CARM1 contributes to skeletal muscle wasting by mediating FoxO3 activity and promoting myofiber autophagy

Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1) is involved in a variety of biological processes in different cell types and disease conditions, including myogenesis. However, the specific function of CARM1 in skeletal muscle wasting under pathologic conditions remains unclear. Here, we identify CARM1 as a novel participant in muscular atrophy. Increases in CARM1 protein levels correlated positively with the loss of muscle mass upon denervation in mice. Notably, the knockdown of CARM1 represses the progression of muscle wasting and the expression of the atrophy-related genes Atrogin-1 and MuRF1 in vivo and in vitro. With respect to the underlying mechanism, we show that CARM1 interacts with and asymmetrically dimethylates FoxO3 (a specific transcription factor that controls atrophy-related gene expression). This methylation modification by CARM1 is required for FoxO3-dependent transcription. Accordingly, a CARM1 methyltransferase inhibitor also restrains the expression of Atrogin-1 and MuRF1 and myotube atrophy. Furthermore, CARM1 knockdown induces a remarkable myofiber autophagic deficit during the atrophy process. Altogether, our study identifies a crucial regulator of skeletal muscle atrophy and suggests that CARM1 is a potential target for the prevention of muscle atrophy.

Keywords: Autophagy; CARM1; FoxO3 methylation; Skeletal muscle wasting.