The METTL3-m6A pathway is a master regulator of muscle maintenance and growth

ABSTRACT: In many members of the animal kingdom, and in particular mammals, skeletal muscle evolved to serve fundamental roles in their health and architectural integrity. While it is clear that dynamic fluctuations of specific gene expression is important for normal muscle function, it is also crucial in the response of skeletal muscle to insults, yet little is known on how such fluctuations are regulated at the post-transcriptional level to impact muscle proteome. Here we report the first genome-wide analysis of mRNA methyladenosine (m6A) dynamics underlying skeletal muscle hypertrophic growth following overload-induced stress. We show that METTL3, the enzyme responsible for m6A formation, orchestrate a previously unrecognized post-transcriptional mechanism controlling skeletal muscle size and function. We found that METTL3 and concomitantly m6A are increased during hypertrophy; manipulating this increase through exogenous delivery of METTL3 is sufficient to induce skeletal muscle growth even in the absence of external triggers. Myofiber-specific conditional genetic deletion of METTL3 abrogated the ability of muscle to undergo overload-induced hypertrophy and led to a spontaneous muscle wasting phenotype over time. In turn, isolation of muscle-specific ribosome-associated transcripts showed that METTL3 affects the translation of specific m6A-modified mRNAs participating in the activin/myostatin pathway, which includes key regulators of muscle size. METTL3 is essential to repress the translation of activin type 2A receptors (ACVR2A), consequently blunting downstream activation of anti-hypertrophic signaling. Notably, the observed hypertrophic growth defect of METTL3-deficient mice can be overcome with co-administration of a myostatin inhibitor. Our findings identify a novel post-transcriptional mechanism of regulating the activin receptor pathway and demonstrate that the N6-adenosine methyltransferase METTL3 is required for and promotes the hypertrophic response of skeletal muscle.

ORGANISM(S): Mus musculus

PROVIDER: GSE179368 | GEO | 2021/12/10

REPOSITORIES: GEO