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Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease.

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.

SUBMITTER: Thome T

PROVIDER: S-EPMC7821598 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease.

Thome Trace T Kumar Ravi A RA Burke Sarah K SK Khattri Ram B RB Salyers Zachary R ZR Kelley Rachel C RC Coleman Madeline D MD Christou Demetra D DD Hepple Russell T RT Scali Salvatore T ST Ferreira Leonardo F LF Ryan Terence E TE

JCI insight 20201208 1

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 oxidat ...[more]

PMID: 33290279

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Project description:Chronic kidney disease (CKD) leads to increased skeletal muscle fatigue, weakness, and atrophy. Previous work has implicated mitochondria within the skeletal muscle as a mediator of muscle dysfunction in CKD; however, the mechanisms underlying mitochondrial dysfunction in CKD are not entirely known. The purpose of this study was to define the impact of uremic metabolites on mitochondrial energetics. Skeletal muscle mitochondria were isolated from C57BL/6N mice and exposed to vehicle (DMSO) or varying concentrations of uremic metabolites: indoxyl sulfate, indole-3-acetic-acid, l-kynurenine, and kynurenic acid. A comprehensive mitochondrial phenotyping platform that included assessments of mitochondrial oxidative phosphorylation (OXPHOS) conductance and respiratory capacity, hydrogen peroxide production (JH2O2), matrix dehydrogenase activity, electron transport system enzyme activity, and ATP synthase activity was employed. Uremic metabolite exposure resulted in a ~25-40% decrease in OXPHOS conductance across multiple substrate conditions (P < 0.05, n = 5-6/condition), as well as decreased ADP-stimulated and uncoupled respiratory capacity. ATP synthase activity was not impacted by uremic metabolites; however, a screen of matrix dehydrogenases indicated that malate and glutamate dehydrogenases were impaired by some, but not all, uremic metabolites. Assessments of electron transport system enzymes indicated that uremic metabolites significantly impair complex III and IV. Uremic metabolites resulted in increased JH2O2 under glutamate/malate, pyruvate/malate, and succinate conditions across multiple levels of energy demand (all P < 0.05, n = 4/group). Disruption of mitochondrial OXPHOS was confirmed by decreased respiratory capacity and elevated superoxide production in cultured myotubes. These findings provide direct evidence that uremic metabolites negatively impact skeletal muscle mitochondrial energetics, resulting in decreased energy transfer, impaired complex III and IV enzyme activity, and elevated oxidant production.

Dataset Information

Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease.

Publications

Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease.

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