Role of Mitochondrial Dysfunction in the Response to Exercise in Patients with Advanced Kidney Disease

项目摘要 终末期肾病（ESRD）是慢性肾病（CKD）的最后阶段，需要肾功能衰竭。 替代疗法，如血液透析。每年有超过10万人开始血液透析。 接受血液透析的患者虚弱和肌肉减少的风险增加。脆弱是一个多系统 与易受压力相关的损伤，其特征是存在无意的 体重减轻，自我报告的疲惫或疲劳，测量的肌肉无力，缓慢的步行速度，和低 体力活动。肌肉减少症，定义为肌肉质量和/或肌肉力量的减少，是其中一种。 脆弱表型的组成部分。在一般人群中，体育锻炼可以防止肌肉的流失 质量和改善虚弱状态。然而，在终末期肾病患者中，运动并不像在一般情况下那样有效。 人口线粒体对于肌肉的正常功能是必不可少的，最近的研究表明， 线粒体功能障碍导致肌肉质量的减少。我们和其他人发现， 在患有ESRD的患者中存在线粒体异常和线粒体含量降低。的 线粒体的数量取决于生物发生（新线粒体的产生）和 线粒体自噬（mitophagy）：线粒体的降解。体育锻炼可以改善线粒体功能， 一般人群骨骼肌中线粒体数量的变化。但是锻炼的好处 尚未研究ESRD患者的线粒体功能。 在这项研究中，我们将评估线粒体功能障碍阻碍细胞增殖的总体假设。 运动对终末期肾病患者的有益影响。因此，在具体目标1中，我们将检验假设 辅酶Q10是一种靶向治疗，可以改善肌肉对运动训练的适应性， ESRD患者。为此，ESRD患者将参加为期12周的运动计划或 观察组。患者还将接受辅酶Q10补充剂或安慰剂。因此，在本发明中， 患者将被分配到四个不同的组，运动加安慰剂，运动加辅酶Q10， 观察加安慰剂观察加辅酶Q10这项研究设计将使我们能够评估 干预的个体效应和干预的累加效应。我们预计 运动和辅酶Q10的结合将在改善线粒体功能方面产生叠加效应 和体能的影响。在具体目标2中，我们将测试假设， 运动训练和辅酶Q10的组合通过以下方式改善ESRD患者的线粒体功能： 增加线粒体呼吸和含量，并改善线粒体动力学（即，重塑 通过裂变和聚变）。因此，我们将测量线粒体呼吸和线粒体标记物， 来自特定目标1的患者亚组内肌肉活检的生物发生和动力学。结果 这些研究可以通过改善身体功能和生活质量来影响数百万的终末期肾病患者。

Project Summary End-stage renal disease (ESRD), the final stage of chronic kidney disease (CKD), requires renal replacement therapy such as hemodialysis. Every year more than 100,000 individuals start hemodialysis. Patients undergoing hemodialysis are at increased risk of frailty and sarcopenia. Frailty is a multisystem impairment associated with vulnerability to stressors, and it is characterized by the presence of unintentional weight loss, self-reported exhaustion or fatigue, measured muscle weakness, slow walking speed, and low physical activity. Sarcopenia, defined as a reduction of muscle mass and/or muscle strength, is one of the components of the frailty phenotype. In the general population, physical exercise prevents the loss of muscle mass and improves frailty status. In patients with ESRD, however, exercise is not as effective as in the general population. Mitochondria are essential for proper muscle function, and recent studies suggest that mitochondrial dysfunction contributes to the reduction in muscle mass. We and others have found that mitochondrial abnormalities and decreased mitochondrial content are present in patients with ESRD. The number of mitochondria depends on the balance between biogenesis (generation of new mitochondria) and mitophagy (degradation of mitochondria). Physical exercise improves mitochondrial function and increases the mitochondrial number in skeletal muscle in the general population. But the benefits of exercise on mitochondrial function in patients with ESRD have not been studied. In this study, we will evaluate the overarching hypothesis that mitochondrial dysfunction hinders the beneficial effects of exercise in patients with ESRD. Thus, in Specific Aim 1, we will test the hypothesis that Coenzyme Q10, a mitochondrial-targeted therapy, improves muscle adaptation to exercise training in patients with ESRD. For this aim, patients with ESRD will be enrolled in a 12-week exercise program or in an observational group. Patients will also receive either Coenzyme Q10 supplementation or placebo. As a result, patients will be assigned to four different groups, exercise plus placebo, exercise plus Coenzyme Q10, observational plus placebo, observational plus Coenzyme Q10. This study design will allow us to evaluate the individual effect of the interventions and the additive effect of the interventions. We anticipate that the combination of exercise and Coenzyme Q10 will have an additive effect in improving and mitochondrial function and physical performance in patients with ESRD. In Specific Aim 2 we will test the hypothesis that the combination of exercise training and Coenzyme Q10 improves mitochondrial function in patients with ESRD by increasing mitochondrial respiration and content, and improving mitochondrial dynamics (i.e., remodeling through fission and fusion). Therefore, we will measure mitochondrial respiration and markers of mitochondrial biogenesis and dynamics in muscle biopsies within a sub-group of patients from Specific Aim 1. Results from these studies could affect millions of people with ESRD by improving physical function and their quality of life.