Endurance exercise remodels skeletal muscle by suppressing Ythdf1-mediated myostatin expression

Abstract Exercise can improve health via skeletal muscle remodeling. Elucidating the underlying mechanism may lead to new therapeutics for aging-related loss of skeletal muscle mass. Here, we show that endurance exercise suppresses expression of YT521-B homology domain family (Ythdf1) in skeletal muscle, which recognizes the N6-methyladenosine (m6A). Ythdf1 deletion phenocopies endurance exercise-induced muscle hypertrophy in mice increases muscle mitochondria content and type I fiber specification. At the molecular level, Ythdf1 recognizes and promotes the translation of m6A-modified Mstn mRNA, which encodes a muscle growth inhibitor, Myostatin. Loss of Ythdf1 leads to hyperactivation of skeletal muscle stem cells (MuSCs), also called satellite cells (SCs), enhancing muscle growth and injury-induced regeneration. Our data reveal Ythdf1 as a key regulator of skeletal muscle homeostasis, provide insights into the mechanism by which endurance exercise promotes skeletal muscle remodeling and highlight potential strategies to prevent aging-related muscle degeneration.