Cellular repressor of E1A-stimulated genes 1 enhances skeletal muscle performance through the stimulation of muscle differentiation and Akt-mTOR signaling pathway activation

Abstract

Cellular repressor of E1A-stimulated genes 1 (CREG1), a glycoprotein secreted by various cell types, plays a crucial role in cellular differentiation and energy metabolism. While previous research has linked CREG1 deficiency in skeletal muscles to impaired exercise capacity and altered muscle fiber-type composition, its specific role in skeletal muscle function and differentiation remains unclear. In this study, we investigated the impact of CREG1 on muscle performance and fiber-type composition in adipocyte P2-CREG1-transgenic (Tg) mice and explored muscle differentiation in C2C12 myotubes. Tg mice exhibited significantly improved muscle performance compared to wild-type mice, as indicated by enhanced grip strength. Additionally, the proportion of type IIx fiber in the soleus muscle was significantly increased in Tg mice, along with a tendency towards elevated Myh1 mRNA expression. Enhanced CREG1 expression and activation of the Akt-mTOR signaling pathway, which is involved in muscle protein synthesis, were observed in the skeletal muscles of Tg mice. In C2C12 myotubes, Creg1 knockdown appears to decrease myoblast determination protein 1 (Myod1) expression, while recombinant CREG1 treatment restored Myod1 expression and promoted Akt-mTOR phosphorylation. These findings suggest that CREG1 stimulates muscle differentiation by enhancing protein synthesis, thereby influencing skeletal muscle function.