Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis
| Autor: | Hui-Xian Sun, Xiang Lu, Man Wang, Xiao-Qing Li, Yun-Ling Bu, Wei Gao, Li Wang, Xin-Feng Jiao, Kang-Zhen Zhang, Jia-Wen Li, Fan Xu, Can Zhao, Chen-Lu Chang, Xi-Yu Shen, Cheng Wu, Li Liu |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
medicine.medical_specialty Immunology Trimetazidine Skeletal muscle Article Cellular and Molecular Neuroscience Atrophy Internal medicine medicine Protein kinase B RC254-282 PI3K/AKT/mTOR pathway QH573-671 Myogenesis Chemistry Pyroptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens Musculoskeletal abnormalities Cell Biology medicine.disease Muscle atrophy medicine.anatomical_structure Endocrinology medicine.symptom Cytology medicine.drug |
| Zdroj: | Cell Death Discovery Cell Death Discovery, Vol 7, Iss 1, Pp 1-11 (2021) |
| ISSN: | 2058-7716 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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