High phosphate induces skeletal muscle atrophy and suppresses myogenic differentiation by increasing oxidative stress and activating Nrf2 signaling.
High phosphate induces skeletal muscle atrophy and suppresses myogenic differentiation by increasing oxidative stress and activating Nrf2 signaling.
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DOI：
10.18632/aging.103896
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发表时间：
2020-11-02
期刊：
影响因子：
--
通讯作者：
Hsu YJ
中科院分区：
文献类型：
--
作者：
Chung LH;Liu ST;Huang SM;Salter DM;Lee HS;Hsu YJ
骨骼肌萎缩既是一种常见的衰老表型，也是慢性肾脏疾病（CKD）等病理条件的特征。尽管临床数据和小鼠基因实验都表明高磷血症加速肌肉萎缩，但其潜在机制尚不清楚。在这里，我们发现无机磷酸盐（Pi）剂量依赖性地降低小鼠C2C12骨骼肌细胞的肌管大小、融合指数和肌原素表达。这些变化伴随着活性氧（ROS）生成、Nrf2和p62表达的增加，以及线粒体膜电位（MMP）和Keap1表达的降低。抑制Pi进入、胞内ROS生成或Nrf2激活逆转了高Pi对Nrf2、p62和肌原素表达的影响。Nrf2的过表达分别增加和降低p62-Luc和myogenin-Luc报告子的启动子活性。对高Pi （2% Pi）日粮小鼠腓肠肌核提取物的分析显示，假手术小鼠和5/6肾切除（CKD）小鼠Nrf2磷酸化增加，CKD小鼠p62磷酸化增加，肌原素表达减少。这些数据表明，高Pi通过氧化应激介导的蛋白质降解以及典型（ros介导）和非典型（p62介导）Nrf2信号的激活，在体外抑制成肌分化，并在体内促进肌肉萎缩。
Skeletal muscle wasting represents both a common phenotype of aging and a feature of pathological conditions such as chronic kidney disease (CKD). Although both clinical data and genetic experiments in mice suggest that hyperphosphatemia accelerates muscle wasting, the underlying mechanism remains unclear. Here, we showed that inorganic phosphate (Pi) dose-dependently decreases myotube size, fusion index, and myogenin expression in mouse C2C12 skeletal muscle cells. These changes were accompanied by increases in reactive oxygen species (ROS) production and Nrf2 and p62 expression, and reductions in mitochondrial membrane potential (MMP) and Keap1 expression. Inhibition of Pi entry, cytosolic ROS production, or Nrf2 activation reversed the effects of high Pi on Nrf2, p62, and myogenin expression. Overexpression of Nrf2 respectively increased and decreased the promoter activity of p62-Luc and myogenin-Luc reporters. Analysis of nuclear extracts from gastrocnemius muscles from mice fed a high-Pi (2% Pi) diet showed increased Nrf2 phosphorylation in sham-operated and 5/6 nephrectomized (CKD) mice, and both increased p62 phosphorylation and decreased myogenin expression in CKD mice. These data suggest that high Pi suppresses myogenic differentiation in vitro and promotes muscle atrophy in vivo through oxidative stress-mediated protein degradation and both canonical (ROS-mediated) and non-canonical (p62-mediated) activation of Nrf2 signaling.
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影响因子：
7.3
作者：
Al-Sawaf, Othman;Fragoulis, Athanassios;Wruck, Christoph Jan
通讯作者：
Wruck, Christoph Jan
影响因子：
4.8
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
37.8
作者：
Peri-Okonny, Poghni;Baskin, Kedryn K.;Vongpatanasin, Wanpen
通讯作者：
Vongpatanasin, Wanpen
DOI：
10.1002/jcsm.12202
发表时间：
2017-10
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Enoki Y;Watanabe H;Arake R;Fujimura R;Ishiodori K;Imafuku T;Nishida K;Sugimoto R;Nagao S;Miyamura S;Ishima Y;Tanaka M;Matsushita K;Komaba H;Fukagawa M;Otagiri M;Maruyama T
通讯作者：
Maruyama T
影响因子：
19.6
作者：
Johansen, KL;Shubert, T;Kent-Braun, JA
通讯作者：
Kent-Braun, JA