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

• 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
• 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

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.

摘要 肺动脉高压与生活质量差、功能耐受性受损和 体力活动。尽管对PH有最好的治疗方法，但患者报告疲劳，功能下降 能力，以及不断恶化的生活质量。运动不耐受(即最大摄氧量降低)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， 电子传递链复合体组织结构的改变可以显著改变线粒体的呼吸作用 和能源生产。单个电子传递链复合体与大分子量的结合 超复合体(SC)可提高呼吸效率，减少有害的ROS，并促进ATP的产生。 Sc可以由络合物I和多个直接缔合的络合物III和IV单元组成，以允许直接电子 调职。在初步研究中，我们发现，高血压大鼠的SKM显著减少了I/III/IV 超复杂的装配，这与由最大跑步机确定的最大摄氧量减少有关 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 而增加SC可以减轻PH诱导的SKM功能障碍。我们将对此进行测试 假设使用一种公认的大鼠肺动脉高压模型，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耐量不足。在目标1中，我们将 评估PH诱导的SKM线粒体SC形成的变化以及与之相关的呼吸变化 临床前PH模型和PH患者的功能、线粒体含量和冠状突起结构。此外 我们将验证这些变化确实存在于来自PH患者的人类SKM样本中。在目标2中，我们将 确定分离的SKM线粒体功能和SC组装改变的分子机制 来自对照组和PH动物的纤维和分化的原代SKM肌管最终在目标3中，我们将 确定运动或药物治疗增加SKM中线粒体超复合体的形成是否会导致 改进的功能容量(即最大摄氧量)。这将是第一次评估线粒体的作用的研究。 运动不耐受与慢性疾病相关的SC，如PH，以及第一个研究 直接靶向SC组件以缓解SKM功能障碍。