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、功能耐受力受损和活动能力受限有关。体力活动。尽管有针对 PH 的最佳可用疗法，患者仍报告疲劳、功能下降能力，以及生活质量的恶化。运动不耐受（即最大摄氧量降低）与降低骨骼肌 (SkM) 线粒体功能和细胞呼吸。最近的研究表明电子传递链复合物组织的变化可以显着改变线粒体呼吸和能源生产。将单个电子传输链复合物结合成大分子量超级复合物 (SC) 提高呼吸效率，减少有害的 ROS，并提高 ATP 的产生。 SC 可以由直接关联的复合物 I 和复合物 III 和 IV 的多个单元组成，以允许直接电子转移。在初步研究中，我们发现PH大鼠中的SkM大大降低了I/III/IV 超级复杂的组装，这与最大跑步机确定的最大摄氧量降低有关锻炼能力。我们的中心假设是 SkM 中线粒体 SC 的减少有助于运动 PH 不耐受，增加 SC 可以缓解 PH 引起的 SkM 功能障碍。我们将测试这个使用完善的肺动脉高压大鼠模型提出的假设，该模型概括了在 PH 患者中观察到的病理生理学方面以及运动不耐受。在目标 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相关的变化临床前 PH 模型和 PH 患者的功能、线粒体含量和嵴结构。此外我们将验证这些变化确实存在于 PH 患者的人类 SkM 样本中。在目标 2 中，我们将确定分离的 SkM 中线粒体功能和 SC 组装改变的分子机制来自对照和 PH 动物的纤维和分化的初级 SkM 肌管最后在目标 3 中，我们将确定通过运动或药物治疗增加 SkM 中线粒体超复合物的形成是否会导致提高功能能力（即最大摄氧量）。这些将是第一个评估线粒体作用的研究 SC 与 PH 等慢性疾病相关的运动不耐受，以及第一个研究直接靶向 SC 组装以缓解 SkM 功能障碍。