GCN2 deficiency protects mice from denervation-induced skeletal muscle atrophy via inhibiting FoxO3a nuclear translocation

Guo, Yuting; Wang, Huiwen; Yi, Tang; Wang, Yue; Zhang, Mengqi; Yang, Zhiguang; Nyirimigabo, Eric; Wei, Bin; Lu, Zhigang; Ji, Guangju

doi:10.1007/s13238-018-0504-0

Cited by 8 publications

(7 citation statements)

References 16 publications

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“…Similar results were observed in the protein levels of Atrogin-1 and MuRF1 (Figure 3C). Previous studies have suggested that the FoxO3a is involved in the activation of atrophy-linked ubiquitin ligases, including Atrogin-1 and MuRF1 [26,27]. We found that the phosphorylation of FoxO3a was decreased by dexamethasone and was reversed by trimetazidine in C2C12 myotubes (Figure 3D).…”

Section: Trimetazidine Attenuates Dexamethasone-induced C2c12 Myotube Atrophysupporting

confidence: 57%

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: Trimetazidine Attenuates Dexamethasone-induced C2c12 Myotube Atrophysupporting

confidence: 57%

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

Wang¹,

He²,

Shen³

et al. 2020

Preprint

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“…Plenty of evidence indicates that glucocorticoids can cause muscle atrophy via decreasing protein synthesis and increasing degradation; in particular, the ubiquitin‐proteasome system is the most prominent mechanism of protein breakdown [ 25 , 27 ]. In the ubiquitin-proteasome pathway, FoxO3a is considered as a key player in the control of skeletal muscle protein turnover [ 28 , 29 ]. Inhibition of the PI3K/AKT signaling pathway has been implicated in the induction of muscle atrophy via dephosphorylating FoxO3a and promoting the nuclear translocation of FoxO3a, which in turn increases the expression of the E3 ubiquitin ligases, Atrogin-1 and MuRF1 [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Jiao

et al. 2021

Cell Death Discov.

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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 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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“…Under conditions of amino acid deprivation, GCN2 maintains amino acid homeostasis through phosphorylating eukaryotic initiation factor 2α at Ser51 (eIF2α Ser51 ) and selectively stimulating the expression of amino acid biosynthetic genes [13] , [14] . In addition to regulating amino acid starvation response, GCN2 is also involved in memory formation [15] , immune response [16] , [17] and muscle atrophy [18] . Interestingly, GCN2 was found to promote sodium salicylate- or histone deacetylase inhibitor-induced apoptosis [19] , [20] , and it has been suggested that GCN2 expression levels determine the sensitivity of cancer cells to Na + , K + -ATPase ligand-induced apoptosis [21] .…”

Section: Introductionmentioning

confidence: 99%

GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and myocardial oxidative stress

et al. 2018

Self Cite

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The clinical use of doxorubicin for cancer therapy is limited by its cardiotoxicity, which involves cardiomyocyte apoptosis and oxidative stress. Previously, we showed that general control nonderepressible 2 (GCN2), an eukaryotic initiation factor 2α (eIF2α) kinase, impairs the ventricular adaptation to chronic pressure overload by affecting cardiomyocyte apoptosis. However, the impact of GCN2 on Dox-induced cardiotoxicity has not been investigated. In the present study, we treated wild type (WT) and Gcn2−/− mice with four intraperitoneal injections (5 mg/kg/week) to induce cardiomyopathy. After Dox treatment, Gcn2−/− mice developed less contractile dysfunction, myocardial fibrosis, apoptosis, and oxidative stress compared with WT mice. In the hearts of the Dox-treated mice, GCN2 deficiency attenuated eIF2α phosphorylation and induction of its downstream targets, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and preserved the expression of anti-apoptotic factor Bcl-2 and mitochondrial uncoupling protein-2(UCP2). Furthermore, we found that GCN2 knockdown attenuated, whereas GCN2 overexpression exacerbated, Dox-induced cell death, oxidative stress and reduction of Bcl-2 and UCP2 expression through the eIF2α-CHOP-dependent pathway in H9C2 cells. Collectively, our data provide solid evidence that GCN2 has a marked effect on Dox induced myocardial apoptosis and oxidative stress. Our findings suggest that strategies to inhibit GCN2 activity in cardiomyocyte may provide a novel approach to attenuate Dox-related cardiotoxicity.

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GCN2 deficiency protects mice from denervation-induced skeletal muscle atrophy via inhibiting FoxO3a nuclear translocation

Cited by 8 publications

References 16 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 attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis

GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and myocardial oxidative stress

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