Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis

• Published in: Cell death discovery Vol. 7; no. 1; pp. 251 - 11
• Main Authors: Wang, Li, Jiao, Xin-Feng, Wu, Cheng, Li, Xiao-Qing, Sun, Hui-Xian, Shen, Xi-Yu, Zhang, Kang-Zhen, Zhao, Can, Liu, Li, Wang, Man, Bu, Yun-Ling, Li, Jia-Wen, Xu, Fan, Chang, Chen-Lu, Lu, Xiang, Gao, Wei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.09.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 692/698/1671/1668/1973; 692/699/1670/1669; AKT protein; Apoptosis; Atrophy; Biochemistry; Biomedical and Life Sciences; Caspase-1; Cell Biology; Cell Cycle Analysis; Cell death; Dexamethasone; FOXO3 protein; Glucocorticoids; Inflammation; Life Sciences; Lipopolysaccharides; Musculoskeletal system; Myotubes; Phosphorylation; Pyrin protein; Pyroptosis; Skeletal muscle; Stem Cells; Steroids; Trimetazidine
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-021-00648-0

Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can improve skeletal muscle performance both in humans and mice. We here showed that dexamethasone-induced atrophy, as evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression, and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin-D (GSDMD). Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine treatment ameliorated dexamethasone-induced muscle pyroptosis and atrophy both in vivo and in vitro. Activation of NLRP3 using LPS and ATP not only increased the cleavage and activation of Caspase-1 and GSDMD, but also increased the expression levels of atrophy markers MuRF1 and Atrogin-1 in trimetazidine-treated C2C12 myotubes. Mechanically, dexamethasone inhibited the phosphorylation of PI3K/AKT/FoxO3a, which could be attenuated by trimetazidine. Conversely, co-treatment with a PI3K/AKT inhibitor, picropodophyllin, remarkably increased the expression of NLRP3 and reversed the protective effects of trimetazidine against dexamethasone-induced C2C12 myotube pyroptosis and atrophy. Taken together, our study suggests that NLRP3/GSDMD-mediated pyroptosis might be a novel mechanism for dexamethasone-induced skeletal muscle atrophy. Trimetazidine might be developed as a potential therapeutic agent for the treatment of dexamethasone-induced muscle atrophy.