N6-methyladenosine-mediated changes in SOCS3 expression regulate skeletal muscle stem cell senescence

Abstract: N6-methyladenosine (m6A)-associated mechanisms are involved in cellular metabolic activities; however, their role in skeletal muscle stem cell (SkMSC) senescence is unknown. In this study, m6A RNA modification and METTL3 expression were decreased in aged SkMSCs from mice. Transcriptional analysis of m6A modification further revealed that suppressor of cytokine signaling 3 (SOCS3) was downregulated in aged SkMSCs, and that downregulation of METTL3 promoted SkMSC senescence. In addition, the upregulation of METTL3 alleviated the senescence of SkMSCs. Mechanistically, deletion of m6A modifications promoted senescence and inhibited SOCS3 expression, whereas downregulation of SOCS3 promoted senescence. Moreover, insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) was identified as an important regulator in the recognition and stabilization of m6A modified SOCS3 expression. IGF2BP1 binds to SOCS3 and reinforces its stability by suppressing the phosphorylation of JAK2/STAT3. Therefore, METTL3 inhibits SkMSC senescence through m6A modification-dependent stabilization of SOCS3 expression and inhibition of JAK2-STAT3 signaling. This study thus highlights a novel mechanism underlying SkMSC senescence.