochem J. 2026 Oct 09. pii: BCJ20260026. [Epub ahead of print]

MyoD and Myogenin regulatory cascade is targeted by tumor signals to repress myogenesis in cancer cachexia.

Kai-Fan Huang, Yi-Shiuan Liao, Huang-Bin Lin, I-Ning Lu, Xin-Ray Lin, Yi-Ju Wu, Huai-Jen Chang, Yu-Ching Huang, Wan-Ting Feng, Po-Hong Chang, Yu-Hsuan Chang, Yu-Xiang Chiang, Ting-Hsiang Lung, Chuan-Che Wu, Tzu-Han Weng, Hsiang-Cheng Chi, Shen-Liang Chen.

  It is estimated that about 20-30% cancer death is directly linked to the syndrome called cancer cachexia (CAC), which is characterized by debilitating skeletal muscle (SKM) and fat wasting. Recent studies have found that the myogenic ability of myogenic stem cells (MuSC) in the cachectic SKM is compromised, but the mechanisms remain to be clarified. Using the C26 colon cancer cells mediated cachexia model, the down-regulation of myogenic regulatory factors (MRF) MyoD and MyoG, but not Myf5 and Mrf4, was confirmed in vitro and in vivo. We further found the repression of myogenesis by C26 cells conditioned medium (C26M) in vitro could be rescued by inducible over-expression of either MyoD or MyoG, but not Myf5 or Mrf4. As MyoD is the major upstream activator of MyoG, these findings suggest the targeting of the MyoD-MyoG regulatory cascade by CAC signals. The transactivation of myogenic gene promoters by MyoD was also constantly repressed by C26M, suggesting MyoD dysfunction is critical to myogenesis repression in CAC.   The repression of MyoD gene transcription by C26M was found to be mediated by the core enhancer (CE) located in the distal enhancer (DE) region. The activation of CE mediated promoter activity by MyoD, ß-Catenin*, and Pbx1 was significantly reduced by C26M, implying the repression of MyoD positive feedback loop. Taken together, these observations suggest that CAC signals repress both MyoD transactivational activity on target genes and its transcriptional activation by upstream activators, which subsequently leads to repression of myogenesis and failed regeneration in cachectic SKM.

Keywords:  MyoD; cachexia; cancer; muscle; myogenesis; promoter

DOI:  https://doi.org/10.1042/BCJ20260026
Adv Sci (Weinh). 2026 Oct 04. e77648

Single-Nucleus Atlas of Spinal Sarcopenia Patients Reveals Disruption of Quiescent and Regenerative Satellite Cell Niches in Fatty-Infiltrated Muscle.

Wenkai Wu, Renxian Wang, Dingding Wang, Quanzhong Ren, Ling Wang, Fangfang Duan, Guihe Yang, Ruixuan Yu, Yi Wang, Yingyu Zhang, Zetong Zang, Chuqi Li, Weijia Liu, Wenshuang Zhang, Yi Yuan, Zitong Cheng, Xiaoguang Cheng, Junbo Liang, Yajun Liu.

  Severe muscle fat infiltration is a contributing factor to muscle loss, particularly in the spinal sarcopenia population. However, the underlying mechanism largely remains elusive. Here, we identified the intramuscular fat fraction (IMFF), rather than perimuscular fat fraction, as an independent determinant of trunk muscle strength. Individuals with higher IMFF (10-15% and >15%) exhibited significantly lower paraspinal muscle mass and strength compared to those with lower IMFF (<5%). Using single-nucleus RNA sequencing, we established the first cellular atlas of fat-infiltrated paraspinal muscle, revealing profound remodeling of muscle architecture, extracellular matrix organization, and satellite cell niches. Among the adipose-derived factors, ANGPTL4 emerged as a key paracrine suppressor of myogenesis, acting through upregulation of syndecan-2 (SDC2) in satellite cells. Inhibition of SDC2 partially rescued ANGPTL4-induced myogenic impairment in C2C12 cells. Furthermore, we identified a GPC3+ fibro/adipogenic progenitor (FAP) subpopulation with enhanced lipogenic potential, characterized by high expression of GPC3, PPARG, ADIPOQ, and FABP4, representing a transition from MMEhigh GPC3low FAPs into MMElowGPC3high adipogenic FAPs. Collectively, our findings delineate the cellular landscape and signaling interactions that underlie pathological fat infiltration in spinal muscles, providing mechanistic insight and potential therapeutic targets for spinal sarcopenia.

