Department of Animal Sciences, Purdue University, West Lafayette, IN, USA.
Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
EMBO Rep. 2023 Aug 3;24(8):e57306. doi: 10.15252/embr.202357306. Epub 2023 Jun 19.
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 (Prmt5 ) mice. We observe reduced muscle mass, oxidative capacity, force production, and exercise performance in Prmt5 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, Prmt5 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.
骨骼肌除了具有收缩功能外，在全身能量稳态中也起着关键作用，但连接这些功能的机制尚不清楚。精氨酸甲基转移酶 5（PRMT5）是一种众所周知的癌蛋白，但也在健康组织中表达，其生理功能尚不清楚。由于成年肌肉中表达高水平的 Prmt5，我们生成了骨骼肌特异性 Prmt5 敲除（Prmt5）小鼠。我们观察到 Prmt5 小鼠的肌肉质量、氧化能力、力量产生和运动表现降低。运动缺陷与肌纤维中脂质滴稀少有关，这是由于脂质生物合成缺陷和降解加速所致。具体而言，PRMT5 缺失会降低从头合成脂质的主调节因子固醇调节元件结合转录因子 1a（SREBP1a）的二甲基化和稳定性。此外，Prmt5 会损害 Pnpla2 启动子上 H4R3 对称二甲基化的抑制作用，从而提高其编码蛋白 ATGL 的水平，ATGL 是催化脂肪分解的限速酶。因此，骨骼肌特异性的 Pnpla2 和 Prmt5 双敲除可使肌肉质量和功能正常化。总之，我们的研究结果描绘了 PRMT5 将脂质代谢与肌纤维收缩功能联系起来的生理功能。
