Sun Zhiyuan, Shan Xinqi, Fan Chun'e, Liu Lutao, Li Shuai, Wang Jiahui, Zhou Na, Zhu Minsheng, Chen Huaqun
The Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Sciences, Nanjing Normal University, Nanjing 210023, People's Republic of China.
State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210008, People's Republic of China.
Stem Cells. 2024 Oct 9;42(10):902-913. doi: 10.1093/stmcls/sxae048.
It has been documented that caspase 3 activity is necessary for skeletal muscle regeneration, but how its activity is regulated is largely unknown. Our previous report shows that intracellular TMEM16A, a calcium activated chloride channel, significantly regulates caspase 3 activity in myoblasts during skeletal muscle development. By using a mouse line with satellite cell (SC)-specific deletion of TMEM16A, we examined the role of TMEM16A in regulating caspase 3 activity in SC (or SC-derived myoblast) as well as skeletal muscle regeneration. The mutant animals displayed apparently impaired regeneration capacity in adult muscle along with enhanced ER stress and elevated caspase 3 activity in Tmem16a-/- SC derived myoblasts. Blockade of either excessive ER stress or caspase 3 activity by small molecules significantly restored the inhibited myogenic differentiation of Tmem16a-/- SCs, indicating that excessive caspase 3 activity resulted from TMEM16A deletion contributes to the impaired muscle regeneration and the upstream regulator of caspase 3 was ER stress. Our results revealed an essential role of TMEM16A in satellite cell-mediated skeletal muscle regeneration by ensuring a moderate level of caspase 3 activity.
已有文献证明，半胱天冬酶3的活性对于骨骼肌再生是必需的，但其活性如何调节在很大程度上尚不清楚。我们之前的报告表明，细胞内的TMEM16A（一种钙激活氯离子通道）在骨骼肌发育过程中显著调节成肌细胞中的半胱天冬酶3活性。通过使用一种卫星细胞（SC）特异性缺失TMEM16A的小鼠品系，我们研究了TMEM16A在调节SC（或SC衍生的成肌细胞）中的半胱天冬酶3活性以及骨骼肌再生中的作用。突变动物在成年肌肉中表现出明显受损的再生能力，同时Tmem16a-/- SC衍生的成肌细胞中的内质网应激增强且半胱天冬酶3活性升高。通过小分子阻断过度的内质网应激或半胱天冬酶3活性可显著恢复Tmem16a-/- SCs受抑制的肌源性分化，这表明TMEM16A缺失导致的过度半胱天冬酶3活性导致肌肉再生受损，且半胱天冬酶3的上游调节因子是内质网应激。我们的结果揭示了TMEM16A通过确保适度水平的半胱天冬酶3活性在卫星细胞介导的骨骼肌再生中发挥的重要作用。
