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Abstract: PO2013

Indoxyl Sulfate Modulates Expression of Myosin Heavy Chain Isoforms and induces Sarcopenic Phenotype in Mouse

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1300 Health Maintenance, Nutrition, and Metabolism

Authors

  • Higashihara, Takaaki, Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  • Nishi, Hiroshi, Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  • Takemura, Koji, Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  • Nangaku, Masaomi, Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Background

In patients with chronic kidney disease, sarcopenia is frequently associated with decreased renal function and correlates with increased morbidity and mortality. However, the molecular mechanism to underlie uremic sarcopenia is not fully elucidated yet. We hypothesized that the accumulation of uremic toxin might have a direct negative effect on skeletal muscle, and investigated the mechanism of indoxyl sulfate (IS) induced toxicity on mouse skeletal muscle.

Methods

We conducted the vivo experiments using C57BL/6j mice. After unilateral nephrectomy, vehicle (PBS) or high dose IS was intraperitoneally administered daily for 1 week, and evaluated exercise tolerance (treadmill fatigue test and four limbs grip test), skeletal muscle wet weight, cross-sectional area, and protein levels of myosin heavy chain isoforms characterizing fast/slow twitch muscle fibers (fluorescent immunostaining and western blot, respectively), and the expression of muscle atrophy related genes (quantitative-PCR).

Results

In mice treated with IS, exercise tolerance was deteriorated and gastrocnemius muscle wet weight were decreased compared to the control group. Intriguingly, IS administration also reduced a cross-sectional area of fast twitch myofiber and protein levels of fast twitch myosin heavy chain. Also, IS treatment tended to up-regulated mRNA expression of muscle atrophy related genes (Atrogin-1 and Myostatin) of the gastrocnemius muscle tissue.

Conclusion

IS induces direct sarcopenic effect on mouse skeletal muscle and predominantly decreases on fast-twitch muscle fibers. In the future, we will further investigate the molecular mechanism of uremic toxin induced sarcopenia.