Chronic Kidney Disease Causes Skeletal Mitochondrial Myopathy Through Disruption of the Electron Transport System
Authors: Thome Trace , Coleman Madeline D. , Kumar Ravi A. , Salyers Zachary R. , Skinner Sarah , Scali Salvatore T. , Ferreira Leonardo F. , Ryan Terence E. 
Published: April 2020

Introduction

Chronic kidney disease (CKD) is associated with debilitating myopathic symptoms including muscle wasting, weakness, and fatigue. Mitochondria have been implicated as a mediator of skeletal muscle dysfunction in CKD, however, the underlying mechanisms of mitochondrial dysfunction in CKD are unknown.

Purpose

The purpose of this study was to define the impact of CKD on muscle mitochondrial energy transduction, metabolomic profiles, and muscle contractile function.

Methods

8‐week old C57BL/6J mice (N=6–10/group/sex) were fed a casein control or adenine supplemented‐diet for 10‐weeks. CKD was confirmed through measurement of glomerular filtration rate (GFR), blood urea nitrogen, and kidney histology. A comprehensive mitochondrial phenotyping platform included respiratory function, H2O2 emission, matrix dehydrogenase and OXPHOS enzyme activity, and ATP synthase activity was employed. Muscle function, size, metabolomic profiles were also assessed.

Results

CKD resulted in a 30–40% decrease in OXPHOS sensitivity supported by pyruvate/malate, glutamate/malate, succinate/rotenone, and octanoylcarnitine/malate (all P<0.05) using a creatine kinase clamp to control the extracellular energy demand for mitochondria. CKD decreased maximal ADP‐stimulated respiratory capacity (4139.1 ± 564.4 vs 3448.7 ± 782.2 pmols/s/mg, P<0.05), despite no change in mitochondrial content (citrate synthase activity and western blotting). Significant correlations between GFR and skeletal muscle mitochondrial respiratory function were observed in all substrate conditions (all P<0.03). Enzymatic assays demonstrated significant decreases (~35%) in the activity of pyruvate and alpha‐ketoglutarate dehydrogenases (P<0.05), and non‐significant decreases in glutamate dehydrogenase, malic enzyme, and isocitrate dehydrogenase (12–36%). Mitochondrial H2O2 production was modestly increased with pyruvate/malate (P=0.043) but not different with octanoylcarnitine/malate or glutamate/malate (P=0.18 and 0.23 respectively). With both sexes combined, muscle force production was not different, however, when separated male CKD mice had lower force production (293.1 ± 20.8 vs 236.8 ± 25.5, P<0.05). Muscle weights and myofiber areas confirmed atrophy in male CKD mice. Metabolomics analyses indicated alterations in amino acid catabolism including arginine, tryptophan, phenylalanine/tyrosine, increased allantoin, and accumulation of uremic metabolites previously found to negatively impact mitochondrial energetics.

Conclusion

To our knowledge, this is the first study to define the exact mechanisms by which CKD alters skeletal muscle mitochondrial function. Using mitochondrial phenotyping, CKD was found to disrupt OXPHOS enzymes and matrix dehydrogenases resulting in impaired oxidative phosphorylation and elevated H2O2 production. These discoveries provide the foundation for targeted mitochondrial therapies aimed to treat skeletal myopathy in CKD patients.

Support or Funding Information

Supported by R01 HL148597 (STS and TER).