Keywords:  adipokine; fatty infiltration; microenvironment; sequencing; spinal sarcopenia

DOI:  https://doi.org/10.1002/advs.77648
Biochem Biophys Res Commun. 2026 Oct 08. pii: S0006-291X(26)01476-2. [Epub ahead of print]839 154710

In silico discovery and cellular validation of PBM-342: a novel PPAR-β/δ modulator for skeletal muscle differentiation.

Manuel Gutiérrez-Rodríguez, José Manuel Hernández-Díaz, Rodolfo Daniel Ávila-Avilés, Magally Ramírez-Ramírez, J Manuel Hernández-Hernández.

  Modulation of the peroxisome proliferator-activated receptor beta/delta (PPAR-β/δ) holds therapeutic potential for skeletal muscle regeneration and metabolism. However, the clinical development of classical agonists has been hampered by severe issues of non-specificity and metabolic toxicity. In this study, we implemented an in-silico strategy coupled with in-vitro functional validation to discover selective and safe modulators. Through a ligand-based virtual screening of the ZINC database, using the crystallographic agonist 'Compound 9' (PBM-0) as a structural template to favor isotype selectivity, and molecular docking analysis, PBM-342 was identified as the top-ranked candidate, exhibiting a favorable docking score (ΔG = -12.86 kcal/mol by flexible docking). Subsequent molecular dynamics simulations revealed that PBM-342 constrains the conformational dynamics of Tyrosine-437 in Helix-12, the structural determinant of the receptor transcriptional activation. Pharmacokinetic (ADME) profiling confirmed its optimal lipophilicity (Log P = 3.86) and the absence of inhibition of the critical hepatic isoenzyme CYP2D6. Consequently, in murine C2C12 cultures, the working concentration of PBM-342 (100 nM) promoted morphologically and transcriptionally, myotube fusion index (p < 0.0001) and fiber-type reprogramming, as evidenced by selective upregulation of the specific oxidative muscle fibers, myosin isoform MHCIIa (p < 0.01).

Keywords:  C2C12 myoblasts; Drug design; Molecular docking; Molecular dynamics; Myogenic differentiation; Oxidative muscle phenotype; PPAR-β/δ

DOI:  https://doi.org/10.1016/j.bbrc.2026.154710
Brain Pathol. 2026 Oct 07. e70155

Identifying regulatory muscle processes in infantile and adult Pompe patients using a multi-omic and morphological approach.

Alexander Schaiter, Keerthika Lohanadan, Alexander Mensch, Andreas Hentschel, Angela Rosenbohm, Cornelia Kornblum, Angela Roth, Tara Procida-Kowalski, Heidrun H Krämer, Andreas Hahn, Jörg Höhfeld, Dieter O Fürst, Werner Stenzel, Peter F M van der Ven, Andreas Roos, Marek Bartkuhn, Anne Schänzer.

  Pompe disease is a lysosomal glycogen storage disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). There are two different clinical phenotypes, which are based on the age of onset, GAA variants, and residual enzyme activity. To better understand the regulation of age-dependent pathways in Pompe disease, we performed a multi-modal approach. We included mass spectrometry (MS) (liquid chromatography coupled to tandem mass spectrometry) and bulk-RNA sequencing on skeletal muscle samples from patients with late onset Pompe disease (LOPD) (n = 21) and infantile-onset Pompe disease (IOPD) (n = 11) naive to enzyme replacement therapy (ERT), IOPD patients with ERT (n = 5) and age-matched controls. The findings were verified by immunofluorescence studies and ultrastructural analysis using samples with different disease progression. We identified deregulated muscle processes in LOPD and IOPD samples, with different levels of regulation evident at the transcriptome and protein levels. Transcriptomic profiling revealed upregulation of immune processes in both Pompe subtypes, while metabolic processes were downregulated mainly in LOPD. Downregulation of transcripts associated with muscle development and myogenesis was only observed in IOPD samples. MS analysis revealed a decrease in the expression of sarcomeric proteins mainly in LOPD, while chaperone-assisted selective autophagy was altered in both Pompe subtypes. Proteins linked to vesicle trafficking and biosynthesis correlated with the degree of muscle pathology in LOPD, highlighting their role in the progression of the disease. IOPD patients treated with ERT showed normalised deregulated transcripts, though not fully back to baseline. Proteins increased with ERT were linked with mitochondrial and protein control pathways, and sarcomeric function, indicating ERT's positive effect on skeletal muscle function at the molecular level. Our findings reveal that combining a multi-omic approach, including morphological observations, enables the detection of a greater number of deregulated muscle processes, indicating both similar and distinct muscle processes in IOPD and LOPD.

