Enhancing Fatty Acid Oxidation Will Improve Skeletal Muscle & Enable Exercise Adaptation in CKD

项目摘要/摘要 慢性肾脏病(CKD)是一种世界性流行病，影响着约3000万美国人，导致骨折， 住院和肌肉骨骼损伤导致的生活质量受损。锻炼一般都是 推荐用于肌肉骨骼损伤，然而，在CKD中，缺乏一致的临床和前期 临床疗效。临床前研究中的运动效应表明，强迫跑步机跑步会导致 氧化应激和肌肉分解代谢，而车轮运行出现了轻微的改善。整体而言 科学前提是尿毒症会干扰运动对肌肉骨骼的适应。 应用骨骼肌(比目鱼肌和指长伸肌)代谢组学方法鉴定 有限运动适应的潜在机制。慢性肾功能不全大鼠跑轮前后的代谢组学研究 和正常产仔，表明脂肪酸(FA)氧化(即肉碱减少)和一氧化氮(NO)存在缺陷 信号转导(即增加瓜氨酸，减少精氨酸)，这将在本提案中进行研究。中环 假说是，改善肉碱缺乏可以促进FA的氧化，减轻过量的NO以改善 CKD患者的肌肉骨骼健康和运动适应能力。我将通过以下方式验证这一假设 在慢性肾脏病大鼠中补充L肉碱(口服和腹腔注射)以最大限度地提高脂肪酸b氧化水平。最优的 目标1a中的剂量和给药将用于目标1b中，以确定肉碱补充是否改变一氧化氮 有氧运动诱导的信号传递。预计运动+肉毒碱组将有所改善 结果与仅在锻炼中的有害结果进行比较。这一R03将为 存在FA氧化、NO产生、补充反应和有氧运动适应受损。 随后的R01将通过以下方式调查高、中、低强度有氧运动的反应 关注锻炼的全身性益处，同时平衡对肌肉的潜在负面影响(例如，酶或 FA氧化或NO途径的分子调节器)。从这项研究中收集的数据对我的 随后的R01和确定安全有效的治疗方法以实现运动反应的长期目标 在慢性肾脏病患者中。

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.