bims-moremu 2026-04-12 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–04–12
thirty-two papers selected by
Anna Vainshtein, Craft Science Inc.

Adrβ2 in skeletal muscle cells is required for exercise-induced Pgc1α but not for metabolic benefits of exercise on diet-induced obesity.
Dual Roles of CCN5/WISP2 in Cytosol and Secretome for Maintaining Muscle Homeostasis and Preventing Sarcopenia.
Exercise induces sex-specific assembly of mitochondrial supercomplexes.
A Distinct Population of Mitochondrial miRNA in Human Male Skeletal Muscle Assessed Before and After Exercise.
Exercise as A Biological Driver of Skeletal Muscle Regeneration and Repair: Implications for Regenerative Rehabilitation.
TGFβ1-loaded extracellular matrix hydrogels promote skeletal muscle stem cell regeneration via m6A-mediated integrin-ERK signaling.
Diving into the unknown: Evidence of enhanced skeletal muscle lactate efflux potential and blood-muscle exchange in competitive breath-hold.
How to train your rodent: Recommendations for the preclinical study of exercise-induced benefits in metabolic research.
Vitamin D binding protein induces skeletal muscle atrophy and contributes to cancer-associated muscle wasting independently of vitamin D status in preclinical models.
Loss of FoxO in skeletal muscle leads to disrupted muscle metabolism and exacerbates starvation-induced hepatic steatosis.
From calcium pump to metabolic hub: emerging genetic phenotypes and metabolic networks of SERCA2 in skeletal muscle.
Perilipin 5 enhances glycogen storage and mitigates excessive fatty acid oxidation in skeletal muscle to alleviate mitochondrial impairment.
A 3D skeletal muscle system for disease modelling and secretome profiling of Duchenne muscular dystrophy.
Engineering a skeletal muscle model to study extracellular vesicle dynamics.
Myonuclear Domain-Associated and Central Nucleation-Dependent Spatial Restriction of Dystrophin Protein Expression.
Metabolite biomarkers present in urine predict alterations in skeletal muscle associated with sarcopenia.
Ageing-related structural and cellular alterations in the mouse muscle-tendon junction.
An Intermediate Mesoderm Premyogenic Niche Supports Early Human Myogenic Lineage Progression.
Injectable antifibrotic drug-loaded hydrogels reduce fibrosis and restore myogenesis by enhancing mitochondrial metabolism and cell mechanics in an in vitro coculture model.
Pharmacological PIK3C2B inhibition rescues XLMTM phenotype in mouse models and identifies molecular markers of disease.
Serpina1e mediates the exercise-induced enhancement of hippocampal memory in male mice.
Skeletal Muscle-Cardiac Muscle Aging: Shared Mechanisms and Multimodal Interventions.
Multi-omics and machine learning reveal a critical mediator of PRKCA in quercetin-mediated protection against Sarcopenia.
Gmppb-mutant mice exhibit dystroglycanopathy symptoms that are rescued with GSK3β inhibition or AAV-mediated GMPPB gene replacement.
Vitamin B3 rescues mitochondrial homeostasis in dexamethasone-induced skeletal muscle atrophy by reducing oxidative stress.
Cell-cycle regulation of sarcomere integrity-Role for Actn2 phosphorylation.
BRD4 directs myofiber identity and metabolic adaptation through CHD4 cooperation.
Positive allosteric modulator of SERCA pump NDC-1171 attenuates cardiac functional decline in mouse model of Duchenne muscular dystrophy.
Acetate and combinations of short-chain fatty acids increase oxidative phenotype and contribute to muscle fiber type shift in myotubes.
Histone Deacetylases Inhibitor Chidamide Mitigates Inflammation and Insulin Resistance by Targeting VDR in Skeletal Muscle Cells.
Emerging roles of microRNAs and other non-coding transcriptome in muscular dystrophies.
17β-estradiol and progesterone have independent and combined effects on C2C12 myotubes following electrical pulse stimulation.

bioRxiv. 2026 Mar 31. pii: 2026.03.27.714812. [Epub ahead of print]

Adrβ2 in skeletal muscle cells is required for exercise-induced Pgc1α but not for metabolic benefits of exercise on diet-induced obesity.

Marco Galvan, Mina Fujitani, Jasmine Dushime, Safia Baset, Bandy Chen, Shreya Thomas, Carlos M Castorena, Joel K Elmquist, Teppei Fujikawa.

β2-Adrenergic receptor ( Adrβ2 ) is the most abundant form of adrenergic receptors in skeletal muscle. Our previous studies have shown that the ventromedial hypothalamic nucleus (VMH) regulates metabolic benefits of exercise, potentially by skeletal muscle Adrβ2 . Although a large body of literature has shown the importance of Adrβ2 on skeletal muscle physiology, it remains unexplored whether skeletal muscle Adrβ2 contributes to metabolic benefits of exercise, such as prevention of diet-induced obesity (DIO). Here, we generated mice lacking Adrβ2 in skeletal muscle cells (SKM Adrβ2 ) and tested whether SKM Adrβ2 is required for metabolic benefits of exercise on DIO. Deletion of SKM Adrβ2 completely abolished the induction of peroxisome proliferator-activated receptor gamma coactivator 1-alpha ( Pgc-1α ) in skeletal muscle by β2-agonist, which is a potent activator of Pgc-1α . Exercise upregulates Pgc-1α, which regulates a broad range of skeletal muscle physiology, including hypertrophy and mitochondrial function. Deletion of SKM Adrβ2 hampers augmented Pgc-1α in skeletal muscle by a single bout of exercise. Intriguingly, we found that deletion of SKM Adrβ2 increased endurance capacity. Further, our data showed that body weight in DIO mice lacking SKM Adrβ2 is comparable to that of control DIO mice during exercise training, suggesting that deletion of SKM Adrβ2 did not affect the metabolic benefits of exercise in DIO. Collectively, our data indicate that SKM Adrβ2 contributes to exercise-induced transcriptional changes and endurance capacity, however, it is not required for exercise benefits on bodyweight in DIO mice.

DOI: https://doi.org/10.64898/2026.03.27.714812
J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70282

Dual Roles of CCN5/WISP2 in Cytosol and Secretome for Maintaining Muscle Homeostasis and Preventing Sarcopenia.

Zile Shen, Zhang Liu, Guowei Huang, Lian Cui, Wenhao Chen, Wenxi Dong, Xialin Yan, Peng Zhang, Zhen Yu.

   BACKGROUND: Sarcopenia is a progressive and systemic skeletal muscle disorder characterized by the decline of muscle mass and function. Despite its early-stage, 'possible sarcopenia' has been emphasized for prompt intervention; there are currently no specific biomarkers for the diagnosis and treatment.
METHODS: RNA sequencing of human skeletal muscle across sarcopenia stages identified CCN5. Adeno-associated virus (AAV) is intramuscularly injected into young C57BL/6J mice to knockdown CCN5 in skeletal muscle. Phenotypic alterations are assessed through behavioural testing, body composition analysis, oil red O staining and transmission electron microscopy. Mechanisms were investigated in C2C12 myotubes using lentiviral infection, Western blotting, immunofluorescence, cellular electron microscopy and seahorse assays. Finally, aged C57BL/6J mice received intramuscular AAV injections to overexpress CCN5 in skeletal muscle, evaluating its therapeutic efficacy against sarcopenia.
RESULTS: Clinical samples included 56 participants (48.2% female; mean age: 63.21 ± 8.76 years). By comparing gene expression in human skeletal muscle across three stages of sarcopenia, we identified CCN5 as a gene exhibiting decreased protein expression in possible sarcopenia stage (approximately 33% reduction, p = 0.0245), with this decline persisting into sarcopenia stage (p = 0.0093). In young mice, CCN5 knockdown induced a sarcopenia-like phenotype, encompassing skeletal muscle dysfunction and myosteatosis (fat mass: p < 0.01; intramyocellular triglyceride: 66.02 ± 3.798 vs. 104.5 ± 8.542 μg/mg tissue, p < 0.01). CCN5 deficiency also impaired mitochondrial content and function, particularly by reducing lipid droplet-mitochondrial (LD-Mt) interaction (approximately 47% reduction, p < 0.05). In C2C12 cells, CCN5 knockdown disrupted lipid metabolism (particularly reduced lipid oxidation, CPT1A: approximately 56% reduction, p < 0.001), promoted lipid accumulation and compromised mitochondrial content and function. Mechanistically, secreted CCN5 enhanced LD-Mt interaction and stimulated mitochondrial biogenesis by activating nuclear β-catenin translocation to enhance FOXO3A-dependent transcription, while intracellular CCN5 mitigated myosteatosis by inhibiting PPARγ signalling. In aged mice, CCN5 overexpression improved skeletal muscle function, reduced myosteatosis (fat mass: p < 0.001; intramyocellular triglyceride: 175.0 ± 11.18 vs. 92.18 ± 10.53 μg/mg tissue, p < 0.001) and restored mitochondrial function.
CONCLUSIONS: CCN5 mitigates myosteatosis and counteracts sarcopenia by promoting mitochondrial biogenesis and enhancing LD-Mt interactions through dual pathways, positioning it as a promising therapeutic target for muscle aging and sarcopenia.

