CREG1 improves the capacity of the skeletal muscle response to exercise endurance via modulation of mitophagy
CREG1 improves the capacity of the skeletal muscle response to exercise endurance via modulation of mitophagy
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CREG1 通过调节线粒体自噬提高骨骼肌对运动耐力的反应能力
DOI：
10.1080/15548627.2021.1904488
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发表时间：
2021-03
期刊：
影响因子：
13.3
通讯作者：
Yaling Han
中科院分区：
文献类型：
--
作者：
Haixu Song;Xiaoxiang Tian;Dan liu;Meili Liu;Yanxia Liu;Jing Liu;Mei Zu;Chenghui Yan;Yaling Han
CREG 1（cellular repressor of E1 A-stimulated genes 1）参与组织内环境的稳定，并影响巨自噬/自噬以保护心血管功能。然而，CREG 1在骨骼肌中的生理和病理作用尚不清楚。在这里，我们建立了一个骨骼肌特异性creg 1基因敲除小鼠模型（creg 1;Ckm-Cre）通过交叉的Creg 1-floxed小鼠（Creg 1fl/fl）与转基因线表达Cre重组酶下的肌肉特异性Ckm（肌酸激酶，肌肉）启动子。In creg 1; Ckm-Cre小鼠在9月龄时的运动至力竭时间和跑步距离与Creg 1fl/fl小鼠相比显著减少。此外，重组（re）CREG 1蛋白的施用改善了9个月大的creg 1;Ckm-Cre小鼠的运动功能。此外，9个月大的creg 1;Ckm-Cre小鼠的电子显微镜图像显示，线粒体质量和数量异常，并与PINK 1（PTEN诱导的推定激酶1）和PRKN/PARKIN（parkin RBR E3泛素蛋白连接酶）水平升高相关，但线粒体蛋白PTGS 2/COX 2、COX 4 I1/COX 4和TOMM 20水平降低相关。这些结果表明，CREG 1缺陷加速了骨骼肌中线粒体自噬的诱导。从机制上讲，Creg 1的功能获得性和丧失性突变改变了线粒体的形态和功能，损害了C2 C12细胞的线粒体自噬。此外，热休克蛋白1（HSP 1/HSP 60）（401-573 aa）与CREG 1（130-220 aa）相互作用，拮抗CREG 1的降解，参与线粒体自噬的调控。这是第一次证明CREG 1定位于线粒体，并在线粒体自噬调节中发挥重要作用，该调节决定了生长过程或疾病条件下的骨骼肌萎缩。缩略语名称：CCCP：羰基氰间氯苯腙; CKM：肌酸激酶，肌肉; COX 4 I1/COX 4：细胞色素c氧化酶亚基4 I1; CREG 1：E1 A刺激基因1的细胞阻遏物; DMEM：杜氏改良艾德伊格尔培养基; DNM 1 L/DRP 1：发动蛋白1样; FCCP：羰基氰对三氟甲氧基苯腙; HSPD 1/HSP 60：热休克蛋白1（伴侣蛋白）; IP：免疫沉淀; MAP 1 LC 3B/LC 3B：微管相关蛋白1轻链3 β; MFF：线粒体分裂因子; MFN 2：线粒体融合蛋白2; MYH 1/MHC-I：肌球蛋白，重多肽1，骨骼肌，成人; OCR：耗氧率; OPA 1：OPA 1，线粒体动力蛋白样GT3; PINK1：PTEN诱导的推定激酶1; PPARGC 1A/PGC-1α：过氧化物酶体增殖激活受体，γ，共激活因子1 α; PRKN/PARKIN：帕金RBR E3泛素蛋白连接酶; PTGS 2/COX 2：胰高血糖素-内过氧化物合酶2; RFP：红色荧光蛋白; RT-qPCR：实时定量PCR; SQSTM 1/p62：隔离体1; TFAM：转录因子A，线粒体; TOMM 20：线粒体外膜转位酶20; VDAC：电压依赖性阴离子通道。
ABSTRACT CREG1 (cellular repressor of E1A-stimulated genes 1) is involved in tissue homeostasis and influences macroautophagy/autophagy to protect cardiovascular function. However, the physiological and pathological role of CREG1 in the skeletal muscle is not clear. Here, we established a skeletal muscle-specific creg1 knockout mouse model (creg1;Ckm-Cre) by crossing the Creg1-floxed mice (Creg1fl/fl ) with a transgenic line expressing Cre recombinase under the muscle-specific Ckm (creatine kinase, muscle) promoter. In creg1;Ckm-Cre mice, the exercise time to exhaustion and running distance were significantly reduced compared to Creg1fl/fl mice at the age of 9 months. In addition, the administration of recombinant (re)CREG1 