Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis.
Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis.
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Trimetazidine 通过抑制 NLRP3/GSDMD 通路介导的焦亡来减轻地塞米松诱导的肌肉萎缩。
DOI：
10.1038/s41420-021-00648-0
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发表时间：
2021-09-18
影响因子：
7
通讯作者：
Gao W
中科院分区：
文献类型：
--
作者：
Wang L;Jiao XF;Wu C;Li XQ;Sun HX;Shen XY;Zhang KZ;Zhao C;Liu L;Wang M;Bu YL;Li JW;Xu F;Chang CL;Lu X;Gao W
骨骼肌萎缩是大剂量或持续使用糖皮质激素的主要副作用之一。焦亡是一种新型的促炎性程序性细胞死亡，可能导致骨骼肌损伤。曲美他嗪是一种著名的抗心绞痛药物，可以改善人和小鼠的骨骼肌性能。我们在这里发现，地塞米松诱导的萎缩，如肌萎缩F-box（Atrogin-1）和肌肉环指1（MuRF 1）表达的增加，以及C2 C12肌管中肌管直径的减小所证明的。地塞米松还诱导了焦亡，这通过上调焦亡相关蛋白NLR家族pyrin domain containing 3（NLRP 3）、Caspase-1和gasdermin-D（GSDMD）来表示。NLRP 3或GSDMD的敲低减弱地塞米松诱导的肌管焦亡和萎缩。曲美他嗪治疗在体内和体外均改善了地塞米松诱导的肌肉焦萎和萎缩。使用LPS和ATP激活NLRP 3不仅增加了Caspase-1和GSDMD的切割和激活，而且增加了曲美他嗪处理的C2 C12肌管中萎缩标记物MuRF 1和Atrogin-1的表达水平。地塞米松可抑制PI 3 K/AKT/FoxO 3a的磷酸化，而曲美他嗪可使其减弱。相反，与PI 3 K/AKT抑制剂，苦鬼臼脂素，共同治疗，显着增加NLRP 3的表达和逆转曲美他嗪对地塞米松诱导的C2 C12肌管焦亡和萎缩的保护作用。综上所述，我们的研究表明，NLRP 3/GSDMD介导的焦亡可能是地塞米松诱导的骨骼肌萎缩的一种新机制。曲美他嗪可能是一种潜在的治疗药物，用于治疗地塞米松诱导的肌肉萎缩。
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.
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