Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase

Abstract

Chronic kidney disease impairs physical performance. Here the time course and mechanism of muscle insufficiency in renal failure and the influence of dietary protein were studied using 5/6 nephrectomized C57Bl/6 mice, focusing on muscle mass and mitochondria. A decrease in muscle mitochondria and running distance was found in young (16-20 weeks) 5/6 nephrectomized mice, despite the preservation of muscle volume and power. However, a decrease in muscle volume, associated with a reduction in muscle power, was found in aged (48-52 weeks) 5/6 nephrectomized mice. A high-protein diet feeding from 8 weeks increased muscle volume and power in the mice; but this further decreased running distance. Activation of pyruvate dehydrogenase by dichloroacetate effectively recovered running distance that was decreased by dietary protein. These findings indicate the mechanism of muscle insufficiency in renal failure and suggest that activation of muscle mitochondria would serve as a potential strategy for improving the physical performance of the patients with chronic kidney disease.

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

“…Increased oxidative stress and inflammatory cytokines decrease mitochondria function 6. The present study revealed that IS decreases the expression of PGC‐1α (mitochondrial biosynthesis‐related factor) and increases autophagy (mitochondrial degradation‐related factor) in skeletal muscle in both in vivo and in vitro experiments.…”

“…Previous reports and our in vitro experiments ( Figure 1) demonstrated that there is mutual relationship between exercise capacity in treadmill experiments and muscular mitochondrial function 6, 9, 10, 19. We therefore further evaluated the mitochondrial status in skeletal muscle of CKD mice.…”

“…It has been reported that a reduction in exercise capacity was observed even in an early stage of CKD 2, 6. Recent studies further indicated that such an impaired exercise capacity was induced prior to the development of muscle atrophy, and this was mainly caused by mitochondrial dysfunction in skeletal muscle 6.…”

“…It is currently thought that the enhancement in oxidative stress and inflammatory cytokines is closely associated with CKD‐induced muscle atrophy 1, 23, 24. Interestingly, feeding a high protein diet not only reduces exercise endurance despite an increased muscle mass and muscle power in CKD mice6 but also exacerbates impaired renal function that is accompanied by an increased production of uremic toxins 25. This body of experimental evidence led us to hypothesize that uremic toxins play an important role in the mutual relationship between the aggravation of renal function, exercise capacity, and a high protein diet.…”

Mitophagy: Basic Mechanism and Potential Role in Kidney Diseases

“…In a rat model with chronic cyclosporin A (CsA) treatment, mitochondrial DNA copy number, along with the expression of nuclear and mitochondrial DNA-encoded oxidative phosphorylation (OXPHOS) proteins, peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, and mitochondrial transcription factor-A (Tfam) was dramatically decreased [87]. Interestingly, in a mouse model with 5/6 nephrectomy, decreases of mitochondrial content also happened in muscles, which resulted in impaired exercise endurance, a well-documented feature in chronic kidney diseases [88]. Mitochondrial biogenesis increases the mitochondrial mass and functional capacity or helps preserve it by replacing damaged mitochondria, so defects in mitochondrial biogenesis may deteriorate kidney injury.…”