Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

Abstract

BackgroundChronic 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.MethodsThe 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.ResultsIn 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.ConclusionsOur 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.

Reductions in skeletal muscle mitochondrial mass are not restored following exercise training in patients with chronic kidney disease

“…D, Densitometry analysis of OXPHOS complex abundance. 28,55,56 In line with previous results from animal models of CKD, 26,28 we have shown that patients with moderate to severe CKD stage 3b-5 display a 46% reduction in skeletal muscle CS activity and a 86% decrease in the porin/β-actin ratio suggesting a substantial reduction in mitochondrial mass compared to healthy matched controls. E, Representative western blot analysis of OXPHOS protein complexes in healthy controls and CKD patients ageing and also in other disease states.…”

Muscle wasting and sarcopenia in heart failure: a brief overview of the current literature

“…Chronic kidney disease promotes muscle inflammation through an up-regulation of toll-like receptor 4, which may activate downward inflammatory signals such as tumour necrosis factor and nuclear factor κB-regulated genes. 68 In patients on haemodialysis, the valid detection of sarcopenia may be particularly difficult among obese subjects. In vitro and in vivo models have used, for example, dexamethasone administration as well as ursolic acid derived from plants.…”

The double‐edged sword of endoplasmic reticulum stress in uremic sarcopenia through myogenesis perturbation

“…Because uremic patients prolongedly and continually exposed to pathological IS concentration, higher IS concentration would be rational in in‐vitro shorten exposure cell culture study. The same concept is also mentioned in another study …”

“…By the action of intestinal bacteria, dietary tryptophan is metabolized to indole, which is absorbed, metabolized, and sulfonated to IS in the liver . The failure of renal excretion causes IS accumulation, which causes numerous uremic symptoms and promotes premature aging . Accordingly, it is considered that CKD is a premature aging syndrome and uremic milieu provides a good model to study the aging process.…”