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Although SkM\u2010EVs are increasingly being explored as a therapeutic strategy to enhance muscle regeneration or to induce the myogenic differentiation of induced pluripotent stem cells (iPSCs), the mechanisms governing their release from muscle cells remain poorly described. Moreover, because muscle regeneration involves a tightly regulated inflammatory response it also important to determine how inflammation alters SkM\u2010EV cargo and function in order to design more effective EV\u2010based therapies. To address this knowledge gap, we isolated and characterized the large and small EVs (lEVs, sEVs) released from SkM cells under basal conditions and in response to TNF\u2010\u03b1, a well\u2010established inflammatory mediator elevated in both acute muscle injury and chronic inflammatory conditions such as type 2 diabetes. We then evaluated the regenerative roles of these EV subtypes in vivo using a mouse model of cardiotoxin\u2010induced muscle injury, with a specific focus on their bioactive sphingolipid content. Using transmission, scanning or cryo\u2010electron microscopy, lipidomic profiling and an adenoviral construct to express labelled CD63 in myotubes, we demonstrated that SkM cells release both sEVs and lEVs primarily from the plasma membrane. Notably, sEVs were generated from specialized membrane folds enriched in the EV markers ALIX (ALG\u20102 interacting protein X) and TSG101, as well as lipid raft\u2010associated lipids. During regeneration, sEVs promoted M1 macrophage polarization and migration and muscle stem cell (MuSC) differentiation, thereby accelerating muscle repair. In contrast, lEVs inhibited and promoted MuSC proliferation and impaired the transition from the pro\u2010inflammatory to the anti\u2010inflammatory response, an essential step for promoting MuSC differentiation. Treatment of isolated muscle fibres with SkM\u2010EVs revealed that the distinct effects of sEVs and lEVs on MuSC behaviour and macrophage phenotype could be largely explained by differences in their lipid composition, particularly the ratio of sphingosine\u20101\u2010phosphate (S1P) subspecies. However, TNF\u2010\u03b1 exposure altered these ratios in sEVs and impaired their regenerative functions on MuSC and their effect on macrophage migration and polarization. These results demonstrate for the first time the importance of the sphingolipid content of EVs released by skeletal muscle in their regenerative function within muscle tissue, largely explained by their role as carriers of different subspecies of sphingosine\u20101\u2010phosphate. This suggests that modulating the sphingolipid composition of EVs could be a viable strategy to enhance the regenerative potential of muscle tissue in addition to therapeutic interventions.<\/jats:p>","DOI":"10.1002\/jev2.70164","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T06:37:19Z","timestamp":1758609439000},"source":"Crossref","is-referenced-by-count":9,"title":["Sphingolipids in Extracellular Vesicles Released From the Skeletal Muscle Plasma Membrane Control Muscle Stem Cell Fate During Muscle Regeneration"],"prefix":"10.1002","volume":"14","author":[{"given":"Rhyma","family":"Hakkar","sequence":"first","affiliation":[{"name":"Laboratory of Cardiology, Metabolism, Nutrition and Diabetes (CarMeN), UMR INSERM 1060\u2010INRAE 1397 University of Lyon Pierre Benite France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2824-5221","authenticated-orcid":false,"given":"Caroline 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