TMEM16A regulates satellite cell-mediated skeletal muscle regeneration by ensuring a moderate level of caspase 3 activity.

IF 4 2区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY STEM CELLS Pub Date : 2024-10-09 DOI:10.1093/stmcls/sxae048
Zhiyuan Sun, Xinqi Shan, Chun'e Fan, Lutao Liu, Shuai Li, Jiahui Wang, Na Zhou, Minsheng Zhu, Huaqun Chen
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Abstract

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.

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TMEM16A 通过确保适度的 Caspase 3 活性来调节卫星细胞介导的骨骼肌再生。
有文献表明,caspase 3 的活性是骨骼肌再生所必需的,但其活性如何调节却在很大程度上是未知的。我们之前的报告显示,细胞内的 TMEM16A(一种钙激活的氯离子通道)能显著调节骨骼肌发育过程中肌母细胞内的 caspase 3 活性。通过使用卫星细胞(SC)特异性缺失 TMEM16A 的小鼠品系,我们研究了 TMEM16A 在调节 SC(或 SC 衍生的肌母细胞)中的 caspase 3 活性以及骨骼肌再生中的作用。突变动物的成肌再生能力明显受损,ER应激增强,Tmem16a-/-SC衍生的成肌细胞中的caspase 3活性升高。用小分子药物阻断过高的ER应激或caspase 3活性可显著恢复Tmem16a-/-SC抑制的成肌分化,这表明TMEM16A缺失导致的caspase 3活性过高是肌肉再生能力受损的原因之一,而caspase 3的上游调节因子是ER应激。我们的研究结果揭示了TMEM16A在卫星细胞介导的骨骼肌再生中的重要作用,它确保了caspase 3的适度活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
STEM CELLS
STEM CELLS 医学-生物工程与应用微生物
CiteScore
10.30
自引率
1.90%
发文量
104
审稿时长
3 months
期刊介绍: STEM CELLS, a peer reviewed journal published monthly, provides a forum for prompt publication of original investigative papers and concise reviews. STEM CELLS is read and written by clinical and basic scientists whose expertise encompasses the rapidly expanding fields of stem and progenitor cell biology. STEM CELLS covers: Cancer Stem Cells, Embryonic Stem Cells/Induced Pluripotent Stem (iPS) Cells, Regenerative Medicine, Stem Cell Technology: Epigenetics, Genomics, Proteomics, and Metabonomics, Tissue-Specific Stem Cells, Translational and Clinical Research.
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