Keywords:  CCN5; lipid droplet‐mitochondria interaction; mitochondrial dysfunction; myosteatosis; sarcopenia

DOI:  https://doi.org/10.1002/jcsm.70282
Cell Rep. 2026 Apr 03. pii: S2211-1247(26)00295-0. [Epub ahead of print]45(4): 117217

Exercise induces sex-specific assembly of mitochondrial supercomplexes.

Jesús R Huertas, Jerónimo Aragón-Vela, Andreas Breenfeldt Andersen, Jacob Bejder, Lars Nybo, Nikolai B Nordsborg, Andrea Rodríguez-Carrillo, José A Enriquez, Sara Cogliati, Rafael A Casuso.

  The mitochondrial respiratory complexes of the electron transport chain (ETC) form supramolecular structures known as supercomplexes (SCs) whose functions remain partially understood. An increase in carbohydrate oxidation, such as that induced by high-intensity contractions within skeletal muscle (SKM), has been proposed to promote the assembly of high molecular weight SCs (HMWSCs). Here, healthy, active young subjects (7 females and 9 males) performed a moderate- followed by a high-intensity exercise bout. We found that males increased the assembly of complex III (CIII) into SCs, particularly HMWSCs, in an intensity-dependent manner within SKM. Females showed a stable content of both HMWSCs and I+III2 SCs during exercise. In contrast, the assembly of CIV into SCs was not promoted by exercise in either sex. These findings indicate that the ETC complex organization can be modulated by exercise, and the mitochondrial supercomplex assembly in human SKM appears to be regulated in a sex-specific manner.

Keywords:  CP: metabolism; CP: molecular biology; electron transport chain; electron transport chain remodeling; high-intensity exercise; human muscle bioenergetics; lactate; mitochondrial complexes; sex-specific mitochondrial adaptation; sexual dimorphism; skeletal muscle; skeletal muscle metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.117217
FASEB J. 2026 Apr 30. 40(8): e71764

A Distinct Population of Mitochondrial miRNA in Human Male Skeletal Muscle Assessed Before and After Exercise.

Jessica L Silver, Danielle Hiam, Stella Loke, Larry Croft, Megan Soria, Adam J Trewin, Søren Nielsen, Séverine Lamon, Glenn D Wadley.

  Initially thought to localize at the cytosol and nucleus only, emerging evidence indicates that miRNAs also localize within mitochondria where they could regulate diverse pathological and physiological processes. Therefore, the aim of the current study was to profile the population of miRNAs in isolated mitochondria and whole-tissue from human skeletal muscle at rest and in response to acute endurance exercise. Twelve healthy males (age 26 ± 4 years, mean ± SD) cycled for 60 min at 70% VO2peak and muscle biopsies were collected at rest, immediately after and 3 h after exercise. The mitochondria were isolated by immunoprecipitation, enzymatically purified, then the resident RNA was sequenced to assess the mitochondrial transcriptome. Small RNA sequencing revealed that mitochondria isolated from male skeletal muscle tissue contain a distinct population of miRNAs. Of the approximately 127 mature miRNAs detected in skeletal muscle mitochondria at each time point, the canonical muscle-specific miRs (myo-miRs) miR-1, miR-133 and miR-206 families constituted on average 45% of total mitochondria miRNA reads. However, none of these canonical myo-miRs were differentially expressed in mitochondria following endurance exercise. One miRNA, hsa-miR-146b-5p, was differentially expressed 3 h after exercise when compared to pre-exercise in both mitochondria (log2 fold-change = 5.4, p = 0.003, FDR = 0.82) and whole muscle tissue (log2 fold-change = 2.3, p < 0.0001, FDR = 0.060) but not when adjusted for multiple testing. Future research is now required to investigate miRNA-mRNA interactions in the mitochondria of skeletal muscle tissue.

Keywords:  exercise; mitochondria; non‐coding RNA; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202500435R
Am J Phys Med Rehabil. 2026 Mar 25.

Exercise as A Biological Driver of Skeletal Muscle Regeneration and Repair: Implications for Regenerative Rehabilitation.

Thomas A Rando.

  The Joel A. DeLisa Lecture on regenerative rehabilitation was presented by Dr. Thomas Rando on February 27, 2025, at the Association of Academic Physiatrists Annual Scientific Meeting. This article follows the key themes presented in that lecture, exploring the regenerative potential of exercise as a biophysical stimulus and focusing on its ability to modulate muscle stem cell (MuSC) function and enhance tissue repair following muscle injury. In aged mice, exercise restores youthful properties to MuSCs, thereby enhancing regenerative capacity that declines with age. In models of volumetric muscle loss (VML), exercise improves the engraftment and integration of transplanted MuSCs by promoting myogenesis, angiogenesis, and reinnervation. Additionally, exercise shifts systemic and local immune responses toward a pro-regenerative state, enhancing stem cell function across multiple tissues. Exercise acts as a potent, non-invasive regenerative intervention with direct effects on stem cell biology and tissue repair. These findings highlight the potential for integrating exercise-based rehabilitation with emerging biologic therapies in clinical practice, offering new strategies for improving recovery after injury. In this context, physiatrists and physical therapists will play a central role in the emerging field of regenerative rehabilitation.

Keywords:  Exercise; Muscle; Regenerative Rehabilitation; Stem Cells

DOI:  https://doi.org/10.1097/PHM.0000000000002988
J Transl Med. 2026 Apr 06.

TGFβ1-loaded extracellular matrix hydrogels promote skeletal muscle stem cell regeneration via m6A-mediated integrin-ERK signaling.

Menghai Zhu, Peng Zou, Gang Chen, Chong Lian, Benggang Qin.

   BACKGROUNS: Skeletal muscle stem cells (SkMSCs) are essential for muscle regeneration and represent a promising therapeutic target for muscle disorders. However, effective strategies to precisely regulate SkMSC fate by integrating biochemical and mechanical cues remain limited.
METHODS: A decellularized extracellular matrix (ECM) hydrogel replicating the native muscle microenvironment was developed. The hydrogel was loaded with TGFβ1 and applied to SkMSCs in vitro and in Sprague-Dawley rat models. Signaling activation, m6A methylation of integrin mRNA, ERK phosphorylation, and functional outcomes were assessed through molecular and physiological analyses.
RESULTS: The TGFβ1-loaded ECM hydrogel significantly enhanced SkMSC proliferation and differentiation by activating ERK signaling. Mechanistically, TGFβ1 promoted m6A methylation of integrin mRNA, leading to sustained ERK phosphorylation. In vivo, ECM hydrogels and TGFβ1 synergistically improved SkMSC function and muscle regeneration via m6A-modulated integrin signaling.
CONCLUSION: This study reveals a novel m6A-mediated pathway that integrates biochemical (TGFβ1) and mechanical (ECM hydrogel) signals to direct SkMSC fate and provides a promising biomaterial-based strategy for treating muscle diseases through microenvironment-mimicking regenerative engineering.

Keywords:  N6-methyladenosine (m6A) RNA; Skeletal muscle extracellular matrix hydrogel; Skeletal muscle stem cells; TGFβ1

DOI:  https://doi.org/10.1186/s12967-026-08092-3
J Physiol. 2026 Apr 09.

Diving into the unknown: Evidence of enhanced skeletal muscle lactate efflux potential and blood-muscle exchange in competitive breath-hold.

Antonis Elia, Matthew Lees, John O'Hara, Nathan Hodson, Jordan Acheson, Oliver Wilson, Paul Parker, Matthew Barlow.

