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.

项目概要终末期肾病（ESRD）是慢性肾病（CKD）的最后阶段，需要肾病替代疗法，例如血液透析。每年有超过 100,000 人开始进行血液透析。接受血液透析的患者虚弱和肌肉减少症的风险增加。衰弱是一个多系统的问题与易受压力源相关的损害，其特征是存在无意的压力体重减轻、自我报告的疲惫或疲劳、测量到的肌肉无力、步行速度缓慢和低体力活动。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流失质量并改善虚弱状况。然而，对于 ESRD 患者来说，运动并不像一般患者那样有效。人口。线粒体对于正常的肌肉功能至关重要，最近的研究表明线粒体功能障碍导致肌肉质量减少。我们和其他人发现 ESRD 患者存在线粒体异常和线粒体含量减少。这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（线粒体降解）。体育锻炼可以改善线粒体功能并增加一般人群骨骼肌中的线粒体数量。但运动的好处尚未研究 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的总体假设运动对 ESRD 患者的有益作用。因此，在具体目标 1 中，我们将检验假设辅酶 Q10 是一种线粒体靶向疗法，可改善肌肉对运动训练的适应终末期肾病患者。为此，ESRD 患者将参加为期 12 周的锻炼计划或参加观察组。患者还将接受辅酶 Q10 补充剂或安慰剂。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措施的个体效应和干预措施的累加效应。我们预计运动与辅酶Q10的结合将对改善线粒体功能产生相加效果 ESRD 患者的身体机能。在具体目标 2 中，我们将检验以下假设：运动训练与辅酶 Q10 相结合可改善 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 的患者亚组中肌肉活检的生物发生和动力学。结果来自这些研究可以通过改善身体机能和生活质量来影响数百万终末期肾病患者。