PRMT5 links lipid metabolism to contractile function of skeletal muscles

Abstract

AbstractThe skeletal muscle plays a key role in systemic energy homeostasis besides its canonical contractile function, but what couples these functions is poorly defined. Protein Arginine MethylTransferase 5 (PRMT5) is a well-known oncoprotein but also expressed in healthy tissues with unclear physiological functions. As adult muscles express high levels ofPrmt5, we generated myocyte-specificPrmt5knockout (Prmt5MKO) mice. We observed reduced muscle mass, oxidative capacity, force production and exercise performance inPrmt5MKOmice. The motor deficiency is associated with scarce lipid droplets in myofibers due to defects in lipid biosynthesis and degradation. First,Prmt5MKOreduced demethylation and stability of Sterol Regulatory Element-Binding Transcription Factor 1a (SREBP1a), a master regulator ofde novolipogenesis. Second,Prmt5MKOimpaired the repressive H4R3Me2s (histone H4 arginine-3 symmetric demethylation) at thePnpla2gene, elevating the level of its encoded protein ATGL, the rate-limiting enzyme catalyzing lipolysis. Accordingly, myocyte-specific double knockout ofPnpla2andPrmt5normalized muscle mass and function. Together, our findings delineate a physiological function of PRMT5 in linking lipid metabolism to contractile function of myofibers.