Extracellular vesicles derived from immobilization-induced atrophic muscle of male mice contain distinct microRNA profiles and impact mRNA profiles in brain neurons.

Muscle atrophy caused by inactivity leads to declines in multiple physiological functions, including brain function. Although skeletal muscle is known to secrete extracellular vesicles (EVs) such as exosomes, how inactivity-induced muscle atrophy alters the properties and functions of these EVs remains unclear. In this study, we investigated the effects of cast immobilization-induced muscle atrophy on the microRNA (miRNA) profiles of skeletal muscle-derived EVs in mice, as well as their impact on transcriptome changes in brain neurons. Muscle atrophy induced by cast immobilization significantly altered the microRNA profiles of skeletal muscle-derived EVs, with 25 microRNAs upregulated and 2 microRNAs downregulated compared with controls. Moreover, treatment of brain neurons with EVs derived from atrophic skeletal muscle markedly changed neuronal mRNA expression profiles. Gene Ontology (GO) analysis revealed that upregulated mRNAs in EV-treated neurons were enriched in genes involved in the positive regulation of programmed cell death, including apoptosis. Consistently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated activation of apoptosis-related signaling pathways in brain neurons. These findings suggest that muscle atrophy-induced alterations in skeletal muscle-derived EVs may contribute to brain dysfunction by promoting apoptotic processes in brain neurons.