PRMT5 links lipid metabolism to contractile function of skeletal muscles

Abstract

Skeletal muscle plays a key role in systemic energy homeostasis besides its contractile function, but what links these functions is poorly defined. Protein Arginine Methyl Transferase 5 (PRMT5) is a well‐known oncoprotein but also expressed in healthy tissues with unclear physiological functions. As adult muscles express high levels of Prmt5, we generated skeletal muscle‐specific Prmt5 knockout (Prmt5MKO) mice. We observe reduced muscle mass, oxidative capacity, force production, and exercise performance in Prmt5MKO mice. The motor deficiency is associated with scarce lipid droplets in myofibers due to defects in lipid biosynthesis and accelerated degradation. Specifically, PRMT5 deletion reduces dimethylation and stability of Sterol Regulatory Element‐Binding Transcription Factor 1a (SREBP1a), a master regulator of de novo lipogenesis. Moreover, Prmt5MKO impairs the repressive H4R3 symmetric dimethylation at the Pnpla2 promoter, elevating the level of its encoded protein ATGL, the rate‐limiting enzyme catalyzing lipolysis. Accordingly, skeletal muscle‐specific double knockout of Pnpla2 and Prmt5 normalizes muscle mass and function. Together, our findings delineate a physiological function of PRMT5 in linking lipid metabolism to contractile function of myofibers.

PRMT5 mediates FoxO1 methylation and subcellular localization to regulate lipophagy in myogenic progenitors

“…PRMT5 has been shown to regulate lipid metabolism in adipocytes and skeletal muscles. 34 , 36 We have recently identified LD as an important metabolic regulator of SC fate, 14 we therefore explored whether PRMT5 regulates SCs through LDs. We utilized oil red O (ORO) staining to visualize and quantify LD contents in myoblasts.…”

“…Indeed, our recent study has demonstrated that myofiber-specific restoration of LDs rescues the phenotype of myofiber-specific Prmt5 -KO mice very effectively. 82 Future studies should explore the possibility of targeted delivery of HCQ into muscle cells using for example nanoparticle delivery tools. 83 , 84 …”