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Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease
Trace Thome, … , Leonardo F. Ferreira, Terence E. Ryan
Trace Thome, … , Leonardo F. Ferreira, Terence E. Ryan
Published December 8, 2020
Citation Information: JCI Insight. 2021;6(1):e139826. https://doi.org/10.1172/jci.insight.139826.
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Research Article Muscle biology Nephrology

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

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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.

Authors

Trace Thome, Ravi A. Kumar, Sarah K. Burke, Ram B. Khattri, Zachary R. Salyers, Rachel C. Kelley, Madeline D. Coleman, Demetra D. Christou, Russell T. Hepple, Salvatore T. Scali, Leonardo F. Ferreira, Terence E. Ryan

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Figure 3

CKD does not alter skeletal muscle mitochondrial H2O2 production or electron leak under physiological conditions.

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CKD does not alter skeletal muscle mitochondrial H2O2 production or elec...
(A) Mitochondrial H2O2 production (JH2O2) under state 2 (no ADP = no energy demand) for the following substrates: pyruvate + malate, glutamate + malate, FA + malate, and succinate. (B) Mitochondrial H2O2 production levels under conditions mimicking resting energy demand (ΔGATP = –15.24 kcal/mol) for each substrate condition. (C) Calculated percentage electron leak (JH2O2/JO2) for state 2 respiration for the following substrates (pyruvate + malate, glutamate + malate, FA + malate). Succinate was not used due to the presence of rotenone during the OXPHOS conductance experiments. (D) Calculated percentage electron leak (JH2O2/JO2) under resting level energy demand (ΔGATP = –15.24 kcal/mol) for each substrate condition. All data were analyzed using 2-way ANOVA followed by Tukey’s post hoc test when an interaction was established. Error bars show standard deviation.
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