AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress

Mikito Nishikawa, Naoki Ishimori, Shingo Takada, Akimichi Saito, Tomoyasu Kadoguchi, Takaaki Furihata, Arata Fukushima, Shoji Matsushima, Takashi Yokota, Shintaro Kinugawa, Hiroyuki Tsutsui

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background. Exercise capacity and quality of life are markedly impaired in chronic kidney disease (CKD). Increased plasma uremic toxins such as indoxyl sulfate (IS), which induce oxidative stress, may be involved in this process. An oral adsorbent, AST-120, can reduce circulating IS, however, its effects on skeletal muscle and exercise capacity have not been investigated in CKD. Methods. Subtotal-nephrectomy or sham operation was performed in 8-week-old C57BL/6J mice. They were divided into two groups with or without 8% (w/w) of AST-120 in standard diet for 20 weeks. Sham, Sham + AST-120, CKD and CKD + AST-120 (n = 12, each group) were studied. We also conducted a C2C12 cell culture study to determine the direct effects of IS on oxidative stress. Results. Plasma IS levels were significantly increased in CKD compared with Sham (1.05 ± 0.11 versus 0.21 ± 0.03 mg/dL, P <0.05), which was significantly ameliorated in CKD + AST-120 (0.41 ± 0.06 mg/dL). The running distance to exhaustion determined by treadmill tests was significantly reduced in CKD compared with Sham (267 ± 17 versus 427 ± 36 m, P <0.05), and this reduction was also significantly ameliorated in CKD + AST-120 (407 ± 38 m) without altering skeletal muscle weight. Citrate synthase activity and mitochondrial biogenesis gene were downregulated, and superoxide production was significantly increased in the skeletal muscle from CKD, and these changes were normalized in CKD + AST-120. Incubation of C2C12 cells with IS significantly increased NAD(P)H oxidase activity. Conclusions. The administration of AST-120 improved exercise capacity and mitochondrial biogenesis of skeletal muscle via reducing oxidative stress. AST-120 may be a novel therapeutic agent against exercise intolerance in CKD.

Original languageEnglish
Pages (from-to)934-942
Number of pages9
JournalNephrology Dialysis Transplantation
Volume30
Issue number6
DOIs
Publication statusPublished - Jun 1 2015
Externally publishedYes

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Organelle Biogenesis
Chronic Renal Insufficiency
Skeletal Muscle
Oxidative Stress
Indican
AST 120
Citrate (si)-Synthase
Mitochondrial Genes
NADPH Oxidase
Nephrectomy
Exercise Test
Inbred C57BL Mouse
Superoxides
Running
Down-Regulation
Cell Culture Techniques
Quality of Life
Diet
Weights and Measures

All Science Journal Classification (ASJC) codes

  • Nephrology
  • Transplantation

Cite this

AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress. / Nishikawa, Mikito; Ishimori, Naoki; Takada, Shingo; Saito, Akimichi; Kadoguchi, Tomoyasu; Furihata, Takaaki; Fukushima, Arata; Matsushima, Shoji; Yokota, Takashi; Kinugawa, Shintaro; Tsutsui, Hiroyuki.

In: Nephrology Dialysis Transplantation, Vol. 30, No. 6, 01.06.2015, p. 934-942.

Research output: Contribution to journalArticle

Nishikawa, Mikito ; Ishimori, Naoki ; Takada, Shingo ; Saito, Akimichi ; Kadoguchi, Tomoyasu ; Furihata, Takaaki ; Fukushima, Arata ; Matsushima, Shoji ; Yokota, Takashi ; Kinugawa, Shintaro ; Tsutsui, Hiroyuki. / AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress. In: Nephrology Dialysis Transplantation. 2015 ; Vol. 30, No. 6. pp. 934-942.
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T1 - AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress

AU - Nishikawa, Mikito

AU - Ishimori, Naoki

AU - Takada, Shingo

AU - Saito, Akimichi

AU - Kadoguchi, Tomoyasu

AU - Furihata, Takaaki

AU - Fukushima, Arata

AU - Matsushima, Shoji

AU - Yokota, Takashi

AU - Kinugawa, Shintaro

AU - Tsutsui, Hiroyuki

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Background. Exercise capacity and quality of life are markedly impaired in chronic kidney disease (CKD). Increased plasma uremic toxins such as indoxyl sulfate (IS), which induce oxidative stress, may be involved in this process. An oral adsorbent, AST-120, can reduce circulating IS, however, its effects on skeletal muscle and exercise capacity have not been investigated in CKD. Methods. Subtotal-nephrectomy or sham operation was performed in 8-week-old C57BL/6J mice. They were divided into two groups with or without 8% (w/w) of AST-120 in standard diet for 20 weeks. Sham, Sham + AST-120, CKD and CKD + AST-120 (n = 12, each group) were studied. We also conducted a C2C12 cell culture study to determine the direct effects of IS on oxidative stress. Results. Plasma IS levels were significantly increased in CKD compared with Sham (1.05 ± 0.11 versus 0.21 ± 0.03 mg/dL, P <0.05), which was significantly ameliorated in CKD + AST-120 (0.41 ± 0.06 mg/dL). The running distance to exhaustion determined by treadmill tests was significantly reduced in CKD compared with Sham (267 ± 17 versus 427 ± 36 m, P <0.05), and this reduction was also significantly ameliorated in CKD + AST-120 (407 ± 38 m) without altering skeletal muscle weight. Citrate synthase activity and mitochondrial biogenesis gene were downregulated, and superoxide production was significantly increased in the skeletal muscle from CKD, and these changes were normalized in CKD + AST-120. Incubation of C2C12 cells with IS significantly increased NAD(P)H oxidase activity. Conclusions. The administration of AST-120 improved exercise capacity and mitochondrial biogenesis of skeletal muscle via reducing oxidative stress. AST-120 may be a novel therapeutic agent against exercise intolerance in CKD.

AB - Background. Exercise capacity and quality of life are markedly impaired in chronic kidney disease (CKD). Increased plasma uremic toxins such as indoxyl sulfate (IS), which induce oxidative stress, may be involved in this process. An oral adsorbent, AST-120, can reduce circulating IS, however, its effects on skeletal muscle and exercise capacity have not been investigated in CKD. Methods. Subtotal-nephrectomy or sham operation was performed in 8-week-old C57BL/6J mice. They were divided into two groups with or without 8% (w/w) of AST-120 in standard diet for 20 weeks. Sham, Sham + AST-120, CKD and CKD + AST-120 (n = 12, each group) were studied. We also conducted a C2C12 cell culture study to determine the direct effects of IS on oxidative stress. Results. Plasma IS levels were significantly increased in CKD compared with Sham (1.05 ± 0.11 versus 0.21 ± 0.03 mg/dL, P <0.05), which was significantly ameliorated in CKD + AST-120 (0.41 ± 0.06 mg/dL). The running distance to exhaustion determined by treadmill tests was significantly reduced in CKD compared with Sham (267 ± 17 versus 427 ± 36 m, P <0.05), and this reduction was also significantly ameliorated in CKD + AST-120 (407 ± 38 m) without altering skeletal muscle weight. Citrate synthase activity and mitochondrial biogenesis gene were downregulated, and superoxide production was significantly increased in the skeletal muscle from CKD, and these changes were normalized in CKD + AST-120. Incubation of C2C12 cells with IS significantly increased NAD(P)H oxidase activity. Conclusions. The administration of AST-120 improved exercise capacity and mitochondrial biogenesis of skeletal muscle via reducing oxidative stress. AST-120 may be a novel therapeutic agent against exercise intolerance in CKD.

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