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Skeletal muscle-derived extracellular vesicles during eccentric and concentric exercise promote muscle regeneration after injury

ABSTRACT: Background: Skeletal muscle injuries significantly impair mobility and function, yet effective therapeutic interventions remain limited. Both eccentric exercise (EE) and concentric exercise (CE) promote muscle repair, but the underlying mechanisms are not fully understood. Muscle-derived extracellular vesicles (mEVs) have emerged as critical mediators of intercellular communication; however, their role in exercise-induced regeneration remain unclear. Methods: A murine model of barium chloride-induced muscle injury was used to compare the effects of EE and CE on muscle regeneration. mEVs were isolated from sedentary (SED), CE-, and EE-conditioned muscle and characterized by nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Metabolic profiling of mEVs was performed using LC–MS. The functional roles were assessed through intramuscular injection of mEVs and GW4869-mediated inhibition of mEVs secretion. The effects of mEVs on myogenesis were further examined in C2C12 myoblasts. Results: EE significantly enhanced muscle regeneration compared to CE, as evidenced by improved histology, reduced fibrosis, and increased expression of myogenic markers such as Myod , Myog , and eMyhc . EE also induced greater release of mEVs than CE, as indicated by higher expression of mEVs markers and Rab27a/b. Inhibition of mEVs secretion with GW4869 abolished the regenerative benefits of exercise. Exogenous administration of EE-mEVs enhanced muscle repair and C2C12 differentiation more effectively than CE-mEVs or SED-mEVs. Metabolomic analysis revealed significant enrichment of lipid metabolites in EE-mEVs, which was consistent with the upregulation of lipid metabolism-related genes. RNA-seq analyses further indicated that lipid metabolites enriched in mEVs promoted muscle repair by upregulating energy-sensing genes associated with fatty acid metabolism in myoblasts. Conclusions: EE facilitates muscle repair more effectively than CE by promoting the release of mEVs enriched in pro-regenerative lipid metabolites. These findings suggest EE-mEVs as a promising biological therapeutic strategy for muscle injury, particularly in cases where exercise is not feasible.

ORGANISM(S): Mus musculus

PROVIDER: GSE326247 | GEO | 2026/09/02

REPOSITORIES: GEO

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Project description:Introduction: About 1 billion people are living with obesity worldwide. GLP-1-based drugs have massively transformed care, but long-term consequences are unclear in part due to reductions in energy expenditure with ongoing use. Diet-induced thermogenesis (DIT) and cold exposure (CE) raise EE via brown adipose tissue (BAT) activation and beiging of white adipose tissue (WAT). Methionine restriction (MetR) is a candidate DIT stimulus, but its EE effect has not been benchmarked against CE, nor have their tissue-level interactions been defined. Objective & Methods: In a 2×2 design (Control vs. MetR; room temperature, RT: 22 °C vs. CE: 4 °C for 24 h), we used male C57BL/6N mice to benchmark MetR-induced thermogenesis against CE and mapped how diet and temperature interact across tissues. Bulk RNA-seq profiled liver, iBAT, iWAT, and eWAT. Differential expression was modeled with main effects and a diet×temperature interaction. KEGG GSEA was used to assess pathway-level enrichment. Results: MetR increased EE at RT and shifted fuel use towards lipid oxidation, supporting MetR as a bona fide DIT stimulus. CE elevated EE across diets and blunted diet differences. Transcriptomic responses were tissue-specific: in liver, CE dominated gene induction while MetR and CE cooperatively repressed genes. The combination enriched glucagon/AMPK-linked and core metabolic pathways. In iBAT, CE dominated thermogenic and lipid-oxidation programs with minimal MetR contribution. In iWAT, MetR and CE acted largely additively with high concordance, enhancing fatty-acid degradation, PPAR signaling, thermogenesis, and TCA cycle pathways. In eWAT, robust co-dependent and synergistic differential expression emerged only with MetR+CE. Conclusion: MetR is a genuine DIT stimulus that remodels metabolism in a tissue-specific manner. Our study provides a tissue-resolved transcriptomic resource that benchmarks diet-induced (MetR) against cold-induced thermogenesis and maps their interactions across liver, iBAT, iWAT, and eWAT.

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Skeletal muscle-derived extracellular vesicles during eccentric and concentric exercise promote muscle regeneration after injury

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