Project Summary/Abstract
Chronic kidney disease (CKD) is a worldwide epidemic affecting ~30 million Americans that leads to fractures,
hospitalizations, and impaired quality of life due to musculoskeletal impairments. Exercise is generally
recommended for musculoskeletal impairments, however in CKD, there is a lack of consistent clinical and pre-
clinical efficacy. Exercise effects in preclinical studies have demonstrated forced treadmill running inducing
oxidative stress and muscle catabolism, while modest improvements occurred with wheel running. The overall
scientific premise is that the uremic condition interferes with musculoskeletal adaptation from exercise.
Metabolomics of skeletal muscle (soleus and extensor digitorum longus (EDL) were employed to identify the
underlying mechanism of the limited exercise adaptation. Metabolomics of CKD rats with/without wheel running
and normal littermates, indicated defects in fatty acid (FA) oxidation (i.e. reduced carnitine) and nitric oxide (NO)
signaling (i.e. increased citrulline, reduced arginine), which will be investigated in this proposal. The central
hypothesis is that ameliorating the carnitine deficit can improve FA oxidation and mitigate excess NO to improve
musculoskeletal health and enable exercise adaptation in CKD. I will test this hypothesis by administering
supplemental L-carnitine (oral and intraperitoneal) in CKD rats to maximize fatty acid b-oxidation. The optimal
dose and delivery in aim 1a, will be utilized in aim 1b, to determine if carnitine supplementation alters nitric oxide
signaling induced by aerobic exercise. It is anticipated that the exercise + carnitine group will have improved
outcomes compared to detrimental outcomes in exercise alone. This R03 will provide direct evidence for the
existence of impaired FA oxidation, NO production, supplemental response and aerobic exercise adaptation.
The subsequent R01 will investigate the response to high, moderate and low intensity aerobic exercise by
focusing on systemic benefits of exercise while balancing potential negative effects on muscle (i.e. enzymatic or
molecular regulators of the FA oxidation or NO pathways). The data gleaned from this study is vital for my
subsequent R01 and long-term goal of identifying safe and effective treatments to enable an exercise response
in patients with CKD.
