Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA; Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
Cell Rep. 2023 Nov 28;42(11):113329. doi: 10.1016/j.celrep.2023.113329. Epub 2023 Oct 25.
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 Myod1 to drive Prmt5 knockout in embryonic myoblasts (Prmt5), we dissected the role of PRMT5 in myogenesis. The Prmt5 mice are born normally but exhibit progressive muscle atrophy and premature death. Prmt5 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. Prmt5 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 Prmt5 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.
发育受到多种因素的调控，包括蛋白质甲基化状态。PRMT5 通过介导精氨酸的对称二甲基化在肿瘤发生中起着重要作用，但其在正常发育中的作用仍不清楚。我们使用 Myod1 驱动胚胎成肌细胞（Prmt5）中的 Prmt5 敲除，以解析 PRMT5 在肌发生中的作用。Prmt5 小鼠正常出生，但表现出进行性肌肉萎缩和过早死亡。Prmt5 抑制胚胎成肌细胞的增殖并促进其过早分化，减少了出生后小鼠卫星细胞的数量和再生功能。在机制上，PRMT5 甲基化并使 FoxO1 不稳定。Prmt5 增加了 FoxO1 的总水平并促进其细胞质积累，导致自噬的激活和脂滴（LDs）的消耗。在 Prmt5 小鼠中系统性抑制自噬可恢复成肌细胞中的 LD，并适度改善肌肉再生。总之，PRMT5 对于肌肉发育和再生是必不可少的，至少部分通过介导 FoxO1 甲基化和 LD 周转。