  The characterization of skeletal muscle phenotypes in diving populations remains one of the least explored domains of breath-hold physiology, representing a critical gap in our understanding of how skeletal muscle adapts to the unique demands of breath-hold diving. Accordingly the present study investigated specific markers of skeletal muscle structure and metabolism in competitive breath-hold divers. Twenty males volunteered to participate in this study (10 competitive breath-hold divers; 10 non-divers), matched for age, body size and whole-body aerobic capacity ( V̇O2max${\dot{\mathrm{V}}}\rm{O}_{\rm{2max}}$ ). A percutaneous skeletal muscle biopsy was obtained from the m. vastus lateralis to quantify capillarization, fibre-type distribution (i.e. types I, IIa and II other), protein content of mitochondrial complexes, monocarboxylate transporter (MCT) isoforms and citrate synthase activity. MCT4 content was 28% higher in breath-hold divers compared to non-divers (P = 0.020), whereas MCT1 and citrate synthase activity showed no between-group differences (P ≥ 0.161). Complex V content was higher in the non-divers (P = 0.049), whereas no between-group differences were noted for complexes I, II, III and IV (P ≥ 0.253). Capillarization was significantly higher in breath-hold divers (P ≤ 0.048), whereas fibre-type distribution did not differ between groups (P = 0.999). Competitive breath-hold divers exhibited skeletal muscle characteristics indicative of enhanced blood-muscle exchange capacity and augmented lactate efflux potential. Such adaptations may confer an advantage during prolonged breath-holds by preserving glycolytic function and maintaining redox homeostasis. In recovery these traits likely facilitate more efficient clearance of metabolic byproducts. KEY POINTS: The skeletal muscle phenotype of breath-hold divers remains poorly characterized, limiting understanding of how skeletal muscle adapts to the physiological demands of prolonged breath-holding. This study compared skeletal muscle structure and metabolic markers between competitive breath-hold divers and non-diving controls matched for age, body size and whole-body aerobic capacity. Breath-hold divers exhibited greater skeletal muscle capillarization, indicating an enhanced capacity for blood-muscle exchange. They also showed an increased potential to remove lactate from skeletal muscle tissue. These adaptations likely support sustained glycolytic function and redox balance during prolonged breath-holds, while facilitating more efficient clearance of metabolic byproducts during recovery.

Keywords:  breath‐hold divers; capillarization; citrate synthase activity; fibre type; monocarboxylate transporters; oxidative phosphorylation complexes

DOI:  https://doi.org/10.1113/JP290732
Cell Metab. 2026 Apr 06. pii: S1550-4131(26)00099-9. [Epub ahead of print]

How to train your rodent: Recommendations for the preclinical study of exercise-induced benefits in metabolic research.

Steffen H Raun, Tang Cam Phung Pham, Mark R Viggars, Satoru Ato, Yuta Takagaki, Zhen Yan, Katrien De Bock, Troy A Hornberger, Erik A Richter, Johan Auwerx, Laurie J Goodyear, Mark A Febbraio, Karyn A Esser, Lykke Sylow.

  Regular physical activity is fundamental in promoting health and longevity. Numerous studies highlight the beneficial effects of exercise on metabolic parameters, but uncovering the mechanisms underlying the complex cellular responses and adaptations remains challenging in humans. Thus, animal models, in particular rodent models, have been indispensable for unveiling the underlying biological responses to exercise. Studies with precise exercise designs and diverse genetic models are vital for uncovering mechanistic pathways and informing pharmacological and behavioral strategies to combat non-communicable chronic diseases. Despite decades of research, recommendations to design preclinical exercise interventions and to measure key metabolic exercise adaptations in rodents have yet to be established. To enhance animal-to-human translation and ensure reproducibility, exercise studies must be rigorously controlled. Here, we outline key experimental considerations in rodents, including protocol design, exercise modality, sex, age, housing temperature, and circadian rhythm, to guide best practices and promote standardization and translation in future preclinical exercise studies.

Keywords:  adipose tissue; exercise; hypertrophy; metabolism; mouse; muscle; training

DOI:  https://doi.org/10.1016/j.cmet.2026.03.005
Nat Commun. 2026 Apr 10.

Vitamin D binding protein induces skeletal muscle atrophy and contributes to cancer-associated muscle wasting independently of vitamin D status in preclinical models.

Tommaso Raiteri, Simone Reano, Andrea Scircoli, Ivan Zaggia, Alessandro Antonioli, Stefania Faletti, Francesco Favero, Marcello Manfredi, Giuliana Pelicci, Davide Corà, Lorenza Scotti, Richard R Kew, Flavia Prodam, Paolo E Porporato, Nicoletta Filigheddu.

The maintenance of skeletal muscle is of pivotal importance, as its loss is often associated with progressive pathologies, generally worsening the prognosis. Increased levels of vitamin D binding protein (VDBP) were reported in diseases susceptible to muscle wasting, including several tumors. We hypothesized that VDBP might participate in muscle wasting and investigated its direct effects on skeletal muscle homeostasis. Here, we demonstrate that VDBP induces atrophy independently of vitamin D. In C2C12 myotubes, we identified intracellular actin dynamics perturbation and subsequent mitochondrial fragmentation as the main molecular mechanisms of VDBP-induced atrophy. Coherently, the ectopic introduction of VDBP in mice lacking the protein (Gc-knockout mice) induced muscle atrophy and decreased strength. Finally, we present proof-of-concept evidence that VDBP contributes to cancer-associated muscle wasting in Lewis lung carcinoma (LLC)-bearing male mice. Altogether, these findings provide novel insights into the biological function of VDBP as a pro-atrophic hormone with potential implications for the treatment of muscle wasting.

DOI: https://doi.org/10.1038/s41467-026-71530-9
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2600036123

Loss of FoxO in skeletal muscle leads to disrupted muscle metabolism and exacerbates starvation-induced hepatic steatosis.

Mamoru Oyabu, Manato Sakaue, Atsushi Kubo, Kiyoshi Yoshioka, Runa Kawaguchi, Haruki Yamamoto, Yuzuka Kinjo, Jungin Kwon, Hiroki Nishi, Daisuke Yamanaka, Tomoki Sato, Daiki Mori, Takahiro Eguchi, Naoki Ito, So-Ichiro Fukada, Takayoshi Suganami, Shinji Miura, Yusuke Ono, Fumihiko Hakuno, Shin-Ichiro Takahashi, Tsuyoshi Goto, Yasutomi Kamei.

  Up to a third of the global population is afflicted by metabolic dysfunction-associated steatotic liver disease with excessive triglyceride accumulation in the liver. Prolonged fasting rapidly causes hepatic steatosis via excessive influx of free fatty acids from adipose tissue. However, it is unclear whether skeletal muscle is involved in the etiology of hepatic steatosis during starvation. Here, we demonstrate a critical connection between the liver and skeletal muscle via FoxO transcription factors. During prolonged fasting, hepatic steatosis was exacerbated in skeletal muscle-specific FoxO-deficient mice (mFoxO1,3,4-/-) despite preventing skeletal muscle wasting, suggesting that skeletal muscle FoxOs prevent hepatic steatosis during energy deprivation. FoxO deficiency in skeletal muscle weakened fatty acid oxidation and induced abnormal glycogen accumulation in skeletal muscle during fasting. Mechanistically, the starvation-induced transcriptional regulation of triglyceride lipase was attenuated in skeletal muscle of FoxO-deficient mice. Conversely, skeletal muscle-specific FOXO1 overexpression was sufficient to increase triglyceride lipase in vivo and protected the liver from Western diet-induced metabolic dysfunction-associated steatohepatitis-like phenotype. Taken together, our results demonstrate the physiological importance of skeletal muscle FoxO signaling on the liver pathophysiology.

Keywords:  FoxO; MAFLD; hepatic steatosis; muscle metabolism; starvation

DOI:  https://doi.org/10.1073/pnas.2600036123
Front Physiol. 2026 ;17 1775444

From calcium pump to metabolic hub: emerging genetic phenotypes and metabolic networks of SERCA2 in skeletal muscle.

Shunyi Lei, Yanlong Qu, Jin Yan, Fei Nan, Siyao Liu, Wenhao Pan, Chaoyue Yu.

