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

增强脂肪酸氧化将改善骨骼肌

• 批准号: 10041793
• 负责人: Keith G Avin
• 金额: $ 11.89万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-09 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041793
• 关键词: 3-nitrotyrosine; Adenosine Triphosphate; Aerobic Exercise; Affect; Age; American; Apoptosis; Arginine; Biogenesis; Calcium; Carnitine; Catabolism; Chronic Kidney Failure; Citrulline; Clinical; Coenzyme A-Transferases; Complex; Cyclic GMP; Data; Defect; Disease model; Dose; Enzymes; Epidemic; Equilibrium; Exercise; Fatty Acids; Foundations; Fracture; Functional disorder; General Population; Glean; Goals; Health; Homeostasis; Hospitalization; Human; Impairment; Intervention; Investigation; Kidney; Kidney Diseases; Levocarnitine; Light; Link; Liver; Mitochondria; Modeling; Molecular; Muscle; Muscle Contraction; Muscle Fatigue; Muscle Weakness; Musculoskeletal; Musculoskeletal System; Nitrates; Nitric Oxide; Nitric Oxide Pathway; Nitric Oxide Synthase; Nitrites; Oral; Outcome; Oxidative Stress; Oxides; Palmitates; Palmitoyl Coenzyme A; Pathway interactions; Patients; Phospholipids; Physical Function; Process; Production; Protein Isoforms; Protocols documentation; Publishing; Quality of life; Radiolabeled; Rattus; Renal function; Respiratory Chain; Role; Route; Running; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Skeletal Muscle; Soleus Muscle; Speed; Supplementation; Testing; Translating; acylcarnitine; carnitine supplementation; effective therapy; environmental enrichment for laboratory animals; extensor digitorum; fatty acid oxidation; improved; improved outcome; intraperitoneal; metabolomics; mitochondrial membrane; novel; oxidation; pre-clinical; preclinical efficacy; preclinical study; primary outcome; response; secondary outcome; treadmill

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.

项目总结/摘要 慢性肾病（CKD）是一种全球性流行病，影响约3000万美国人，导致骨折， 住院，以及由于肌肉骨骼损伤而导致的生活质量受损。运动一般 推荐用于肌肉骨骼损伤，但在CKD中，缺乏一致的临床和预治疗。 临床疗效临床前研究中的运动效应已经证明了强迫跑步机跑步诱导 氧化应激和肌肉紧张，而适度的改善发生在车轮运行。整体 科学的前提是，尿毒症的条件干扰肌肉骨骼适应运动。 采用骨骼肌（比目鱼肌和趾长伸肌（趾长伸肌））代谢组学方法， 限制运动适应的潜在机制。慢性肾脏病大鼠在有/无轮跑的代谢组学研究 和正常的同窝仔，表明缺陷的脂肪酸（FA）氧化（即减少肉毒碱）和一氧化氮（NO） 信号传导（即瓜氨酸增加，精氨酸减少），这将在本提案中进行研究。中央 假设是改善肉毒碱缺乏可以改善FA氧化并减轻过量的NO以改善 肌肉骨骼健康，并使运动适应CKD。我将测试这个假设， 补充L-肉毒碱（口服和腹膜内），以最大化脂肪酸b-氧化。最优 目标1a中的剂量和递送，将用于目标1b，以确定肉毒碱补充是否改变一氧化氮 有氧运动引起的信号传导。预计运动+肉毒碱组将有所改善 结果相比，有害的结果，在行使单独。这份R 03将为 存在FA氧化、NO产生、补充反应和有氧运动适应的受损。 随后的R 01将通过以下方式研究对高、中、低强度有氧运动的反应： 关注运动的全身益处，同时平衡对肌肉的潜在负面影响（即酶或 FA氧化或NO途径的分子调节剂）。从这项研究中收集的数据对我来说至关重要。 随后的R 01和确定安全有效的治疗方法以实现运动反应的长期目标 在慢性肾病患者中。