Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR-YY1-PGC1α pathway
Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR-YY1-PGC1α pathway
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DOI：
10.1016/j.freeradbiomed.2015.03.020
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发表时间：
2015-07-01
影响因子：
7.4
通讯作者：
Yan, Chuanzhu
中科院分区：
文献类型：
--
作者：
Ji, Kunqian;Zheng, Jinfan;Yan, Chuanzhu
成纤维细胞生长因子21（Fibroblast growth factor 21，FGF 21）是一种具有调节糖脂代谢多效性的生长因子。其表达在患有线粒体疾病的小鼠和人类的骨骼肌中增加。然而，FGF 21对骨骼肌响应线粒体呼吸链缺陷的影响在很大程度上是未知的。在这里，我们证明了FGF 21的表达增加是对呼吸链缺乏的代偿反应。FGF 21的mRNA和蛋白水平在线粒体肌病或MELAS患者的骨骼肌中显著升高。哺乳动物雷帕霉素靶蛋白（mTOR）磷酸化水平及其下游靶蛋白阴阳1（YY 1）和过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC-1 α）在C2 C12成肌细胞中通过FGF 21处理增加。成肌细胞中FGF 21对mTOR-YY 1-PGC 1 α通路的激活调节能量稳态，如细胞内ATP合成、耗氧率、柠檬酸合酶活性、糖酵解、线粒体DNA拷贝数和诱导关键能量代谢基因表达的显著增加所证明的。FGF 21对线粒体功能的影响需要磷酸肌醇3-激酶（PI 3 K），其激活mTOR。抑制PI 3 K、mTOR、YY 1和PGC-1 α活性减弱了FGF 21对细胞内ATP水平和线粒体基因表达的刺激作用。我们的研究结果表明，线粒体呼吸链缺陷引起骨骼肌的代偿性反应，通过增加肌肉中的FGF 21表达水平，这导致骨骼肌中通过mTOR-YY 1-PGC 1 α依赖性途径增强线粒体功能。(C)2015爱思唯尔公司All rights reserved.
Fibroblast growth factor 21 (FGF21) is a growth factor with pleiotropic effects on regulating lipid and glucose metabolism. Its expression is increased in skeletal muscle of mice and humans with mitochondrial disorders. However, the effects of FGF21 on skeletal muscle in response to mitochondrial respiratory chain deficiency are largely unknown. Here we demonstrate that the increased expression of FGF21 is a compensatory response to respiratory chain deficiency. The mRNA and protein levels of FGF21 were robustly raised in skeletal muscle from patients with mitochondrial myopathy or MELAS. The mammalian target of rapamycin (mTOR) phosphorylation levels and its downstream targets, Yin Yang 1 (YY1) and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1 alpha), were increased by FGF21 treatment in C2C12 myoblasts. Activation of the mTOR-YY1-PGC1 alpha pathway by FGF21 in myoblasts regulated energy homeostasis as demonstrated by significant increases in intracellular ATP synthesis, oxygen consumption rate, activity of citrate synthase, glycolysis, mitochondrial DNA copy number, and induction of the expression of key energy metabolic genes. The effects of FGF21 on mitochondrial function required phosphoinositide 3-kinase (PI3K), which activates mTOR. Inhibition of PI3K, mTOR, YY1, and PGC-1 alpha activities attenuated the stimulating effects of FGF21 on intracellular ATP levels and mitochondrial gene expression. Our findings revealed that mitochondrial respiratory chain deficiency elicited a compensatory response in skeletal muscle by increasing the FGF21 expression levels in muscle, which resulted in enhanced mitochondrial function through an mTOR-YY1-PGC1 alpha-dependent pathway in skeletal muscle. (C) 2015 Elsevier Inc. All rights reserved.