METTL1-mediated m7G methylation regulates muscle development in intrauterine growth-restricted pigs by stabilizing eIF3a mRNA

Intrauterine growth restriction (IUGR) severely impairs muscle development, yet the underlying molecular mechanisms remain incompletely understood. Increasing evidence indicates that epigenetic regulation, particularly RNA modifications, plays a crucial role in fetal development. Here, we demonstrate that N7-methylguanosine (m7G), a major RNA modification mediated by the METTL1/WDR4 complex, is dysregulated in IUGR pig muscle. Transcriptome and m7G-MeRIP-seq analyses revealed widespread alterations in gene expression and m7G methylation, especially in pathways related to ribosome biogenesis and protein synthesis. Ribosome profiling further confirmed that global translation efficiency was markedly reduced in IUGR muscle. Functional assays showed that METTL1 is highly conserved and its knockdown in mouse myoblasts decreased m7G levels, suppressed myogenic differentiation, and reduced global protein synthesis. Mechanistically, METTL1 stabilizes eIF3a mRNA in an m7G-methyltransferase-dependent manner, thereby promoting its expression. Loss of eIF3a phenocopied METTL1 knockdown, while eIF3a overexpression rescued the impaired differentiation and protein synthesis. Consistently, knockdown of METTL1 in mice reduced m7G levels, decreased eIF3a expression, and impaired muscle fiber growth in vivo . Collectively, our findings uncover a novel mechanism whereby m7G methylation regulates muscle development in IUGR by stabilizing eIF3a mRNA and maintaining global protein synthesis.