Trimetazidine combined with exercise improves exercise capacity and anti-fatal stress ability through enhancing mitochondrial quality control

Xie, Murong; Jiang, Ling; Dun, Yaoshan; Zhang, Wenliang; Liu, Suixin

doi:10.1016/j.lfs.2019.03.027

Cited by 19 publications

(30 citation statements)

References 59 publications

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“…Interestingly, dexamethasone-induced muscle atrophy was remarkably reversed by trimetazidine which is a well-known anti-anginal agent (Figure 3 and 4). Our results are consistent with previous studies showing that trimetazidine exerts anti-atrophy effects in skeletal muscle either via inducing autophagy [20] or enhancing mitochondrial quality control [33]. Indeed, the improvement of trimetazidine treatment on physical performance and muscle endurance has been demonstrated in patients with ischemic heart disease [34,35].…”

Section: Discussionsupporting

confidence: 92%

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

Wang¹,

He²,

Shen³

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 92%

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

Wang¹,

He²,

Shen³

et al. 2020

Preprint

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“…It could decrease transcription of atrogenes, such as Muscle Atrophy F-boX protein (Atrogin1) and Muscle RING-Finger Protein-1(MuRF1). Our previous study also indicated that exercise remodels MQC and improves mitochondrial functions 15 , 16 .…”

Section: Introductionmentioning

confidence: 81%

“…Our previous research indicated that TMZ alone or with exercise improves muscle function and the efficiency of mitochondrial quality control processes 16 . Our present study aims to further investigate whether exercise and TMZ respectively improve muscle dysfunction induced by a high-fat diet (HFD).…”

Section: Introductionmentioning

confidence: 99%

Trimetazidine and exercise provide comparable improvements to high fat diet-induced muscle dysfunction through enhancement of mitochondrial quality control

Zhang

You

et al. 2021

Sci Rep

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Obesity induces skeletal muscle dysfunction. The pathogenesis of which appears to substantially involve mitochondrial dysfunction, arising from impaired quality control. Exercise is a major therapeutic strategy against muscle dysfunction. Trimetazidine, a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, the effects of Trimetazidine on regulating skeletal muscle function are largely unknown. Our present study used cell culture and obese mice models to test a novel hypothesis that Trimetazidine could improve muscle atrophy with similar results to exercise. In C2C12 cells, high palmitic acid-induced atrophy and mitochondrial dysfunction, which could be reversed by the treatment of Trimetazidine. In our animal models, with high-fat diet-induced obesity associated with skeletal muscle atrophy, Trimetazidine prevented muscle dysfunction, corrected metabolic abnormalities, and improved mitochondrial quality control and mitochondrial functions similarly to exercise. Thus, our study suggests that Trimetazidine successfully mimics exercise to enhance mitochondrial quality control leading to improved high-fat diet-induced muscle dysfunction.

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“…Mitochondrial quality control (MQC), including mitochondrial biogenesis, mitophagy, and fusion/fission, has been used as an important evaluation for mitochondrial function. Our previous studies indicated that exercise activates MQC in skeletal and myocardial muscle (Xie et al, 2019;Jiang et al, 2021). However, exercise lacks a long-term therapeutic efficacy for muscle dysfunction due to poor compliance or disabilities resulted from skeleton-muscle system (Conraads et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The Treatment of Rhodiola Mimics Exercise to Resist High-Fat Diet-Induced Muscle Dysfunction via Sirtuin1-Dependent Mechanisms

You

Dun

et al. 2021

Front. Pharmacol.

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Muscle dysfunction is a complication of high-fat diet (HFD)-induced obesity that could be prevented by exercise, but patients did not get enough therapeutic efficacy from exercise due to multiple reasons. To explore alternative or supplementary approaches to prevent or treat muscle dysfunction in individuals with obesity, we investigated the effects of Rhodiola on muscle dysfunction as exercise pills. SIRT1 might suppress atrogenes expression and improve mitochondrial quality control, which could be a therapeutic target stimulated by exercise and Rhodiola, but further mechanisms remain unclear. We verified the lipid metabolism disorders and skeletal muscle dysfunction in HFD feeding mice. Moreover, exercise and Rhodiola were used to intervene mice with a HFD. Our results showed that exercise and Rhodiola prevented muscle atrophy and dysfunction in obese mice and activating the SIRT1 pathway, while atrogenes were suppressed and mitochondrial quality control was improved. EX-527, SIRT1 inhibitor, was used to validate the essential role of SIRT1 in salidroside benefit. Results of cell culture experiment showed that salidroside alleviated high palmitate-induced atrophy and mitochondrial quality control impairments, but these improvements of salidroside were inhibited by EX-527 in C2C12 myotubes. Overall, Rhodiola mimics exercise that activates SIRT1 signaling leading to improvement of HFD-induced muscle dysfunction.

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Trimetazidine combined with exercise improves exercise capacity and anti-fatal stress ability through enhancing mitochondrial quality control

Cited by 19 publications

References 59 publications

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

Trimetazidine and exercise provide comparable improvements to high fat diet-induced muscle dysfunction through enhancement of mitochondrial quality control

The Treatment of Rhodiola Mimics Exercise to Resist High-Fat Diet-Induced Muscle Dysfunction via Sirtuin1-Dependent Mechanisms

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