  For decades, the sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) in skeletal muscle was primarily recognized for its role in orchestrating slow-twitch muscle fiber relaxation-an essential process dependent on its ability to actively sequester cytoplasmic Ca2+ into the sarcoplasmic reticulum (SR) lumen, thereby sustaining intracellular Ca2+ homeostasis critical for muscle contraction-relaxation cycles. However, recent genetic and molecular biology studies have expanded the function of SERCA2 to a core hub integrating Ca2+ signaling, metabolic homeostasis, and endoplasmic reticulum (ER) stress. This novel function is underpinned by a sophisticated multi-layered regulatory network spanning from transcription to post-translational, which ensures that SERCA2 expression and activity dynamically adapt to the dual demands of Ca2+ homeostasis maintenance and metabolic signaling demands. Dysregulation of this network or mutations in the ATP2A2 gene have been linked to hereditary myopathies, while SERCA2 dysfunction is also a key driver of muscle atrophy and insulin resistance in pathological conditions such as chronic inflammation and obesity. As a metabolic hub, the core mechanism of SERCA2 lies in its role as a critical node connecting local Ca2+ signaling to systemic metabolism through regulating ER Ca2+ homeostasis and SERCA2-SLN uncoupling (mediating non-shivering thermogenesis). Therapeutic strategies targeting SERCA2, including small-molecule activators such as CDN1163, AAV9-SERCA2a gene therapy, mimetic peptides, and exercise interventions, have demonstrated potential in treating various systemic diseases by restoring the "calcium pump-metabolism" dual functions of SERCA2. However, the hierarchical regulatory logic linking SERCA2's calcium-handling and metabolic functions remains fragmented, and subtype-specific therapeutic strategies are undefined. This review synthesizes recent breakthroughs to propose a unified "calcium-metabolism coupling" framework and identifies translational gaps for precision targeting.

Keywords:  ATP2A2; ER stress; SERCA2; metabolic hub; non-shivering thermogenesis; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2026.1775444
Biochim Biophys Acta Mol Cell Res. 2026 Apr 08. pii: S0167-4889(26)00043-1. [Epub ahead of print] 120146

Perilipin 5 enhances glycogen storage and mitigates excessive fatty acid oxidation in skeletal muscle to alleviate mitochondrial impairment.

Yuqiao Xu, Xing Gao, Shenhui Xu, Lele Jian, Jiankkuan Shi, Yuanlin Zhao, Yuying Wang, Ying Yang, Yuan Yuan, Qiulong Dai, Qian Zhang, Jing Li, Lijun Zhang.

  Perilipin 5 (Plin5) is a lipid droplet-associated protein that regulates lipid hydrolysis and mitochondrial oxidative metabolism, and is highly expressed in skeletal muscle. Its role in skeletal muscle glucose metabolism and its relevance to mitochondrial myopathy (MM) remain unclear. We used Plin5-knockout (Plin5-KO) mice in exhaustive swimming tests to assess endurance and anaerobic exercise capacity. Glucose uptake was measured using 2-NBDG; glucose, lactate, NADH/NAD+ ratio, and fatty acid oxidation (FAO) rate were determined with commercial kits. Mitochondrial ultrastructure was evaluated via electron microscopy, and immunoblotting was used to assess proteins related to glucose-lipid metabolism. Muscle biopsies from 26 patients with mitochondrial myopathy were examined morphologically and for Plin5 expression by immunohistochemistry. Plin5-KO mice showed impaired anaerobic capacity, markedly reduced glycogen storage (especially after-exercise), increased lactate production, and reduced AKT phosphorylation, indicating insulin resistance. Mechanistically, Plin5 deficiency promoted excessive FAO, worsened mitochondrial damage, and elevated the NADH/NAD+ ratio, shifting glucose metabolism toward anaerobic glycolysis with excess lactate output. In contrast, Plin5 overexpression improved insulin sensitivity and reduced FAO in skeletal muscle cells. In MM patients, Plin5 expression in skeletal muscle tended to be negatively associated with blood lactate levels. These findings indicate that Plin5 may play a crucial role in improving glycolipid metabolism and protecting mitochondrial function by enhancing glycogen storage and reducing excessive FAO in skeletal muscle cells.

Keywords:  Insulin resistance; Lactate; Mitochondrial dysfunction; Myopathy; NADH/NAD+; Perilipin 5

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120146
Skelet Muscle. 2026 Apr 10.

A 3D skeletal muscle system for disease modelling and secretome profiling of Duchenne muscular dystrophy.

Mariam Zouhair, Marianna Cosentino, Ludovica Apa, Desiree Genovese, Sasha Marco Maria Di Iorio, Carmine Nicoletti, Domenico Liguoro, Giorgia Nanni, Simone Dinarelli, Alessandro Palma, Caterina Boccia, Laura Forcina, Silvia Sideri, Rita Mancini, Monica Ballarino, Antonio Musarò.



Keywords:  Modelling Duchenne Muscular Dystrophy (DMD); Muscle-derived extracellular vesicles (EVs); Skeletal muscle microenvironment; Skeletal muscle tissue engineering; Three-dimensional (3D) in vitro models

DOI:  https://doi.org/10.1186/s13395-026-00423-8
J Tissue Eng. 2026 Jan-Dec;17:17 20417314261427541

Engineering a skeletal muscle model to study extracellular vesicle dynamics.

María Fernández-Rhodes, Rowan Rimington, Jacob Fleming, Andrew J Capel, Owen G Davies, Mark P Lewis.

  Skeletal muscle (SM) functions both mechanically and as a secretory organ, releasing myokines and extracellular vesicles (EVs) involved in myogenic regulation and inter-tissue communication. While 3D bioengineered SM models are widely used for studying muscle physiology, few have been applied to investigate EV dynamics. This study optimised a 3D SM model to support mature myotube formation and evaluated its utility for SM-EV analysis. Myosin heavy chain expression was reduced at higher Matrigel® concentrations (40%-60% v/v), highlighting the importance of matrix composition in model design. EVs were successfully isolated using size-exclusion chromatography and ultrafiltration, with yield influenced by cellular differentiation status. Common EV markers (Alix, CD9, CD63) were consistently expressed. Importantly, sarcoplasmic reticulum markers α- and β-sarcoglycan were identified in SM-EV preparations. These findings validate our SM model as a defined platform for studying SM-EV biology and defining molecular cargo.

Keywords:  3D culture; extracellular vesicles; model; myoblast; skeletal muscle; tissue engineering

DOI:  https://doi.org/10.1177/20417314261427541
J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70284

Myonuclear Domain-Associated and Central Nucleation-Dependent Spatial Restriction of Dystrophin Protein Expression.

Katarzyna Chwalenia, Vivi-Yun Feng, Nicole Hemmer, John C W Hildyard, Liberty E Roskrow, Richard J Piercy, Eric T Wang, Annemieke Aartsma-Rus, Maaike van Putten, Matthew J A Wood, Thomas C Roberts.

   BACKGROUND: The restoration of uniformly distributed dystrophin protein expression is an important consideration for the development of advanced therapeutics for Duchenne muscular dystrophy (DMD).
METHODS: We have generated a novel genetic mouse model (mdx52-XistΔhs) that expresses variable and nonuniformly distributed dystrophin protein from birth as a consequence of skewed X-chromosome inactivation. mdx52-XistΔhs myofibers are heterokaryons containing a mixture of myonuclei expressing either wild-type or mutant dystrophin alleles in a mutually exclusive manner, resulting in dystrophin protein being spatially restricted to corresponding dystrophin-expressing myonuclear domains. This phenotype models the situation in female dystrophinopathy and dystrophic muscle in which dystrophin has been incompletely restored by partially effective experimental therapeutics. Dystrophin distribution was assessed in mdx52-XistΔhs muscle sections and isolated single myofibers by immunostaining and RNA-FISH analysis.
RESULTS: Total dystrophin expression increased by ~2.8-fold (p < 0.010) in aged (60-week-old) mdx52-XistΔhs mice relative to 6-week-old adults, suggestive of an aging-associated accumulation of dystrophin-expressing myonuclei through positive selection, although this was insufficient to resolve sarcolemmal dystrophin patchiness. Nonuniformly distributed dystrophin conferred partial protection against pathology-related muscle turnover in an expression-level-dependent manner in both adult and aged mdx52-XistΔhs mice compared to mice expressing no dystrophin. Isolated mdx52-XistΔhs myofibers exhibited patchy 'zebra-like' banding of dystrophin sarcolemmal coverage that colocalized with β-dystroglycan but not neuronal nitric oxide synthase, which was uniformly distributed. Systematic classification of isolated mdx52-XistΔhs myofibers revealed unexpected and profound differences associated with central nucleation, with dystrophin found to be absent in centrally nucleated myofibers and myofiber segments. Muscle injury alone was insufficient to recapitulate this phenomenon, suggesting that it is a feature of the dystrophic environment. Dmd mRNA was found to be present throughout centrally nucleated segments, and proteins such as titin and F-actin were uniformly distributed, suggesting that dystrophin is specifically repressed at the protein level in these regions. The microtubule network was moderately disrupted in mdx52-XistΔhs 'zebra-banded' fibers, but this effect was not different between dystrophin-positive and dystrophin-negative myofiber subdomains. By contrast, centrally nucleated mdx52-XistΔhs myofibers exhibited severe microtubule network disruption.
CONCLUSIONS: These findings reveal new insights into the importance of dystrophin spatial localization and identify a previously unappreciated barrier to effective therapeutic dystrophin restoration, particularly within regenerated or centrally nucleated myofibers.