protein improved the motor function of 9-month-old creg1;Ckm-Cre mice. Moreover, electron microscopy images of 9-month-old creg1;Ckm-Cre mice showed that the mitochondrial quality and quantity were abnormal and associated with increased levels of PINK1 (PTEN induced putative kinase 1) and PRKN/PARKIN (parkin RBR E3 ubiquitin protein ligase) but reduced levels of the mitochondrial proteins PTGS2/COX2, COX4I1/COX4, and TOMM20. These results suggested that CREG1 deficiency accelerated the induction of mitophagy in the skeletal muscle. Mechanistically, gain-and loss-of-function mutations of Creg1 altered mitochondrial morphology and function, impairing mitophagy in C2C12 cells. Furthermore, HSPD1/HSP60 (heat shock protein 1) (401–573 aa) interacted with CREG1 (130–220 aa) to antagonize the degradation of CREG1 and was involved in the regulation of mitophagy. This was the first time to demonstrate that CREG1 localized to the mitochondria and played an important role in mitophagy modulation that determined skeletal muscle wasting during the growth process or disease conditions. Abbreviations: CCCP: carbonyl cyanide m-chlorophenylhydrazone; CKM: creatine kinase, muscle; COX4I1/COX4: cytochrome c oxidase subunit 4I1; CREG1: cellular repressor of E1A-stimulated genes 1; DMEM: dulbecco’s modified eagle medium; DNM1L/DRP1: dynamin 1-like; FCCP: carbonyl cyanide p-trifluoro-methoxy phenyl-hydrazone; HSPD1/HSP60: heat shock protein 1 (chaperonin); IP: immunoprecipitation; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFF: mitochondrial fission factor; MFN2: mitofusin 2; MYH1/MHC-I: myosin, heavy polypeptide 1, skeletal muscle, adult; OCR: oxygen consumption rate; OPA1: OPA1, mitochondrial dynamin like GTPase; PINK1: PTEN induced putative kinase 1; PPARGC1A/PGC-1α: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; RFP: red fluorescent protein; RT-qPCR: real-time quantitative PCR; SQSTM1/p62: sequestosome 1; TFAM: transcription factor A, mitochondrial; TOMM20: translocase of outer mitochondrial membrane 20; VDAC: voltage-dependent anion channel.
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影响因子：
5
作者：
Meng Q;Li BX;Xiao X
通讯作者：
Xiao X
影响因子：
--
作者：
Kim TN;Choi KM
通讯作者：
Choi KM
E1A 刺激基因的细胞阻遏物是血管紧张素 II 引起的血管重塑的关键决定因素
DOI：
10.1161/atvbaha.116.308794
发表时间：
2017-03-01
影响因子：
8.7
作者：
Li, Yang;Liu, Yanxia;Han, Yaling
通讯作者：
Han, Yaling
影响因子：
4
作者：
Balan, Estelle;Schwalm, Celine;Deldicque, Louise
通讯作者：
Deldicque, Louise
影响因子：
5.5
作者：
Carter, Heather N.;Kim, Yuho;Hood, David A.
通讯作者：
Hood, David A.