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.