FTO promotes skeletal muscle differentiation and regeneration by regulating m⁶A-modified c-Myc

Recent studies have revealed the crucial role of m⁶A RNA methylation in various myogenic processes. However, the specific function and underlying molecular mechanisms of this modification in vivo during skeletal muscle differentiation and regeneration remain unclear. In this study, we examine the role and mechanism of the m⁶A RNA demethylase fat mass and obesity-associated protein (FTO) in skeletal muscle differentiation and regeneration in mice. Our findings demonstrate that FTO is upregulated during both skeletal muscle differentiation and regeneration and is essential for these key myogenic processes. We show that exogenous FTO expression in primary myoblasts enhances differentiation, whereas FTO knockdown inhibits it. Additionally, FTO knockout in mouse muscle stem cells impairs muscle regeneration. FTO promotes skeletal muscle differentiation and regeneration by directly targeting and regulating m⁶A-modified c-Myc, a well-known repressor of myogenesis. The IGF2BP2 reader protein recognizes m⁶A-modified c-Myc in undifferentiated myoblasts and stabilizes it. As FTO levels increase during myoblast differentiation, m⁶A levels on c-Myc decrease. This reduction prevents IGF2BP2 from binding to c-Myc, thereby destabilizing c-Myc levels and promoting differentiation. Overall, our findings underscore the significance of the novel FTO/c-Myc/IGF2BP2 axis in skeletal muscle differentiation and regeneration.