PRMT5 regulates lipid metabolism in skeletal muscle via epigenetic suppression of Pnpla2

Skeletal muscle plays a vital role in regulating systemic energy metabolism. Defects in skeletal muscle energy production exacerbate chronic metabolic disorders. Protein arginine methyltransferase 5 (PRMT5) catalyzes arginine methylation and regulates a plethora of cellular processes in many tissues, but its function in skeletal muscle is poorly defined. Using a skeletal muscle specific Prmt5 knockout mouse model (Prmt5MKO ), we observed that Prmt5 KO led to a reduction of myofiber size, compromised contractile function, and exercise performance. In addition, Prmt5KO muscles had fewer oxidative fiber type and correspondingly more glycolytic myofibers. Prmt5MKO mice also exhibit systemic metabolic defects and abnormal lipid droplet biogenesis within skeletal muscle, resulting in reduced fat mass in response to high-fat-diet. Mechanistic studies demonstrated that PRMT5 mediates dimethylation of H4R3 in the promoter region of Pnpla2 (encoding ATGL, the rate-limiting enzyme in lipolysis), and loss of Prmt5 results in elevated level of ATGL. Accordingly, constitutive deletion of Pnpla2in skeletal muscle rescued muscle mass and function of Prmt5MKO mice. Taken together, our findings delineate a novel function of Prmt5 as a regulator of lipid metabolism in myocytes through repressing Pnpla2 expression. © FASEB.