Keywords:  DMD; X‐chromosome inactivation; central nucleation; dystrophin; myonuclear domain

DOI:  https://doi.org/10.1002/jcsm.70284
Front Aging. 2026 ;7 1736916

Metabolite biomarkers present in urine predict alterations in skeletal muscle associated with sarcopenia.

Rafaela Andrade-Vieira, Hirad A Feridooni, Alyne Teixeira, Dylan Deska-Gauthier, Xingjian Chang, Tobias Karakach, Rebecca Moyer, John P Frampton.

   Introduction: Sarcopenia, characterized by the progressive loss of skeletal muscle mass and strength with age, is associated with adverse health outcomes and reduced health span in aging populations. Early detection is critical for implementing preventive strategies; however, current diagnostic methods are often costly, specialized, and not suitable for routine screening. This study aimed to identify metabolite biomarkers associated with early alterations in muscle metabolism that may support accessible screening approaches.
Methods: In this cross-sectional observational study, serum samples from 200 individuals aged 550-70 years from the general population were analyzed. Participants completed the International Physical Activity Questionnaire (IPAQ). In a subset of 60 participants, urine samples were also collected, and participants underwent additional assessments including the Short Physical Performance Battery (SPPB), dual-energy X-ray absorptiometry (DXA), IPAQ, and a supplementary health questionnaire. Targeted metabolomic analyses were performed to identify metabolites associated with early sarcopenia-related metabolic changes.
Results: A panel of metabolites in serum-L-glutamic acid, xanthine, taurine, succinate, and L-carnitine-was associated with early alterations in muscle metabolism. These metabolites were also detectable in urine samples. Importantly, predictive performance for sarcopenia-related changes was observed when the metabolites were analyzed as a combined panel rather than as individual biomarkers.
Conclusion: Our findings identify a metabolite panel detectable in urine that reflect early metabolic alterations associated with sarcopenia. This panel provide a foundation for developing accessible screening tools to support early detection and preventive strategies for muscle health decline in aging populations.

Keywords:  aging; metabolomic and musculoskeletal health; metabolomics; musculoskeletal health; sarcopenia; urinary biomakers

DOI:  https://doi.org/10.3389/fragi.2026.1736916
Biogerontology. 2026 Apr 04. pii: 80. [Epub ahead of print]27(3):

Ageing-related structural and cellular alterations in the mouse muscle-tendon junction.

Chavaunne T Thorpe, Nodoka Iwasaki.

  The muscle-tendon junction (MTJ) is a specialised interface between muscle and tendon and transmits muscle-generated force to the tendon. The MTJ is particularly vulnerable to injuries compared to muscle and tendon and becomes more injury prone with age. Despite its clinical importance, the mechanisms driving MTJ ageing and age-related functional deterioration remain poorly understood. In this study, young (3-month-old) and old (23-month-old) male mice were used to provide the first comprehensive three-dimensional characterisation of age-related structural and cellular changes at the mouse Achilles MTJ. This was achieved using the high-resolution imaging techniques, micro-computed tomography (µCT) and confocal microscopy. µCT analysis revealed a 27% reduction in muscle fibre diameter with age, accompanied by a trend toward increased MTJ surface area and a 19% reduction in pennation angle, which may indicate diminished force generation capacity. Confocal imaging showed a 49% reduction in endothelial cell volume (VWF-labelled) in the old mouse muscle-tendon unit, suggesting a loss of vascularity. In situ hybridisation demonstrated increased expression of senescence markers p16 and p21 in endothelial and MTJ-specific cells, with MTJ-specific cells showing the greatest accumulation of p16 and p21 (270% and 310% increases, respectively) with age, and immunofluorescence also showed increased expression of p21. These findings suggest that vascular and MTJ-specific cells are particularly susceptible to ageing and may collectively contribute to the age-related functional decline of the MTJ. Understanding these mechanisms may help to develop targeted therapeutic strategies to preserve or restore MTJ integrity and function in ageing populations.

Keywords:  Ageing; Endothelial cells; Immunolabelling; Muscle tendon junction; Senescence; µCT

DOI:  https://doi.org/10.1007/s10522-026-10428-x
bioRxiv. 2026 Mar 31. pii: 2026.03.28.715044. [Epub ahead of print]

An Intermediate Mesoderm Premyogenic Niche Supports Early Human Myogenic Lineage Progression.

Olga G Jaime, Katherine F Bazan, Angela Li, Asja A Deai, Anita Lakatos, Michael R Hicks.

Transient cell states that precede and support human myogenic lineage commitment, and the intrinsic and extrinsic signals that control them, remain poorly defined in vitro. Here, we used longitudinal single-nucleus profiling, together with a SIX1:H2B-GFP hPSC reporter for lineage tracing, resolved previously uncaptured transient intermediates and sequential waves of human myogenesis across differentiation and in vivo . We show that hPSC-directed myogenesis gives rise in parallel to paraxial mesoderm and a transient PAX8+ intermediate mesoderm population that forms a 3-dimensional pre-myogenic niche supporting the PAX3-to-PAX7 myogenic progenitor transition. LIANA+ analysis further identified a temporally restricted BMP7-BMPR1B interaction, together with laminin-linked signaling, between PAX8+ niche cells and skeletal muscle progenitors before commitment. We further show that dynamic SIX1 cofactor switching, including EYA3 activity, is required for PAX3-to-PAX7 progression, and that disruption of this program compromises multi-lineage niche integrity. Together, these findings define how transient niche populations and intrinsic regulatory networks coordinate early human myogenic lineage progression and provide a human in vitro platform to study parallel intermediate and paraxial mesoderm development during myogenesis.
Highlights: SIX1+PAX8+ niche progenitors promote myogenic differentiation via BMP7- and laminin-dependent signaling.Loss of SIX1-EYA3 activity disrupts the pre-myogenic niche and impairs the PAX3-to-PAX7 transitionMulti-omics single-cell optimal transport resolves previously uncaptured transient intermediates and sequential waves of human myogenesisSIX1 lineage tracing identifies CREB5 as a top regulator of the PAX7+ state in human myogenesis.

DOI: https://doi.org/10.64898/2026.03.28.715044
Mater Today Bio. 2026 Jun;38 103033

Injectable antifibrotic drug-loaded hydrogels reduce fibrosis and restore myogenesis by enhancing mitochondrial metabolism and cell mechanics in an in vitro coculture model.

Varshiny Gopinath, Nirav Patel, Ramamurthy Chitteti, Nidhish Balakrishnan, Manesh Kumar Panner Selvam, Hemal H Patel, Ratnesh Lal, Vignesh Muthuvijayan, Mahadevan Rajasekaran.

  Aging significantly alters cellular mechanics and mitochondrial physiology, with chronic low-grade inflammation (inflammaging). However, its role in skeletal muscle atrophy and fibrosis is poorly understood. This study addressed the unresolved mechanism using a 2.5D coculture model of RAW264.7 macrophages and C2C12 myoblasts, exposed to lipopolysaccharide (LPS, a fibrosis inducer), with a focus on myogenesis, fibrogenesis, cellular stiffness, and mitochondrial metabolism. Paracrine signals from LPS-stimulated macrophages decreased myogenic markers MyHC and MyoG, increased fibrosis markers, and elevated fibrotic cell stiffness. Mitochondrial metabolism was disrupted, indicated by lowered maximal respiration and increased proton leak, demonstrating impaired energy production. To explore the alleviation of muscle atrophy and promote regeneration, a biomaterial-based therapeutic approach involving the use of pirfenidone (PFD, pulmonary antifibrotic drug)-loaded hydrogels composed of silk fibroin and agarose was investigated. Treatment reduced fibrotic stiffness by ∼40%, increased myotube formation by 33%, improved mitochondrial function, and restored mitochondrial structure, with a 20% increase in maximal respiration and a 50% decrease in proton leak in the seahorse assay. Sustained release of PFD from tissue-mimicking hydrogels effectively suppressed the expression of fibrotic markers such as α-SMA and COL1 while simultaneously increasing the expression of myogenic genes. RNA transcriptomics further corroborated the upregulation of myogenic pathways and the downregulation of fibrogenic signaling. This study highlights the potential of PFD-loaded hydrogels as a novel therapeutic strategy to target inflammation-induced muscle fibrosis and promote skeletal muscle regeneration, demonstrating both the prevention of fibrotic progression and reversal of the established inflammation-induced fibrosis in vitro, with promising translational potential for treating sarcopenia.

