Skeletal muscle metabolic responses to physical activity are muscle type specific in a rat model of chronic kidney disease

Keith G Avin,Meghan C Hughes,Debora L Gisch,Ranjani N Moorthi,Neal X Chen,Kalisha D O’Neill,Thomas M O’Connell,Christopher G R Perry,Sharon M Moe,Robert L Bacallao,Shruthi Srinivasan,Michael L Schulte,Andrew P Evan

doi:10.1038/s41598-021-89120-8

Abstract

Chronic kidney disease (CKD) leads to musculoskeletal impairments that are impacted by muscle metabolism. We tested the hypothesis that 10-weeks of voluntary wheel running can improve skeletal muscle mitochondria activity and function in a rat model of CKD. Groups included (n = 12–14/group): (1) normal littermates (NL); (2) CKD, and; (3) CKD-10 weeks of voluntary wheel running (CKD-W). At 35-weeks old the following assays were performed in the soleus and extensor digitorum longus (EDL): targeted metabolomics, mitochondrial respiration, and protein expression. Amino acid-related compounds were reduced in CKD muscle and not restored by physical activity. Mitochondrial respiration in the CKD soleus was increased compared to NL, but not impacted by physical activity. The EDL respiration was not different between NL and CKD, but increased in CKD-wheel rats compared to CKD and NL groups. Our results demonstrate that the soleus may be more susceptible to CKD-induced changes of mitochondrial complex content and respiration, while in the EDL, these alterations were in response the physiological load induced by mild physical activity. Future studies should focus on therapies to improve mitochondrial function in both types of muscle to determine if such treatments can improve the ability to adapt to physical activity in CKD.

Highlights

Chronic kidney disease (CKD) leads to musculoskeletal impairments that are impacted by muscle metabolism
The results revealed 44 metabolites that were significantly altered in one of the groups with 33 differences between normal littermates (NL) and CKD, 35 between NL and CKD-10 weeks of voluntary wheel running (CKD-W) and no differences between CKD and CKD-W
Taurine and carnosine were reduced, while citrulline was increased in CKD and CKD-W as compared to NL

Summary

Introduction

Chronic kidney disease (CKD) leads to musculoskeletal impairments that are impacted by muscle metabolism. We tested the hypothesis that 10-weeks of voluntary wheel running can improve skeletal muscle mitochondria activity and function in a rat model of CKD. Voluntary wheel running, a parallel form of exercise to walking in humans, was more effective in improving musculoskeletal health[7] These differences suggest that exercise and physical activity, may have differential effects on muscle metabolism, but further exploration is needed to identify the underlying mechanisms. We expanded the current analyses to test the hypothesis that 10-weeks of voluntary wheel running improves skeletal muscle mitochondrial function in a rat model of CKD. We utilized these techniques to assess metabolic changes associated with CKD and physical activity in normal littermates, CKD rats and CKD-rats with voluntary wheel running The inclusion of both primarily slow- and fast-tissue types is important given fast muscle types are more susceptible to atrophy and loss of force with general aging. As there is conflicting evidence regarding muscle type alterations in C KD10,34 a greater understanding of the metabolic influences of each muscle type can inform and guide appropriate therapies

Methods

Results

Conclusion