Abstract
Chronic kidney disease (CKD) causes progressive skeletal myopathy involving atrophy, weakness, and fatigue. Mitochondria have been thought to contribute to skeletal myopathy; however, the molecular mechanisms underlying muscle metabolism changes in CKD are unknown. We employed a comprehensive mitochondrial phenotyping platform to elucidate the mechanisms of skeletal muscle mitochondrial impairment in mice with adenine-induced CKD. CKD mice displayed significant reductions in mitochondrial oxidative phosphorylation (OXPHOS), which was strongly correlated with glomerular filtration rate, suggesting a link between kidney function and muscle mitochondrial health. Biochemical assays uncovered that OXPHOS dysfunction was driven by reduced activity of matrix dehydrogenases. Untargeted metabolomics analyses in skeletal muscle revealed a distinct metabolite profile in CKD muscle including accumulation of uremic toxins that strongly associated with the degree of mitochondrial impairment. Additional muscle phenotyping found CKD mice experienced muscle atrophy and increased muscle protein degradation, but only male CKD mice had lower maximal contractile force. CKD mice had morphological changes indicative of destabilization in the neuromuscular junction. This study provides the first comprehensive evaluation of mitochondrial health in murine CKD muscle to our knowledge and uncovers several unknown uremic metabolites that strongly associate with the degree of mitochondrial impairment.
Highlights
Chronic kidney disease (CKD) affects more than 25 million Americans [1]
Much like the damage to the kidneys, these muscle-related symptoms often develop over long periods, and epidemiological and cross-sectional clinical studies have reported strong associations between the severity of myopathy and kidney function (GFR or diagnosed CKD stage) [42,43,44]
Much of the CKD literature examining the basis for myopathy has focused on mechanisms of protein degradation [3, 7]
Summary
Chronic kidney disease (CKD) affects more than 25 million Americans [1]. CKD has no cure and available treatment options for end-stage renal disease are limited to kidney transplant or chronic hemodialysis. Loss of muscle mass in CKD has been attributed to imbalances in protein synthesis and protein degradation pathways [3], resulting in a cachectic phenotype. Consistent with this idea, previous studies have demonstrated activation of proteolytic processing, including ubiquitin-proteasome pathway, caspase-3 and other atrophy signaling pathways, as well as myostatin, in CKD [4,5,6,7,8,9]. The activation of pathways contributing to muscle loss has been largely attributed to the multitude of CKD complications, including metabolic acidosis, inflammation, elevated glucocorticoid levels, and impaired IGF-1 signaling. Evidence for crosstalk between the kidneys and skeletal muscle has garnered support [10, 11], suggesting systemic factors directly link kidney function to skeletal muscle health in CKD
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