Myostatin knockout mice muscle derived exosome inhibited dexamethasone-induced muscle atrophy

Long-term administration of dexamethasone (DEX) to treat severe inflammation or autoimmune disorders often result in skeletal muscle atrophy and functional decline. Exosomes facilitate intercellular communication by transferring bioactive molecules, reflecting the characteristics of their tissue of origin. Myostatin-knockout (MSTN^-/-) mice exhibit muscle hypertrophy, and their muscle-derived exosomes (KO-EXOs) retain this phenotype. This study investigates the inhibitory effects and underlying mechanisms of KO-EXOs in counteracting DEX-induced muscle atrophy.

WT-EXOs and KO-EXOs (EXOs) were isolated from mice using a tissue culture method followed by ultracentrifugation. A DEX-induced muscle atrophy model was established in mice, and EXOs were administered via intramuscular injection into the gastrocnemius (GA) muscle. Body Composition, muscle function, histology, single muscle fiber and molecular markers were assessed in vivo, alongside C2C12 myotube assays in vitro. Potential regulatory microRNAs (miRNA) involved in KO-EXOs-mediated effects were preliminarily identified through miRNA sequencing of MSTN knockout C2C12 cells.

Compared to the DEX and DEX + WT-EXOs group, KO-EXOs treatment restored body weight, lean mass, and free water content. It significantly increased the GA muscle wet weight ratio, enhanced the average myofiber cross-sectional area, and downregulated genes and proteins associated with muscle atrophy. In vitro, KO-EXOs reversed DEX-induced myotube atrophy and improved the fusion index, and downregulated the expression of atrophy-related genes and proteins. miRNA sequencing revealed enrichment of miR-455-3p and miR-143-5p supporting the anti-atrophic effects of KO-EXOs.

KO-EXOs mitigate DEX-induced muscle atrophy and represent a promising therapeutic strategy based on natural myostatin inhibition for condition such as sarcopenia.