Mechanisms of Interventions to Ameliorate Sarcopenia in Chronic Kidney Disease

慢性肾脏疾病（CKD）影响着2000万美国人，并导致肌肉减少症，其中包括 肌肉损失（萎缩）、肌肉无力和/或活动性降低。肌肉减少症在临床上很重要， 导致跌倒风险、发病率和死亡率增加。尽管CKD患者肌肉减少症的病理生理学 目前尚不清楚，CKD中的肌肉减少症可能是由于肌肉代谢，catalysis， 和再生。我们认为，这些肌肉减少的变化的中心组成部分受损 骨骼肌线粒体和肌生长抑制素增加。本提案的总体目标是测试 假设运动或肌肉生长抑制素阻断疗法可以预防萎缩，但需要运动来改善 CKD中骨骼肌代谢和功能。这一目标将通过以下方式实现： 使用我们建立的进行性CKD模型（Cy/+大鼠）的临床实验，药理学和非药理学实验。 药物干预。我们将使用高分辨率呼吸测定法评估线粒体功能， 通过VO 2 max评估有氧能力，通过电刺激评估肌肉力量和疲劳， 最大随意握力、肌肉质量和整体身体活动水平。跨学科 指导团队和我完全有能力承担这项基于我们的临床和 CKD、肌肉生长抑制素和骨骼肌的临床前专业知识。在目标1中，我们将评估中度 高强度有氧运动改善CKD患者骨骼肌代谢和有氧能力 大鼠在目标2中，我们将评估中等强度和高强度抗阻训练对骨骼肌的疗效。 CKD大鼠的肌肉大小和强度。在目标3中，我们将评估肌肉生长抑制素阻断疗法的疗效。 与最佳运动相比，增加肌肉质量，肌肉代谢和功能。当前 该提案将开发所需的一些技能是一个成功的，独立的翻译研究。而 我的长期目标是耐心的实施，建立一个坚实的基础科学技能集将允许平行研究 提供了一种机械的理解。如果这些研究显示有益于骨骼肌功能 和/或质量，这些治疗可以迅速转化为临床环境。

Chronic kidney disease (CKD) affects 20 million Americans and contributes to sarcopenia, which includes muscle loss (atrophy), muscle weakness and/or reduced mobility. Sarcopenia is clinically important as it contributes to increased fall risk, morbidity and mortality. Although, the pathophysiology of sarcopenia in CKD remains unknown, sarcopenia in CKD is likely due to aberrant signaling for muscle metabolism, catabolism, and regeneration. We propose that central components of these to sarcopenic alterations are impaired skeletal muscle mitochondria and increased myostatin. The overall goal of this proposal is to test the hypothesis that exercise or myostatin blocking therapy prevents atrophy, but exercise is needed to improve skeletal muscle metabolism and function in CKD. This goal will be accomplished through a combination of pre- clinical experiments using our established model of progressive CKD (the Cy/+ rat), pharmacological and non- pharmacological interventions. We will assess mitochondrial function using high resolution respirometry, aerobic capacity via VO2max assessment, muscle strength and fatigue assessed by electrical stimulation and maximal voluntary grip strength, muscle mass, and overall physical activity levels. The interdisciplinary mentoring team and I are perfectly positioned to undertake this translational work based on our clinical and preclinical expertise in CKD, myostatin and skeletal muscle. In aim 1 we will assess the efficacy of moderate and high intensity AEROBIC exercise in improving skeletal muscle metabolism and aerobic capacity in CKD rats. In aim 2, we will assess the efficacy of moderate and high intensity RESISTANCE training on skeletal muscle size and strength in CKD rats. In aim 3 we will assess the efficacy of myostatin blocking therapy compared to optimal exercise in increasing muscle mass, muscle metabolism and function. The current proposal will develop a number of skills required to be a successful, independent translational research. While my long term goal is patient implementation, building a solid basic science skill set will allow for parallel studies that provide a mechanistic understanding. If these studies show efficacy in benefiting skeletal muscle function and/or mass, these treatments could be rapidly translated into the clinical setting.