PDF(Pubmed)
Abstract：
Development is regulated by various factors, including protein methylation status. While PRMT5 is well known for its roles in oncogenesis by mediating symmetric di-methylation of arginine, its role in normal development remains elusive. Using Myod1Cre to drive Prmt5 knockout in embryonic myoblasts (Prmt5MKO), we dissected the role of PRMT5 in myogenesis. The Prmt5MKO mice are born normally but exhibit progressive muscle atrophy and premature death. Prmt5MKO inhibits proliferation and promotes premature differentiation of embryonic myoblasts, reducing the number and regenerative function of satellite cells in postnatal mice. Mechanistically, PRMT5 methylates and destabilizes FoxO1. Prmt5MKO increases the total FoxO1 level and promotes its cytoplasmic accumulation, leading to activation of autophagy and depletion of lipid droplets (LDs). Systemic inhibition of autophagy in Prmt5MKO mice restores LDs in myoblasts and moderately improves muscle regeneration. Together, PRMT5 is essential for muscle development and regeneration at least partially through mediating FoxO1 methylation and LD turnover.
摘要：
发展受各种因素调节,包括蛋白质甲基化状态。虽然众所周知PRMT5通过介导精氨酸的对称二甲基化在肿瘤发生中的作用，它在正常发展中的作用仍然难以捉摸。使用Myod1Cre驱动胚胎成肌细胞（Prmt5MKO）中的Prmt5基因敲除，我们剖析了PRMT5在肌生成中的作用。Prmt5MKO小鼠正常出生，但表现出进行性肌肉萎缩和过早死亡。Prmt5MKO抑制增殖并促进胚胎成肌细胞的过早分化，减少出生后小鼠卫星细胞的数量和再生功能。机械上,PRMT5甲基化并使FoxO1不稳定。Prmt5MKO增加总FoxO1水平并促进其细胞质积累，导致自噬的激活和脂滴（LD）的消耗。Prmt5MKO小鼠自噬的系统抑制可恢复成肌细胞的LDs，并适度改善肌肉再生。一起,PRMT5对肌肉发育和再生至关重要，至少部分通过介导FoxO1甲基化和LD转换。