Keywords:  autophagy; glycogen storage; lysosome storage; muscle proteomics; muscle transcriptomic; vacuolar myopathy

DOI:  https://doi.org/10.1111/bpa.70155
Microsyst Nanoeng. 2026 Oct 09. pii: 340. [Epub ahead of print]12(1):

Differentiated skeletal myotubes coupled with bimodal biosensing for dynamic functional evaluation of inflammatory myotube dysfunction.

Huimin Li, Cheng-Wen He, Haote Han, Wei Wei, Jiaru Fang, Ning Hu, Chong Teng.

Inflammatory skeletal muscle atrophy is a growing clinical challenge, driven by chronic inflammatory conditions and life-threatening illnesses that cause progressive muscle loss. This condition leads to premature muscle fatigue and a decline in muscle function, highlighting the necessity for highly sensitive diagnostic methods to detect impairment prior to the occurrence of structural damage. Conventional diagnostic methods, including electromyography, serum biomarker assays, and medical imaging, often fail to detect early and subtle alterations in myotube electrophysiological responsiveness because of limited temporal accuracy and insufficient target specificity. Furthermore, these techniques are limited in resolving dynamic electrophysiological fluctuations as well as characterizing the coupling between electrical signaling and intracellular calcium dynamics. Herein, we have developed an integrated bimodal biosensing platform that combines microelectrode array (MEA)-based electrophysiological recording with high-resolution, fluorescence-based calcium imaging. This platform performs coordinated and real-time tracking of extracellular field potentials and intracellular calcium transients across networks of differentiated C2C12 myotubes. Using an in vitro model of LPS-induced inflammatory skeletal muscle atrophy, LPS exposure progressively disrupted spontaneous electrical firing, field potential amplitude, and intracellular calcium transients in a concentration- and time-dependent manner. Diclofenac, a clinically applied anti-inflammatory agent, effectively maintained both electrophysiological function and calcium homeostasis in myotubes under inflammatory stress. Therefore, our bimodal platform functions as a robust, real-time preclinical tool for the detection of incipient inflammatory myopathy. Its integrated capabilities enable the precise quantification of drug responses and the scalable screening of therapeutic candidates, thereby establishing a versatile, translationally-oriented platform for the investigation of skeletal muscle atrophy mechanisms and interventions.

DOI: https://doi.org/10.1038/s41378-026-01468-x
Am J Physiol Cell Physiol. 2026 Oct 06.

More than just adipose. The impact of GLP1Ra on lean tissue.

Maxime Julien, Stewart Jeromson, David C Wright.

  Glucagon-like peptide 1 receptor agonists (GLP1Ra) are widely used for the management of obesity and cardiometabolic disease. While causing robust weight loss, GLP1Ra also result in reductions in lean tissue, including skeletal muscle and bone. The purpose of the current review is to discuss key findings demonstrating the effects of GLP1Ra treatment on skeletal muscle and bone, approaches that have been implemented to mitigate these changes, and to highlight important areas of future research.

Keywords:  GLP1 receptor agonists; bone; obesity; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.90062.2026
Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2534671123

Titin extension explains residual force enhancement in skeletal muscle.

Christopher Tiessen, Armaan Sekhon, Dhairya Desai, Tim Leonard, Fatima Abu Shagra, Samhar Samer Alouch, Walter Herzog.

  Residual force enhancement (RFE) is an inherent property of mammalian skeletal muscle. After eccentric stretch, muscle produces increased steady-state force compared to purely isometric contraction at the same sarcomere length and activation level. This property has been known for over 70 y and yet remains largely unexplained. Titin, a giant spring-like protein responsible for passive force generation and stabilization of the sarcomere, has been suggested as a potential candidate for causing RFE. To test whether titin may be responsible for RFE, we used multiple titin immunolabels on single isolated myofibrils to approximately track the migration of individual titin segments in real-time. In comparison to many previous attempts to label titin in sarcomeres, our labeling using N2A and distal PEVK labels did not impact mechanical properties of the myofibril and thus permitted accurate tracking of titin segments within single sarcomeres. We found the approximate length of titin's PEVK segment was significantly longer in RFE compared to isometric control activations at similar final sarcomere lengths, indicating increased force on titin filaments in RFE. Using a modified worm-like chain model, we predict titin-associated force contributes up to 62% of increased force during RFE. Additionally, using a continuous eccentric stretch protocol, we provide indirect evidence suggesting titin-actin interactions may be responsible for increased force on titin during RFE. To date, this represents one of the most convincing pieces of evidence suggesting that titin is responsible for RFE. Thus, our data indirectly support the proposed "three-filament model" where muscle activation induces cross-bridge interactions and titin-actin interactions.

