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Abstract: PO2010

CKD Remodels Skeletal Muscle Metabolism Toward Carbohydrate Oxidation

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1300 Health Maintenance, Nutrition, and Metabolism

Authors

  • Avin, Keith G., Indiana University Purdue University at Indianapolis, Indianapolis, Indiana, United States
  • Chen, Neal X., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Srinivasan, Shruthi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Hughes, Meghan C., York University, Toronto, Ontario, Canada
  • Oconnell, Thomas, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Bacallao, Robert L., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Perry, Christopher G., York University, Toronto, Ontario, Canada
  • Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Skeletal muscle health progressively declines from chronic kidney disease (CKD). To test the hypothesis that exercise mitigates abnormal muscle metabolism in CKD, we utilized high-resolution mitochondrial respiration and metabolomics techniques for indices of skeletal muscle carbohydrate and fat metabolism in a progressive CKD rat model.

Methods

Animals- 1) Cy/+ (CKD) rats, 2) CKD + wheel running, and 3) normal littermates (NL) (N=12/gr). Running wheel was accessible 24 hr/day 25-35 weeks of age; moderate to severe CKD, respectively. Extensor digitorum longus (EDL) and soleus were harvested at sacrifice. Mitochondrial respiratory subunit complexes were quantified by Western blot. Mitochondrial respiration: Measured in the presence of multiple substrates (Oxygraph-2k, Oroboros). Metabolomics: Targeted mass spectrometry (MS) and nuclear magnetic resonance (NMR) were performed.

Results

In the EDL, protein content of Complex 1 was reduced, but pyruvate-stimulated respiration increased with CKD wheel running. Metabolomic analysis (MS) of the EDL supported this, as wheel running lowered long-chain fatty acids (C14-18; p<0.05). In the soleus, Complex 1 content decreased and pyruvate-stimulated respiration increased in both CKD and CKD running compared to NL (p<0.05). Soleus MS demonstrated lower long-chain fatty acids (C14-18; p<0.05). Serum NMR demonstrated increased pyruvate and reduced lactate concentrations suggesting greater re-direction of pyruvate to mitochondrial oxidative phosphorylation. Carnitine levels were low in serum and muscle, suggesting impaired transport of fatty acids to the mitochondria.

Conclusion

These intriguing results indicate CKD impairs skeletal muscle mitochondrial oxidative capacity despite increased pyruvate oxidation. In addition, metabolomics data suggests impaired fatty acid oxidation that worsened with wheel running due to low carnitine levels. These results suggest dual alterations in response to mild exercise in CKD: 1- impaired fatty acid oxidation from deficient carnitine; 2- enhanced pyruvate oxidation consistent with lower lactate production. These cellular metabolic reprogramming events suggests that skeletal muscle may shift away from fatty acid metabolism towards carbohydrates which may explain why patients with CKD do not experience the usual benefit of exercise.

Funding

  • NIDDK Support