Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China.
State Key Laboratory of Reproductive Medicine, Gusu School, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.
Cell Prolif. 2023 Aug;56(8):e13410. doi: 10.1111/cpr.13410. Epub 2023 Feb 1.
Muscle stem cells are required for the homeostasis and regeneration of mammalian skeletal muscles. It has been reported that RNA N6-methyladenosine (m6A) modifications play a pivotal role in muscle development and regeneration. Nevertheless, we know little about which m6A reader regulates mammalian muscle stem cells. Here, we discovered that the m6A reader Ythdc1 is indispensable for mouse skeletal muscle regeneration and proliferation of muscle stem cells. In the absence of Ythdc1, Muscle stem cells in adult mice are unable to exit from quiescence. Mechanistically, Ythdc1 binds to m6A-modified Pi4k2a and Pi4kb mRNAs to regulate their alternative splicing and thus PI4K-Akt-mTOR signalling. Ythdc1-null muscle stem cells show a deficiency in phosphatidylinositol (PI) 3,4,5-trisphosphate, phospho-Akt and phospho-S6, which correlates with a failure in exit from quiescence. Our findings connect dynamic RNA methylation to the regulation of PI4K-Akt-mTOR signalling during stem cell proliferation and adult tissue regeneration.
肌肉干细胞对于哺乳动物骨骼肌的稳态和再生是必需的。据报道，RNA N6-甲基腺苷（m6A）修饰在肌肉发育和再生中发挥关键作用。然而，我们对调节哺乳动物肌肉干细胞的哪些 m6A 阅读器知之甚少。在这里，我们发现 m6A 阅读器 Ythdc1 对于小鼠骨骼肌再生和肌肉干细胞的增殖是必不可少的。在没有 Ythdc1 的情况下，成年小鼠的肌肉干细胞无法从静止状态中退出。在机制上，Ythdc1 结合到 m6A 修饰的 Pi4k2a 和 Pi4kb mRNA 上，调节它们的选择性剪接，从而调节 PI4K-Akt-mTOR 信号通路。Ythdc1 缺失的肌肉干细胞表现出磷脂酰肌醇（PI）3,4,5-三磷酸、磷酸化 Akt 和磷酸化 S6 的缺乏，这与从静止状态中退出的失败有关。我们的发现将动态 RNA 甲基化与 PI4K-Akt-mTOR 信号通路在干细胞增殖和成人组织再生中的调节联系起来。
