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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 4

Adenine-induced CKD did not change mitochondrial content in skeletal muscle.

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Adenine-induced CKD did not change mitochondrial content in skeletal mus...
(A) Representative Western blotting for select protein subunits of the electron transport system (ETS) in individual mitochondrial enzyme complexes along with corresponding total protein imaging. (B–F) Quantification of protein abundance from Western blotting using standard densitometry and normalization to each lane’s protein value (n = 3–4/group/sex). (G) Quantification of total protein in all samples confirms even loading and transfer (n = 3–4/group/sex). (H) Citrate synthase activity measured in whole gastrocnemius muscle lysates further confirms similar mitochondrial content in skeletal muscle of CKD mice (n = 5–7/group/sex). All data were analyzed using 2-way ANOVA with Tukey’s post hoc test when an interaction was detected. Error bars show standard deviation.
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