MicroRNA cargo of extracellular vesicles released by skeletal muscle fibro-adipogenic progenitor cells is significantly altered with disuse atrophy and IL-1b deficiency

Fibro-adipogenic progenitor cells (FAPs) are a population of stem cells in skeletal muscle that play multiple roles in muscle repair and regeneration through their complex secretome; however, it is not well understood how the FAP secretome is altered with muscle disuse atrophy. Previous work suggests that the inflammatory cytokine IL-1I3 is increased in FAPs with dis-use and denervation. Inflammasome activation and IL-1I3 secretion are also known to stimulate the release of extracellular vesicles (EVs). Here, we examined the microRNA (miRNA) cargo of FAP-derived, platelet-derived growth factor receptor A (PDGFRa+) EVs from hindlimb muscles of wild-type and IL-1I3 KO mice after 14 days of single-hindlimb immobilization. Hindlimb muscles were isolated from mice following the immobilization period, and PDGFRa+ extracellular vesicles were iso-lated using size-exclusion chromatography and immunoprecipitation. Microarrays were performed to detect changes in miRNAs with unloading and IL-1I3 deficiency. Results indicate that the PDGFRa+, FAP-derived EVs show a significant increase in miRNAs, such as miR-let-7c, miR-let-7b, miR-181a, and miR-124. These miRNAs have previously been demonstrated to play important roles in cellular senescence and muscle atrophy. Furthermore, the expression of these same miRNAs was not signif-icantly altered in FAP-derived EVs isolated from the immobilized IL-1I3 KO. These data suggest that disuse-related activation of IL-1I3 can mediate the miRNA cargo of FAP-derived EVs, contributing directly to the release of senescence-and atrophy -related miRNAs. Therapies targeting FAPs in settings associated with muscle disuse atrophy may therefore have the potential to preserve muscle function and enhance muscle recovery.

Automated summary

This study found that the microRNA (miRNA) cargo of fibro-adipogenic progenitor cells (FAPs) -derived extracellular vesicles (EVs) is altered in muscle disuse atrophy. The activation of the inflammatory cytokine IL-1I3 can mediate the miRNA cargo of FAP-derived EVs, contributing to the release of senescence- and atrophy-related miRNAs.