SYISL Knockout Promotes Embryonic Muscle Development of Offspring by Modulating Maternal Gut Microbiota and Fetal Myogenic Cell Dynamics

Abstract Embryonic muscle fiber formation determines post‐birth muscle fiber totals. The previous research shows SYISL knockout significantly increases muscle fiber numbers and mass in mice, but the mechanism remains unclear. This study confirms that the SYISL gene, maternal gut microbiota, and their interaction significantly affect the number of muscle fibers in mouse embryos through distinct mechanisms, as SYISL knockout alters maternal gut microbiota composition and boosts butyrate levels in embryonic serum. Both fecal microbiota transplantation and butyrate feeding significantly increase muscle fiber numbers in offspring, with butyrate inhibiting histone deacetylases and increasing histone acetylation in embryonic muscle. Combined analysis of RNA‐seq between wild‐type and SYISL knockout mice with ChIP‐seq for H3K9ac and H3K27ac reveals that SYISL and maternal microbiota interaction regulates myogenesis via the butyrate‐HDAC‐H3K9ac/H3K27ac pathway. Furthermore, scRNA‐seq analysis shows that SYISL knockout alone significantly increases the number and proportion of myogenic cells and their dynamics, independently of regulating histone acetylation levels. Cell communication analysis suggests that this may be due to the downregulation of signaling pathways such as MSTN and TGFβ. Overall, multiple pathways are highlighted through which SYISL influences embryonic muscle development, offering valuable insights for treating muscle diseases and improving livestock production.