Role of Skeletal Muscle Mitochondrial Supercomplexes in Exercise Intolerance

骨骼肌线粒体超级复合物在运动不耐受中的作用

基本信息

批准号：
10292886
负责人：
Gaurav Choudhary
金额：
--
依托单位：
PROVIDENCE VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292886
关键词：
Activities of Daily Living Aerobic Agonist Animals Architecture Area Binding Blood flow Cardiac Output Cell Line Cell Respiration Chronic Chronic Disease Complex Crista ampullaris DNA Sequence Alteration Data Dyspnea Electron Transport Electron Transport Complex III Exercise Exercise Therapy Exercise Tolerance Exhibits Fatigue Fiber Foundations Functional disorder Generations Heart failure Human Impairment Incidence Individual Intervention Investigation Mediating Mediator of activation protein Medical Metabolic Mitochondria Mitochondrial Diseases Modeling Molecular Molecular Weight Muscle Muscle Fibers Muscle Mitochondria Muscle function OPA1 gene Patients Performance Peripheral Peroxisome Proliferator-Activated Receptors Pharmacology Pharmacotherapy Physical activity Population Potassium Channel Pre-Clinical Model Production Proteins Pulmonary Hypertension Quality of life Rattus Reactive Oxygen Species Regulation Reporting Respiration Respiratory physiology Role Sampling Signal Transduction Skeletal Muscle Speed Structure Testing VO2max complex IV exercise capacity exercise intolerance exercise training functional disability hemodynamics improved military veteran mortality muscle hypertrophy new therapeutic target novel novel therapeutics pre-clinical preclinical study targeted treatment therapeutically effective treadmill

项目摘要

ABSTRACT Pulmonary hypertension is associated with poor quality of life, impaired functional tolerance and limitation of physical activity. Despite optimal available therapy for PH, patients report fatigue, decreased functional capacity, and worsening quality of life. Exercise intolerance (i.e. reduced VO2 max) is associated with reduced skeletal muscle (SkM) mitochondrial function and cellular respiration. Recent studies have demonstrated that changes in organization of electron transport chain complexes can significantly alter mitochondrial respiration and energy production. Binding of individual electron transport chain complexes into large molecular weight supercomplexes (SC) increases respiration efficiency, reduces damaging ROS, and improves ATP production. SC can consist of complex I and multiple units of complex III and IV in direct association to allow direct electron transfer. In preliminary studies, we have found that SkM in rats with PH have greatly reduced I/III/IV supercomplex assembly and this is associated with reduced VO2 max determined by maximal treadmill exercise capacity. Our central hypothesis is that reduction in mitochondrial SC in SkM contributes to exercise intolerance in PH, and that increasing SC can alleviate PH-induced SkM dysfunction. We will test this hypothesis using a well-established rat model of pulmonary hypertension that recapitulates the pathophysiological aspects as well as exercise intolerance observed in patients with PH. In Aim 1, we will evaluate PH-induced changes in SkM mitochondrial SC formation and associated changes in respiratory function, mitochondrial content, and cristae architecture in a preclinical PH model and PH patients. In addition we will verify these changes are indeed present in human SkM samples from PH patients. In Aim 2, we will determine molecular mechanisms underlying altered mitochondrial function and SC assembly in isolated SkM fibers and differentiated primary SkM myotubes from control and PH animals Finally in Aim 3, we will determine if increasing mitochondrial supercomplex formation in SkM by exercise or drug therapy results in improved functional capacity (i.e. VO2 max). These will be the first studies to evaluate the role of mitochondrial SC in exercise intolerance associated with chronic medical condition such as PH, and the first studies to directly target SC assembly to alleviate SkM dysfunction.

抽象的肺动脉高压与生活质量差，功能耐受性受损和限制有关体育锻炼。尽管pH值最佳可用疗法，但患者报告疲劳，功能降低能力和生活质量恶化。运动不耐受（即Max减少）与减少有关骨骼肌（SKM）线粒体功能和细胞呼吸。最近的研究表明电子传输链复合物的组织变化可以显着改变线粒体呼吸和能源生产。单个电子传输链复合物与大分子量的结合超复合物（SC）提高了呼吸效率，降低了破坏性ROS并改善了ATP的产生。 SC可以由复合物I和复合物III和IV的多个单位组成，以允许直接电子转移。在初步研究中，我们发现pH大鼠的SKM大大降低I/III/IV 超复合组件，这与最大跑步机确定的vo2 max减少有关运动能力。我们的中心假设是，SKM中的线粒体SC的减少有助于运动 pH值不耐受，而增加的SC会减轻pH诱导的SKM功能障碍。我们将测试这个使用良好的肺动脉高压大鼠模型的假设，该模型概括了在pH患者中观察到的病理生理方面以及运动不耐受。在AIM 1中，我们将评估pH诱导的SKM线粒体SC形成的变化以及呼吸道的相关变化临床前pH模型和pH患者中的功能，线粒体含量和CRISTAE结构。此外我们将验证这些变化确实存在于pH患者的人类SKM样品中。在AIM 2中，我们将确定分离的SKM中的线粒体功能和SC组装的改变的分子机制纤维和分化的主要SKM肌管与控制和pH动物最终在AIM 3中，我们将确定通过运动或药物治疗在SKM中增加线粒体超复合形成是否会导致提高功能能力（即Max）。这些将是评估线粒体作用的最初研究与慢性疾病（例如pH）相关的运动不耐受性的SC，以及首次研究直接靶向SC组件以减轻SKM功能障碍。