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首页> 外文期刊>Journal of Cachexia, Sarcopenia and Muscle >Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction
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Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction

机译：硫酸吲哚酚诱导的线粒体功能障碍对慢性肾脏疾病相关的少肌症的潜在治疗性干预

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Abstract Background 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. Methods 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. Results In C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC-1???± 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-1???± 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. Conclusions 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.
机译：摘要背景慢性肾脏病（CKD）患者经历骨骼肌消耗和运动耐力下降。我们之前的研究表明，尿毒症毒素-吲哚酚硫酸盐（IS）会加速骨骼肌萎缩。这项研究的目的是研究是否IS会导致线粒体功能障碍和使用AST-120抑制IS积累的IS靶向干预，还是使用L-肉碱或Teneligliptin（一种二肽基肽酶4抑制剂）对线粒体进行干预的问题。保留线粒体功能并减轻慢性肾脏疾病小鼠的骨骼肌萎缩和肌肉耐力。方法用小鼠成肌纤维细胞（C2C12细胞）评价IS对线粒体状态的体外作用。将小鼠分为假手术或5/6肾切除术（CKD）小鼠组。慢性肾脏疾病小鼠也被随机分为非治疗组和AST-120，左旋肉碱或替尼格列汀治疗组。结果在C2C12细胞中，IS除了降低线粒体膜电位外，还通过降低PGC-1β的表达并诱导自噬来诱导线粒体功能障碍。与抗氧化剂，抗坏血酸，L-肉碱或Teneligliptine共同孵育可将值恢复到原始状态。与假小鼠相比，CKD小鼠的身体和骨骼肌重量降低。与假手术小鼠相比，CKD小鼠骨骼肌中白介素6和肌萎缩相关因子如肌生长抑制素和阿特罗金-1的表达增加，而肌肉Akt磷酸化减少。另外，观察到CKD小鼠的运动能力降低，这伴随着肌肉PCG-1β表达的降低和肌肉自噬的增加，这由线粒体富集的I型纤维的减少所反映。 AST-120处理可将这些变化（包括在CKD小鼠中观察到的骨骼肌重量）恢复至假水平，同时降低IS水平。 L-肉碱或Teneligliptin治疗也可将其恢复至假水平，而不会改变IS水平。结论我们的结果表明，IS诱导骨骼肌细胞线粒体功能障碍，并提供了潜在的治疗策略，例如以IS为靶点和以线粒体为靶点的干预措施，以治疗CKD引起的肌肉萎缩和运动耐力下降。

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