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

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 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.

Adenophora Stricta Root Extract Protects Lung Injury from Exposure to Particulate Matter 2.5 in Mice

“…On the contrary, significant decrease in body weight was seen from 5 days after the administration of DEXA, as compared to vehicle group ( Figure 2 a). We and others have already reported that DEXA can reduce body weight [ 17 , 27 , 28 ], and that this might be due to muscle atrophy [ 27 , 28 ]. Two nasal instillations of PM 2.5 significantly increased relative lung weight compared to vehicle, while administration of DEXA or three different doses of AsE suppressed the increase in relative lung weight due to PM 2.5 .…”

Quercetin Alleviates the Progression of Breast Cancer-Related Depression via Inhibiting the Pyroptosis and Promoting the Immune Response

“…Recent studies indicated that pyroptosis plays a crucial role in the cellular process [ 27 , 28 ]. Caspase-1, NLRP3, and ASC are known to be the important modulators in cell pyroptosis [ 29 , 30 ]. Meanwhile, IL-1 β is also a pyroptosis-related cytokine [ 31 , 32 ].…”

Pyroptosis and Its Role in Autoimmune Disease: A Potential Therapeutic Target

“…Therefore, whether there is a preference of the limb location for muscle cells going through pyroptosis and the mechanism behind this uneven distribution still warrants further examination. It is noteworthy that glucocorticoids have recently been confirmed to induce skeletal muscle atrophy through the NLRP3/caspase-1/GSDMD pathway ( 194 , 195 ), and glucocorticoids are the first choice in the treatment of patients with DM. Therefore, there may be pathological and pharmacological crosstalk in the occurrence of PFA in the later stage of DM, leading to the use of glucocorticoids should be more cautious.…”