Keywords:  PEVK; myofibril; residual force enhancement; skeletal muscle; titin

DOI:  https://doi.org/10.1073/pnas.2534671123
Front Mol Med. 2026 ;6 1953867

Systemic responses to intravenous rAAV administration in boys with Duchenne muscular dystrophy.

Brooke E Harris, Brooke M Seldin, Sam C Towne, Orinda R Hobson, Eli Zerpa, Victor Prima, H Lee Sweeney, David W Hammers.

   Introduction: Systemic gene therapies utilizing recombinant adeno-associated virus (rAAV) are in the clinic for the treatment of rare monogenic diseases. This includes delandistrogene moxeparvovec for Duchenne muscular dystrophy (DMD), which uses AAVrh74 vector to deliver a micro-dystrophin transgene to striated muscle. While there have been cases of transformative benefits incurred from rAAV therapies, serious adverse events and mortalities have occurred. This study aimed to investigate short-term rAAV dynamics and long-term systemic responses to intravenous rAAV in the phase 1/2a delandistrogene moxeparvovec clinical trial (NCT03375164), which represents the most promising cases of micro-dystrophin gene therapy for DMD.
Methods: Plasma and urine specimens from NCT03375164 were analyzed for rAAV using digital PCR and immunoblotting. The integrity and transduction competency of specimen-derived rAAV was evaluated in vitro. Systemic responses to rAAV treatment were investigated using the SomaScan proteomics platform. Preclinical antiviral responses to rAAV were assayed by real-time PCR in the livers of D2. mdx mice 1 week following systemic treatment with rAAV.
Results: Digital PCR revealed high rAAV content in the plasma at Day 1 following treatment, which substantially reduced by Day 7. Urinary rAAV content was low and variable in all samples tested. The majority of detected vector genomes were packaged in AAVrh74 particles in these specimens, and the vector contained in Day 1 plasma samples was confirmed to be transduction competent. SomaScan data revealed highly significant changes in 99 circulating proteins, which include markers associated with immune activation, interferon responses, complement pathways, and organ injury. Most traditional markers of muscle damage were not changed across the time course, with the limitation that no healthy or untreated DMD samples were analyzed. Features of antiviral and interferon-associated responses were identified in D2. mdx mice.
Conclusion: Systemic rAAV treatments result in high levels of circulating and transduction-competent vector early after treatment in DMD boys and result in wide-spread activation of immune-associated markers. These findings will provide insights for future investigational study design and efforts to improve safety of rAAV gene therapies.

Keywords:  Duchenne muscular dystrophy; SomaScan; adeno-associated virus; complement activation; immune system; interferon response genes; micro-dystrophin

DOI:  https://doi.org/10.3389/fmmed.2026.1953867
J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70394

Chemotherapy-Induced Skeletal Muscle Dysfunction and Cognitive Impairment: A Muscle-Brain Mechanistic Framework With Implications for Exercise Oncology.

SoYoung Ahn, Jin-Soo Kim, Daniel A Galvao, Dennis R Taaffe, Dong Hyun Yoon, Carolyn McIntyre, Christelle Schofield, Yoon Jung Chang, Jihee Min, Wook Song, Robert U Newton.

  Chemotherapy commonly induces skeletal muscle dysfunction and cognitive impairment, complications that reduce treatment tolerance and quality of life. Skeletal muscle mass frequently declines during chemotherapy, with cohort studies reporting losses of 3%-10% across treatment courses, while chemotherapy-induced cognitive impairment affects up to one-third of patients. Emerging evidence indicates that chemotherapeutic agents impair mitochondrial function in peripheral tissues, including skeletal muscle, increasing systemic oxidative stress and inflammatory cytokines. These factors may promote oxidative stress and inflammation within the brain, particularly in the hippocampus, contributing to neuronal mitochondrial dysfunction, apoptosis and cognitive decline. Skeletal muscle may therefore represent an important component within a broader muscle-brain axis linking chemotherapy-induced metabolic dysfunction with brain health. Targeted exercise improves skeletal muscle mitochondrial function, reduces systemic inflammation and oxidative stress and modulates multiple exercise-responsive signalling pathways, including myokines such as brain-derived neurotrophic factor and irisin. Collectively, these adaptations may contribute to improved neuronal health, neurogenesis and cognitive function. Understanding these interconnected mechanisms may inform exercise strategies to mitigate chemotherapy-related cognitive impairment.

Keywords:  cancer; chemotherapy; cognitive impairment; inflammation; myokine; oxidative stress; skeletal muscle dysfunction

DOI:  https://doi.org/10.1002/jcsm.70394