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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Cachexia+Sarcopenia+Muscle
2017 ; 8
(5
): 735-747
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Potential therapeutic interventions for chronic kidney disease-associated
sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction
#MMPMID28608457
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
J Cachexia Sarcopenia Muscle
2017[Oct]; 8
(5
): 735-747
PMID28608457
show ga
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.
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