The m6A reader IGF2BP3 facilitates myogenesis by activating the CAMK2B-MEF2C axis

Skeletal muscle development directly impacts meat quality and productivity in livestock. Although N6-methyladenosine (m6A) RNA methylation has been recognized as a crucial epigenetic mechanism governing myogenesis, the specific functions of Insulin-like Growth Factor 2 mRNA-binding Protein 3 (IGF2BP3), a key m6A reader protein, in goat muscle development remain elusive. This study was designed to dissect the role of IGF2BP3 and its m6A-mediated regulatory mechanisms during goat skeletal muscle development. Our results showed that IGF2BP3 expression was lower in the longissimus muscles of kids and adults than in those of fetuses but increased during in vitro myogenic differentiation. Functional loss-of-function experiments demonstrated that IGF2BP3 depletion led to profound impairments in myoblast proliferation and differentiation. Through a combination of RNA-seq, RIP-qPCR, and mRNA stability assays, we established that IGF2BP3 binds to m6A-modified CAMK2B and MEF2C transcripts. This interaction stabilizes these mRNAs, thereby enhancing gene expression and activating the CAMK2B-MEF2C axis - a newly identified regulatory axis essential for myogenic progression. Our findings not only unveil IGF2BP3 as a pivotal regulator in goat myogenesis but also delineate an m6A-dependent molecular pathway with distinct regulatory features compared to existing models in other species. This novel understanding of epigenetic control in muscle development offers actionable targets for precision breeding strategies, with potential to revolutionize goat meat production by optimizing muscle growth and quality traits.