Keywords:  Fibrogenesis; Fibrotic cell stiffness; Mitochondrial metabolism; Myogenesis; Pirfenidone-loaded hydrogel

DOI:  https://doi.org/10.1016/j.mtbio.2026.103033
JCI Insight. 2026 Apr 09. pii: e198568. [Epub ahead of print]

Pharmacological PIK3C2B inhibition rescues XLMTM phenotype in mouse models and identifies molecular markers of disease.

Andrew Shearer, Melissa L Brooks, Maxine M Chen, Thiwanka Samarakoon, John Hsieh, Gramoz Kondakci, Emanuele Perola, Jason Brubaker, Kristina Fetalvero, Stefanie Schalm, Joana Caetano-Lopes.

  X-linked myotubular myopathy (XLMTM) is a rare genetic disorder that typically presents at birth with progressive muscle weakness and respiratory difficulties and is caused by myotubularin-1 (MTM1) gene mutations. Here we examine the role of phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (PIK3C2B), a lipid kinase that interacts with MTM1, in XLMTM in various models. We examined the effect of BLU3797, a novel, highly potent, selective, orally bioavailable PIK3C2B inhibitor, on survival, muscle development, myofiber phenotypes, and gene expression in MTM1-/y mice. PIK3C2B-deficient XLMTM animals demonstrated increased survival, restored muscle function, fewer myofibers with centralized nuclei, and normalization of disease-associated molecular markers. BLU3797 alleviated the XLMTM phenotype in a dose-dependent and reversible manner. Loss of functional PIK3C2B in XLMTM mice promoted a more differentiated, adult-like myofiber profile, which was strongly associated with normalization of disease surrogates and a reduction in markers of early muscle development and regeneration. BLU3797 treatment appears to modulate the expression of microRNAs associated with satellite cell activation and myofiber fusion. These findings indicate that PIK3C2B inhibition with BLU3797 effectively reverses the XLMTM disease phenotype by enhancing muscle function and promoting development toward a more mature state.

Keywords:  Development; Drug therapy; Genetics; Muscle biology; Neuromuscular disease; Protein kinases

DOI:  https://doi.org/10.1172/jci.insight.198568
Nat Commun. 2026 Apr 09.

Serpina1e mediates the exercise-induced enhancement of hippocampal memory in male mice.

Hyunyoung Kim, Sanghee Shin, Jeongho Han, Kangseok Yun, Jong-Seo Kim, Hyungju Park.

Exercise enhances learning and memory, not only through improved cardiometabolic but also through body-brain interactions mediated by secreted factors. Given the prominent role of skeletal muscle during exercise, muscle-derived factors, myokines, are believed to mediate the exercise-induced cognitive enhancements. Here, we demonstrate that intramuscular Serpina1e is upregulated following exercise in male mice. Systemic delivery of recombinant Serpina1e or intramuscular overexpression of Serpina1e reproduces exercise-induced memory enhancements in sedentary male mice. Conversely, muscle-specific depletion of Serpina1e abolishes hippocampal memory enhancement, indicating a requirement of muscle-derived Serpina1e for these cognitive benefits. Mechanistically, elevated plasma Serpina1e stimulates neurogenesis, brain-derived neurotrophic factor (BDNF) expression, and neurite growth in the hippocampus by crossing the blood-cerebrospinal fluid (CSF) and blood-brain barrier. Our findings identify Serpina1e as a key mediator of skeletal muscle-brain interaction that enables the beneficial effects of exercise on cognitive function.

DOI: https://doi.org/10.1038/s41467-026-71420-0
JACC Adv. 2025 Dec;pii: S2772-963X(25)00777-X. [Epub ahead of print]4(12 Pt 1): 102347

Skeletal Muscle-Cardiac Muscle Aging: Shared Mechanisms and Multimodal Interventions.

Kriti Kalra, Patrick Berchie, Sahib Singh, Yasser Jamil, Nishok Karthikeyan, Oliver Glen Ancheta, Ardeshir Hashmi, Trejeeve Martyn, Samir Kapadia, Venu Menon, David A Zidar, Abdulla A Damluji.

  The progressive age-related deterioration of skeletal and cardiac muscle represents a critical determinant of morbidity and mortality in older adults. This state-of-the-art review examines the interconnected molecular mechanisms underlying muscle aging, including mitochondrial dysfunction, immunosenescence, oxidative stress, hormonal dysregulation, and anabolic resistance. These shared pathways manifest as sarcopenia in skeletal muscle and remodeling in cardiac tissue, creating a complex relationship that accelerates functional decline. Chronic diseases, including heart failure, diabetes, and hypertension, amplify these degenerative processes through metabolic dysregulation and systemic inflammation. Evidence-based interventions combining multicomponent exercise programs (resistance, aerobic, and balance training), optimized protein intake (1.0-1.5 g/kg/day), and emerging pharmacological agents have demonstrated efficacy in preserving muscle mass and function. Digital health technologies offer novel monitoring and intervention delivery platforms. Future directions include expounding on muscle-heart crosstalk mechanisms, developing predictive biomarkers, and implementing integrated care models to address the growing burden of age-related physical decline.

Keywords:  cardiovascular diseases; older adults; sarcopenia

DOI:  https://doi.org/10.1016/j.jacadv.2025.102347
Phytomedicine. 2026 Mar 27. pii: S0944-7113(26)00356-9. [Epub ahead of print]155 158121

Multi-omics and machine learning reveal a critical mediator of PRKCA in quercetin-mediated protection against Sarcopenia.

Xinjie Wu, Zhonghao Li, Xin Xu, Zhimu Yuan, Zhizhuo Li, Benlong Shi, Saihu Mao, Jun Qiao, Zhenhua Feng, Qingyu Zhang.

   BACKGROUND: Sarcopenia, the age-associated loss of skeletal muscle mass and function, poses a growing public health challenge. Although dietary flavonoids have been proposed as protective agents due to their antioxidant and anti-inflammatory properties, their precise roles in sarcopenia prevention remain unclear.
METHODS: We integrated data from the National Health and Nutrition Examination Survey (NHANES, 2017-2018) and the Food and Nutrient Database for Dietary Studies (FNDDS) to examine the relationship between flavonoid intake and sarcopenia risk. Using machine learning, LASSO, CatBoost, and SHAP interpretation, we identified key predictive variables. Drug-target genes were retrieved from Drug-Gene Interaction Database (DGIdb), followed by Mendelian randomization using GWAS and QTL summary data. Bulk RNA-seq and single-cell RNA-seq were analyzed to explore molecular pathways. Experimental validation was performed using C2C12 myoblast differentiation assays.
RESULTS: After propensity score matching, BMI, gender, and PIR remained significantly associated with sarcopenia. Machine learning identified flavonoids, particularly quercetin, as key predictors. SHAP values revealed an inverse, dose-dependent association between quercetin intake and sarcopenia predictions in the model. SMR analysis linked quercetin to genes such as PRKCA. Bulk RNA-seq enrichment analysis revealed enrichment of protein kinase C (PKC)-related signaling and downstream MAPK/ERK pathways after quercetin treatment, while scRNA-seq data identified Prkca as a quercetin-responsive gene in muscle fiber populations. Experimental results confirmed that quercetin promotes myoblast differentiation via PRKCA upregulation, accompanied by enhanced ERK1/2 phosphorylation, an effect abolished by the PRKCA inhibitor Go6976.
CONCLUSIONS: Our integrative multi-omics and experimental approach reveals that quercetin is associated with sarcopenia and influence muscle differentiation through PRKCA-ERK signaling. These findings support the potential of flavonoids as targeted dietary interventions for age-related muscle decline.

Keywords:  Flavonoids; Machine Learning; Mendelian Randomization; PRKCA; Quercetin; Sarcopenia

DOI:  https://doi.org/10.1016/j.phymed.2026.158121
Nat Commun. 2026 Apr 09.

Gmppb-mutant mice exhibit dystroglycanopathy symptoms that are rescued with GSK3β inhibition or AAV-mediated GMPPB gene replacement.

Ziwei Fu, Tongchao Wang, Chenyang Zhang, Tianyu Qi, Yanyan Chen, Ju Yang, Hua Yang, Bing Yan, Baoming Gong, Weiqiao Lu, Sushan Luo, Ying Liu, Lei Sun, Hao Jiang, Bo Chen, Zhao Zhang, Xiuping Liu, Yuxiang Wang.

