Abstract 13033: AST-120 Ameliorates Lowered Exercise Capacity and Mitochondrial Dysfunction of the Skeletal Muscle in Mice with Chronic Kidney Disease via Reducing Oxidative Stress
Background: Chronic kidney disease (CKD) impairs exercise capacity and markedly decreases quality of life with sedentary lifestyle. It increases the plasma levels of uremic toxins such as indoxyl sulfate (IS), which induce oxidative stress and may reduce exercise capacity. An oral adsorbent, AST-120, can reduce circulating IS, however, the effects of AST-120 on the skeletal muscle function and the exercise capacity have not been elucidated in CKD.
Methods and Results: Male 8 weeks old C57BL/6J mice were subtotally nephrectomized and divided into 2 groups of the treatment with or without 8% (w/w) of AST-120 in standard diet for 20 weeks (CKD+AST-120 and CKD; n=12 for each group). Sham-operated mice were served as controls (Sham; n=12). Total body weight, blood pressure, insulin, hemoglobin, and cardiac function did not change among groups. Plasma urea levels were increased by 2.0-folds in CKD groups, but were not affected by AST-120. Plasma IS levels were significantly increased in CKD compared to Sham (1.05±0.11 vs. 0.21±0.03 mg/dL, p<0.05), which was significantly ameliorated in CKD+AST-120 (0.41±0.06 mg/dL, p<0.05 vs. CKD). Running distance to exhaustion determined by treadmill tests was also significantly reduced in CKD compared to Sham (267±17 vs. 427±36 m, p<0.05) and this reduction was also significantly ameliorated in CKD+AST-120 (407±38 m, p<0.05 vs. CKD) without altering skeletal muscle weight. Citrate synthase activity was significantly reduced in the skeletal muscle from CKD by 63% (p<0.05 vs. Sham) and this decrease was significantly ameliorated in CKD+AST-120 (p<0.05 vs. CKD). Superoxide production determined by lucigenin chemiluminescence was significantly increased in isolated skeletal muscle from CKD by 171% (p<0.05 vs. Sham) and was significantly lowered in CKD+AST-120 (p<0.05 vs. CKD).
Conclusions: The administration of AST-120 into CKD mice improved exercise capacity and mitochondrial dysfunction of the skeletal muscle via reducing oxidative stress. AST-120 may be a novel therapeutic agent against exercise intolerance in CKD.
Author Disclosures: M. Nishikawa: None. N. Ishimori: None. S. Takada: None. A. Saito: None. T. Kadoguchi: None. T. Furihata: None. A. Fukushima: None. S. Matsushima: None. T. Yokota: None. S. Kinugawa: None. H. Tsutsui: Research Grant; Significant; MSD, Astellas, Ohtsuka, Shionogi, Daiichi-sankyo, Tanabe-Mitsubishi, Novartis, Pfizer. Honoraria; Significant; Daiichi-Sankyo, Tanabe-Mitsubishi, Pfizer, MSD.
- © 2014 by American Heart Association, Inc.