Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Trimetazidine Attenuates Dexamethasone-Induced Muscle Atrophy via Inhibiting NLRP3/GSDMD Pathway-Mediated Pyroptosis

Version 1 : Received: 24 December 2020 / Approved: 25 December 2020 / Online: 25 December 2020 (07:16:01 CET)

How to cite: Wang, L.; He, M.; Shen, X.; Zhang, K.; Zhao, C.; Liu, L.; Wang, M.; Bu, Y.; Li, J.; Xu, F.; He, H.; Lu, X.; Gao, W. Trimetazidine Attenuates Dexamethasone-Induced Muscle Atrophy via Inhibiting NLRP3/GSDMD Pathway-Mediated Pyroptosis. Preprints 2020, 2020120643 (doi: 10.20944/preprints202012.0643.v1). Wang, L.; He, M.; Shen, X.; Zhang, K.; Zhao, C.; Liu, L.; Wang, M.; Bu, Y.; Li, J.; Xu, F.; He, H.; Lu, X.; Gao, W. Trimetazidine Attenuates Dexamethasone-Induced Muscle Atrophy via Inhibiting NLRP3/GSDMD Pathway-Mediated Pyroptosis. Preprints 2020, 2020120643 (doi: 10.20944/preprints202012.0643.v1).

Abstract

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 also improve skeletal muscle performance both in human and mice. We here showed that dexamethasone induced atrophy, 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 NLRP3, Caspase-1 and GSDMD. Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine administration ameliorated dexamethasone-induced muscle atrophy both in vivo and in vitro. Moreover, trimetazidine improved exercise tolerance, as evidenced by increased running distance and running time, as well as increased skeletal muscle mass in dexamethasone-treated mice. Mechanically, trimetazidine could reverse dexamethasone-induced activation of pyroptosis both in C2C12 myotubes and in mice. Taken together, our present study demonstrated that NLRP3/GSDMD pathway-mediated pyroptosis was involved in dexamethasone-induced skeletal muscle atrophy. Trimetazidine could partially alleviate dexamethasone-induced skeletal muscle atrophy, and increase the diameter of C2C12 myotubes via inhibiting pyroptosis. Thus, trimetazidine might be a potential therapeutic compound for the prevention of muscle atrophy in glucocorticoid-treated patients.

Subject Areas

Dexamethasone; Muscle atrophy; Pyroptosis; Trimetazidine

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