Mutations in GDP-mannose pyrophosphorylase B (GMPPB) cause dystroglycanopathy, a rare neuromuscular disorder characterized by α-dystroglycan hypoglycosylation, yet the pathogenic mechanisms and therapeutic options remain poorly defined. To dissect the molecular basis of dystroglycanopathy, we generate Gmppb knockout and knock-in (P32L and R287Q) mice. We show that homozygous Gmppb knockout and P32L mutant mice (both male and female) display embryonic lethality, while heterozygous Gmppb-P32L (GmppbP32L/+) mice (both male and female) develop progressive muscular dystrophy accompanied by Purkinje cell loss, peripheral demyelination, and impaired nerve conduction. Integrated biochemical, transcriptomic, metabolomic and glycoproteomic analyses reveal widespread protein hypoglycosylation, metabolic dysregulation and suppressed Wnt/β-catenin signaling, resulting in defective differentiation and regeneration of muscle stem cells. Pharmacological activation of Wnt signaling with CHIR-99021 restores myogenic capacity and improves regeneration after injury. Furthermore, AAV-mediated GMPPB gene replacement reinstates α-dystroglycan glycosylation, normalizes GDP-mannose levels, and rescues motor and electrophysiological defects. Collectively, our findings establish GmppbP32L/+ mice as a faithful model of GMPPB-associated dystroglycanopathy and demonstrate that Wnt pathway activation and AAV-based gene therapy represent promising strategies for treating glycosylation-defective muscular dystrophies.

DOI: https://doi.org/10.1038/s41467-026-71524-7
J Bioenerg Biomembr. 2026 Apr 10. pii: 6. [Epub ahead of print]58(1):

Vitamin B3 rescues mitochondrial homeostasis in dexamethasone-induced skeletal muscle atrophy by reducing oxidative stress.

Akash Mitra, Samanwita Mandal, Anna Timothy Dsouza, Debajit Chaudhury, Bipasha Bose, Sudheer Shenoy P.

  Prolonged glucocorticoid exposure leads to oxidative stress, mitochondrial damage and impaired myogenesis reducing the overall health of the skeletal muscles. Dexamethasone (dex), a synthetic glucocorticoid, induces proteolysis and inflammation by disrupting cellular energetics and mitochondrial function. Vitamin B3 (vit B3), an NAD+ precursor, is known to be a natural antioxidant and anti-inflammatory compound. This study investigates the protective role of vit B3 against dex-induced skeletal muscle damage, focusing on mitochondrial homeostasis and the IKK/FoxO3a signalling axis. C2C12 myoblasts were treated with dex (200 µM) and/or vit B3 (1 mM). Oxidative stress, mitochondrial potential and DNA damage was evaluated using DCFDA, JC1, and γH2AX immunostaining, respectively. Gene expression analysis was performed to assess the mitochondrial fission/fusion and the extent of electron transport chain (ETC) gene expression. Protein expression of inflammatory (IKKα/β, NFκB) and atrophy markers were analysed using immunoblotting and flow cytometry. The extent of myogenic differentiation was evaluated using MyoD and MyHC1 immunostaining along with measurement of the morphometric parameters. Vit B3 treatment significantly enhanced C2C12 viability and reduced dex-induced ROS production while restoring Nrf2 expression. It prevented DNA damage and preserved mitochondrial membrane potential. The results also implicated increased mitochondrial fusion upon vit B3 treatment as seen by the elevated gene expression of Mfn1, Mfn2 and Opa1 and decreased fission as observed by the reduced expression of Fis1 and Drp1. The NADH levels were also seen to be rescued by vit B3 supplementation which translates to better energy production by the electron transport system. Additionally, vit B3 was observed to suppress inflammation and prevent muscle proteolysis by modulating an IKK/FoxO3a axis. Finally, vit B3 was able to improve differentiation as seen by the levels of MyoD and MyHC1 expression in the cells. Vit B3 acts in a multifaceted manner and reduces dex-induced skeletal muscle atrophy which is primarily a result of reduced oxidative stress and restored mitochondrial homeostasis. These findings highlight vit B3 as a potential therapeutic and nutritional supplement for maintaining the skeletal muscle health under myopathic conditions.

Keywords:  Mitochondrial fragmentation; Mitochondrial homeostasis; Muscle differentiation; Reactive Oxygen Species; Skeletal muscle atrophy; Vitamin B3

DOI:  https://doi.org/10.1007/s10863-026-10106-0
Physiol Rep. 2026 Apr;14(7): e70826

Cell-cycle regulation of sarcomere integrity-Role for Actn2 phosphorylation.

S S Baksh, I Anwar, X Wang, R E Pratt, V J Dzau, C P Hodgkinson.

  Sarcomeres are the fundamental contractile units of muscle. Despite their importance, sarcomere assembly remains poorly understood. We focused on Actn2, a protein which stabilizes the sarcomere by linking proteins to the Z-disk. During C2C12 differentiation into myoblasts, Actn2 protein levels remained constant. This finding suggested that Actn2 incorporation into the sarcomere arose from a post-translational mechanism. We hypothesized that the post-translational mechanism relied on phosphorylation. Alignment of Actn2 protein sequences from animals with three- or four-chambered hearts identified a conserved sequence, T308P309E310K311, that matches the consensus phosphorylation motif of the cell-cycle kinase CDK1. In vitro kinase assays showed that CDK1 phosphorylates Actn2 at T308. In contrast, CDK1 was unable to phosphorylate Actn2 when T308 was mutated to alanine (T308A). Using CRISPR-Cas9 gene editing, we created Actn2-T308A and phosphomimetic Actn2-T308D variants in C2C12 cells. C2C12 cells expressing Actn2-T308A differentiated rapidly and formed robust sarcomeres. However, C2C12 cells expressing Actn2-T308D failed to form organized sarcomeres. Curiously, Actn2-T308A cells were found to have less proliferative capacity than Actn2-T308D cells. Taken together, these results identify CDK1-dependent phosphorylation of Actn2-T308 as being important for sarcomere assembly. Moreover, the data also suggest a mechanism by which cell-cycle exit promotes sarcomere assembly.

Keywords:  Actn2; cell cycle; gene editing; phosphorylation; sarcomere

DOI:  https://doi.org/10.14814/phy2.70826
Nat Commun. 2026 Apr 09.

BRD4 directs myofiber identity and metabolic adaptation through CHD4 cooperation.

Zheng Zhou, Lin Liu, Zhisheng Xu, Danxia Zhou, Anqi Liu, Jiachen Yuan, Gonghao Shen, Qiqi Guo, Yujing Yin, Yan Mao, Wanping Sun, Liwei Xiao, Cheng Lv, Abdukahar Kiram, Likun Yang, Yuhuan Jia, Lu Ke, Lei Fang, Weiqin Li, Tingting Fu, Zhenji Gan.

Skeletal muscle fiber-type composition is key determinant of systemic metabolism and health. However, how fiber-type-specific gene expression patterns are established and maintained to specify myofiber identity remains unclear. Here we show that BRD4 is a crucial regulator for muscle fiber identity and metabolism. In humans, BRD4 expression correlates with muscle contractile properties, and is notably altered in individuals with obesity. In mice, HFD feeding elevates BRD4 protein levels, preceding body weight changes, while muscle-specific Brd4 deletion induces a slow-oxidative fiber shift, enhances energy expenditure, and protects against diet-induced obesity and insulin resistance. Mechanistically, BRD4 cooperates with MEF2 and CHD4 to regulate fast-twitch myofiber gene expression. CHD4 deletion mirrors the metabolic benefits seen with BRD4 loss. Importantly, BRD4 inhibition with JQ1 replicates these effects in mice and human myotubes. These findings establish BRD4 axis as a critical determinant of myofiber identity and metabolism, offering a potential therapeutic strategy for metabolic disorders.

DOI: https://doi.org/10.1038/s41467-026-71529-2
bioRxiv. 2026 Mar 09. pii: 2026.03.05.709950. [Epub ahead of print]

Positive allosteric modulator of SERCA pump NDC-1171 attenuates cardiac functional decline in mouse model of Duchenne muscular dystrophy.

Niharika Narra, Alyssa M Richards, Conner C Earl, Abigail D Cox, Russell Dahl, Wendy A Koss, Craig J Goergen.

