Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction.
Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction.
复制标题
DOI：
10.1002/jcsm.12202
复制
发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Maruyama T
中科院分区：
文献类型：
--
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
慢性肾脏病(CKD)患者会出现骨骼肌萎缩和运动耐力下降。我们先前的研究表明，尿毒症毒素吲哚硫酸盐(IS)会加速骨骼肌萎缩。本研究的目的是探讨IS是否导致线粒体功能障碍，并使用抑制IS蓄积的AST120进行靶向干预，或者使用L肉碱或替利利普汀进行线粒体靶向干预。TENGLIPTIN是一种保留线粒体功能、缓解骨骼肌萎缩和肌肉耐力的二肽基肽酶-4抑制剂。以小鼠成肌细胞(C2C12细胞)为研究对象，观察IS对线粒体状态的影响。随机分为假手术组和5/6肾切除(CKD)组。慢性肾脏病小鼠也随机分为非治疗组和AST120、L-卡尼汀或替利脂治疗组。在C2C12细胞中，除降低线粒体膜电位外，还通过降低PGC-1α的表达和诱导自噬而诱导线粒体功能障碍。与抗氧化剂、抗坏血酸、L肉碱或替利立普汀共同孵育后，这些值恢复到原来的状态。与假手术组相比，CKD组小鼠的体重和骨骼肌重均降低。与假手术组相比，CKD组小鼠骨骼肌中IL-6及萎缩相关因子Myostatin、Avergin-1的表达增加，而Akt的磷酸化水平降低。此外，观察到慢性肾脏病小鼠的运动能力下降，伴随着肌肉PCG-1α表达减少和肌肉自噬增加，这反映在富含线粒体的I型纤维减少。AST-120治疗显着恢复了这些变化，包括在CKD小鼠中观察到的骨骼肌重量，恢复到假手术水平，同时降低了IS水平。L-卡尼汀或替利格列汀治疗也能在不改变IS水平的情况下将它们恢复到假水平。我们的结果表明，IS导致骨骼肌细胞线粒体功能障碍，并为治疗CKD引起的肌肉萎缩和运动耐力下降提供了一种潜在的治疗策略，如IS靶向和线粒体靶向干预。
Chronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS‐targeted intervention using AST‐120, which inhibits IS accumulation, or mitochondria‐targeted intervention using L‐carnitine or teneligliptin, a dipeptidyl peptidase‐4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice. The in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6‐nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non‐treatment group and AST‐120, L‐carnitine, or teneligliptin treatment groups. In C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC‐1α and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co‐incubation with an anti‐oxidant, ascorbic acid, L‐carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin‐6 and atrophy‐related factors such as myostatin and atrogin‐1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG‐1α and increased muscular autophagy, as reflected by decreased mitochondria‐rich type I fibres. An AST‐120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L‐carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level. Our results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS‐targeted and mitochondria‐targeted interventions for treating CKD‐induced muscle atrophy and decreased exercise endurance.