Introduction: Chronic kidney disease impairs physical performance from an early stage of disease, and the impairment is a critical medical problem because lowered physical activity correlates with renal prognosis and mortality, and constitutes an independent cardiovascular risk for chronic kidney disease patients, with as high an impact as hypertension and diabetes. In this study, the time course and mechanism of muscle insufficiency in renal failure were investigated using 5/6 nephrectomized (5/6Nx) mice, a model of mild chronic kidney disease. Furthermore, the effect of high-protein diet on chronic kidney disease was examined.
Methods: C57bl/6 mice which had undergone 5/6 nephrectomy at 67 weeks were examined for physical performance in young (1620 weeks old) and aged (4852 weeks old) groups. Protein adjusted diets were fed from 8 weeks old.
Results: A decrease in muscle mitochondria and running distance was identified in young 5/6Nx mice, despite the preservation of muscle volume and power. Thereafter, a decrease in muscle volume associated with a reduction in muscle power became apparent in aged 5/6Nx mice. A high-protein diet feeding from 8 weeks old increased muscle volume and power in the mice; however, it further decreased running distance, associated with a decrease in the activity of pyruvate dehydrogenase which promotes aerobic glycolysis. Activation of pyruvate dehydrogenase by dichroloacetate effectively recovered running distance which was decreased by dietary protein.
Conclusion: A decrease in muscle mitochondria was identified as a new mechanism for the reduction in exercise endurance of 5/6 nephrectomy mice. Decreased pyruvate dehydrogenase activity accounted for the further reduction in exercise endurance by dietary protein. These findings clarify the mechanism of muscle insufficiency in renal failure and suggest activation of muscle mitochondria as a potential strategy for the improvement of physical performance of patients with chronic kidney disease.