Progressive cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Dysregulation of calcium handling has been implicated in cardiomyopathy progression in DMD. Here we describe a therapeutic approach to improve calcium homeostasis in a mouse model of DMD using the novel therapeutic NDC-1171, which is a positive allosteric modulator of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump. We synthesized NDC-1171 and treated 4-week-old D2. mdx mice (n=9) via oral gavage. A group of D2. mdx mice (n=9) and a group of DBA/2J mice (n=9; background strain) received a vehicle on the same schedule. We used ultrasound to assess left ventricular function, followed by a treadmill exhaustion test and a 4-paw grip strength test to assess skeletal muscle function. NDC-1171 attenuated cardiac functional decline in D2. mdx mice. At 16 weeks of age, left ventricular ejection fraction (LVEF) was significantly preserved in mice treated with NDC-1171 (57.7□±□0.5%) compared to mice treated with a vehicle (50.7□±□0.9%, p □<□0.05), though remained lower than background strain controls (62.4□±□0.6%). In contrast, functional behavior testing revealed no significant improvement in skeletal muscle function with treatment. These data suggest that treatment with the SERCA pump modulator NDC-1171 helps preserve cardiac function in a murine model of DMD, even as skeletal muscle function was impaired. Future work will be needed to determine if the benefits of this novel SERCA activator translate to large animal and clinical studies, but these initial results are promising and could help guide development of future treatments for pediatric patients with muscular dystrophy.

DOI: https://doi.org/10.64898/2026.03.05.709950
Front Physiol. 2026 ;17 1757576

Acetate and combinations of short-chain fatty acids increase oxidative phenotype and contribute to muscle fiber type shift in myotubes.

Britt M J Otten, Mireille M J P E Sthijns, Harry R Gosker, Marco C J M Kelders, Freddy J Troost.

   Introduction: Intestinal microbial fermentation produces short-chain fatty acids (SCFAs) that signal from the large intestine to skeletal muscle. Skeletal muscle exhibits phenotypic plasticity, with fiber-type composition shifting between oxidative (slow-twitch) and glycolytic (fast-twitch) states in response to metabolic and environmental cues. While SCFAs have been implicated in modulating metabolism, their role in skeletal muscle fiber-type regulation remains poorly defined. This study aimed to investigate whether acetate and SCFA mixtures (acetate, propionate, and butyrate) can promote a shift towards an oxidative skeletal fiber type in skeletal muscle cells.
Methods: Cultured C2C12 myotubes were exposed to SCFAs, and fiber type-specific gene and protein expression was assessed. Exposure: Exposure to ≥0.5 mM of the SCFA mixture for 8 h increased Pgc1α and Tfam gene expression compared to 10 mM acetate. This effect persisted after 24h exclusively in the SCFA mixture. Pparα gene expression at 8h was increased by ≥5 mM acetate and 10 mM SCFA mixture. Myh7 gene expression increased after 24h with ≥0.5 mM SCFA mixture and ≥5 mM acetate. After 48h, ≥0.5 mM acetate increased myosin heavy chain (MyHC) I staining, whereas 10 mM SCFA mixture reduced MyHC II. By 72h, the mixture further enhanced MyHC I and sustained MyHC II reduction.
Conclusion: This study shows that both acetate and SCFA combinations shift muscle myotubes towards oxidative fiber phenotype, with the mixture demonstrating a more pronounced effect at lower concentrations. This supports a role for gut-derived metabolites in muscle adaptation and demonstrates that SCFAs promote a shift toward an oxidative fiber type.

Keywords:  C2C12 myotubes; Myh7; Pgc1α; SCFAs; oxidative fiber type

DOI:  https://doi.org/10.3389/fphys.2026.1757576
Mol Cell Endocrinol. 2026 Apr 04. pii: S0303-7207(26)00078-X. [Epub ahead of print] 112801

Histone Deacetylases Inhibitor Chidamide Mitigates Inflammation and Insulin Resistance by Targeting VDR in Skeletal Muscle Cells.

Lulu Zhang, Maosen Zhang, Meng Zhu, Xinyu Luo, Longfei Cui, Yunfei Zhao, Jia-Mu Zhao.

  The pathogenesis of Type 2 diabetes mellitus (T2DM) is heavily driven by exacerbated insulin resistance and inflammation in skeletal muscle, a major site for insulin-stimulated glucose uptake. Therefore, targeting inflammation and insulin resistance within this tissue represents an effective therapeutic strategy for T2DM. While histone deacetylase inhibitors (HDACi) exhibit therapeutic potential for metabolic diseases, the specific impact of the novel HDACi, Chidamide, on regulating skeletal muscle insulin resistance remains to be elucidated. Here, we provide in vitro evidence that Chidamide mitigates skeletal muscle inflammation and insulin resistance in a palmitic acid (PA)-induced C2C12 cell model. We demonstrate that Chidamide alleviates inflammation and activates the Akt/GSK3β/AS160-mediated insulin signaling thereby promoting cell-surface localization of GLUT4 and glucose uptake. Mechanistically, PA downregulates the expression of the vitamin D receptor (VDR), contributing to the inflammatory response and impairing Akt/GSK3β/AS160-mediated insulin signaling, which ultimately inhibited GLUT4-mediated glucose uptake. Chidamide effectively alleviates these effects by upregulating VDR transcription, potentially through the augmentation of histone H3 acetylation, thereby restoring insulin sensitivity and increasing GLUT4-mediated glucose uptake. In conclusion, our findings provide a proof-of-concept for the potential utility of Chidamide as a therapeutic strategy to enhance skeletal muscle insulin sensitivity.

Keywords:  Chidamide; Inflammation; Insulin Resistance; Skeletal Muscle; VDR

DOI:  https://doi.org/10.1016/j.mce.2026.112801
Inflamm Regen. 2026 Apr 11.

Emerging roles of microRNAs and other non-coding transcriptome in muscular dystrophies.

Farah Gamal Abdelrehim, Zade Sadek, Salma A Fahim, Nada El-Ekiaby, Ahmed Ihab Abdelaziz, Injie Omar Fawzy.

  Muscular dystrophies (MDs) are a set of neuromuscular diseases characterized by progressive muscle weakness and wasting. Their pathophysiology entails several aberrant genetic pathways including the perturbation of microRNA (miRNA) and other non-coding RNA (ncRNA) levels and functions, and the subsequent dysregulation of their downstream targets. In healthy tissue, ncRNAs exert their influence by fine-tuning physiological mechanisms. However, in dystrophic conditions, these ncRNAs become involved in modulation of pathological mechanisms. The main pathomechanism themes that involve ncRNAs and proteins in MD are myogenesis insufficiency, structural instability, destructive pathways, and signaling failure. This review attempts to delineate all the major contributory ncRNAs, particularly miRNAs, as well as their associated proteins involved in disease initiation, maintenance, and outcomes across the spectrum of MD subtypes.

Keywords:  Degeneration; Inflammation; Muscle dystrophy; Myogenesis; NcRNA; Neuromuscular diseases; Non-coding transcriptome; Post-translational modifications; Regeneration

DOI:  https://doi.org/10.1186/s41232-026-00415-7
Am J Physiol Cell Physiol. 2026 Apr 09.

17β-estradiol and progesterone have independent and combined effects on C2C12 myotubes following electrical pulse stimulation.

Mai Wageh, Michael Kamal, Gianni Parise.

  17β-estradiol (E2) and progesterone (P4) may influence exercise-induced muscle damage and repair during the menstrual cycle (MC), but their individual and combined effects remain unclear. This study investigated how hormones influence C2C12 myoblast proliferation, differentiation, and migration under basal conditions and after electrical pulse stimulation (EPS). Myoblasts were treated with E2 and P4 (alone or combined to mimic MC phases). Proliferation (MTT assay), migration (scratch assay), creatine kinase (CK), differentiation (immunohistochemistry), and protein expression (western blot) were assessed. Elevated E2 (>100 pg/mL) and P4 (>1.5 ng/ml) reduced proliferation, as well as in the early follicular phase (EFP) and mid-luteal phase (MLP) (p < 0.05). Migration decreased in EFP and late follicular phase (LFP) (p < 0.05), but not with isolated E2/P4 treatment. Differentiation was impaired across all MC phases (reduced myotube diameter; p < 0.05). While greater E2 accelerated CK recovery post-EPS, the presence of P4 (MC phases) influenced this effect. E2 upregulated HSP70 and myogenin protein content, but P4 counteracted these benefits during specific MC phases. ERɑ increased in all conditions, suggesting a potential role in mediating the EPS response. In conclusion, E2 and P4 independently decrease myoblast activity, but their combined effects vary across the MC, with a potential role of ERɑ in this process. These findings highlight the complex interplay of sex hormones in the myogenic response to contractile stress.

Keywords:  Estrogen; Hormones; Myoblasts; Progesterone

DOI:  https://doi.org/10.1152/ajpcell.00501.2025