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

线粒体功能障碍在晚期肾病患者运动反应中的作用

基本信息

批准号：
10367269
负责人：
Jorge Luis Gamboa
金额：
$ 69.29万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367269
关键词：
Affect Anaerobic Threshold Biogenesis Biopsy Body Weight decreased COVID-19 Chronic Kidney Failure Clinical Clinical Trials Coenzyme Q10 Conflict (Psychology)DNA copy number Data Double-Blind Method Electron Transport End stage renal failure Energy Metabolism Pathway Enrollment Equilibrium Exercise Fatigue Fiber General Population Generations Genetic Transcription Health Hemodialysis Home Impairment Individual Infrastructure Interval training Intervention Investigation Kidney Diseases Kidney Failure Magnetic Resonance Spectroscopy Maintenance Measures Metabolic Mitochondria Mitochondrial DNA Morbidity - disease rate Muscle Muscle Contraction Muscle Fibers Muscle Mitochondria Muscle Weakness Muscle function Muscular Atrophy Oxygen Consumption PPAR gamma Patient Self-Report Patients Persons Phenotype Physical Exercise Physical Function Physical Performance Physical activity Physiological Placebos Play Population Proteins Quality of life Randomized Randomized Clinical Trials Renal Replacement Therapy Reporting Research Design Respiration Risk Role Skeletal Muscle Supplementation Testing Training Training Programs Ubiquinone Uncontrolled Study Variant Vulnerable Populations Walking adverse outcome base exercise capacity exercise intervention exercise intolerance exercise program exercise training exhaustion frailty improved in vivo intervention effect lifestyle intervention mitochondrial dysfunction mortality muscle form muscle strength novel patient subsets placebo controlled trial preservation prevent primary outcome resistance exercise respiratory responders and non-responders response sarcopenia secondary outcome standard of care stressor targeted treatment therapeutic target time use tool transcriptome transcriptome sequencing walking speed

项目摘要

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.

项目摘要慢性肾脏疾病（CKD）的最后阶段末期肾脏疾病（ESRD）需要肾脏替代疗法，例如血液透析。每年有100,000多人开始血液透析。接受血液透析的患者患有脆弱和肌肉减少症的风险增加。脆弱是一个多系统与压力源的脆弱性相关的损害，其特征是存在无意体重减轻，自我报告的疲惫或疲劳，测量的肌肉无力，步行速度缓慢和低体育锻炼。肌肉减少症，被定义为减少肌肉质量和/或肌肉力量，是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丧失质量并改善脆弱状态。但是，在ESRD患者中，运动不像一般人口。线粒体对于适当的肌肉功能至关重要，最近的研究表明线粒体功能障碍有助于减少肌肉质量。我们和其他人发现 ESRD患者存在线粒体异常和线粒体含量降低。这线粒体的数量取决于生物发生（新线粒体产生）和线粒体（线粒体的降解）。体育锻炼可改善线粒体功能并增加一般人群中骨骼肌的线粒体数。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，我们将评估总体假设，即线粒体功能障碍阻碍运动对ESRD患者的有益影响。因此，在特定目标1中，我们将检验假设该辅酶Q10是一种靶向线粒体的疗法，可改善肌肉适应运动训练 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补充或安慰剂。因此，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，观测加安慰剂，观察力加辅酶Q10。这项研究设计将使我们能够评估干预措施的个人效果和干预措施的添加效应。我们预计运动和辅酶Q10的组合将对改善和线粒体功能产生添加作用 ESRD患者的身体表现。在特定目标2中，我们将检验以下假设运动训练和辅酶Q10的组合可改善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（即重塑通过裂变和融合）。因此，我们将测量线粒体的线粒体呼吸和标记特定目的1患者子群体中肌肉活检中的生物发生和动力学1。这些研究可能会通过改善身体机能及其生活质量来影响数百万具有ESRD的人。