Thome 2020 JCI Insight
|Thome T, Kumar RA, Burke SK, Khattri RB, Salyers ZR, Kelley RC, Coleman MD, Christou DD, Hepple RT, Scali ST, Ferreira LF, Ryan TE (2020) Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease. JCI Insight [Epub ahead of print].|
Thome Trace, Kumar Ravi A, Burke Sarah K, Khattri Ram B, Salyers Zachary R, Kelley Rachel C, Coleman Madeline D, Christou Demetra D, Hepple Russel T, Scali Salvatore T, Ferreira Leonardo F, Ryan Terence E (2020) JCI Insight
Abstract: Chronic kidney disease (CKD) results in a progressive skeletal myopathy involving atrophy, weakness, and fatigue. Mitochondria have been thought to contribute to skeletal myopathy, however, the molecular mechanisms underlying changes in muscle metabolism in CKD are unknown. This study 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 principally 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 that CKD mice experienced muscle atrophy and increased muscle protein degradation, but only male CKD mice had lower maximal contractile force. CKD mice also had morphological changes indicative of destabilization in the neuromuscular junction. This study provides the first comprehensive evaluation of mitochondrial health in murine CKD muscle and uncovers several unknown uremic metabolites that are strongly associated with the degree of mitochondrial impairment.
Labels: MiParea: Respiration Pathology: Myopathy, Other
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Isolated mitochondria
Regulation: PCr;Cr Coupling state: LEAK, OXPHOS Pathway: F, N, S HRR: Oxygraph-2k