Mechanisms of Adaptation to Exercise in Health and COPD

健康和慢性阻塞性肺病的运动适应机制

• 批准号: 8197314
• 负责人: PETER D WAGNER
• 金额: $ 203.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-08 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197314
• 关键词: Acute; Address; Affect; Animals; Apoptosis; Area; Biological; Biopsy; Biopsy Specimen; Blood Vessels; Capillarity; Cardiovascular system; Cellular biology; Chronic Obstructive Airway Disease; Clinical; Commit; Disease; Exercise; Faculty; Fiber; Functional disorder; Gene Expression; Health; Heart; Human; Human Biology; Hypoxia; Image; Inflammation; Interdisciplinary Study; Laboratories; Lead; Lung; Lung diseases; Magnetic Resonance Imaging; Medicine; Molecular; Molecular Biology; Morphology; Mus; Muscle; Muscle Fibers; Muscle function; Myocardium; Oxidative Stress; Pathway interactions; Patient Selection; Patients; Phenotype; Physiological; Physiology; Pneumonia; Publishing; Quality of life; Reporting; Research; Research Personnel; Role; Seasons; Signal Transduction; Skeletal Muscle; Source; Stratification; Structure; TNF gene; Technology; Tissues; Training; Transgenic Mice; Transgenic Organisms; Vascular Endothelial Growth Factors; Work; base; human tissue; improved; medical schools; member; mouse model; multidisciplinary; muscular structure; overexpression; programs; research study; response; wasting

DESCRIPTION (provided by applicant): The objective of this multidisciplinary proposal is to understand key mechanisms of muscle adaptation to exercise in health and, especially, in COPD. Exercise capacity is impaired in COPD, and increasingly skeletal muscle and cardiovascular dysfunction are implicated. Increased oxidative stress and reduced muscle capillarity have been reported and will be a major theme in this application. Studies will be performed in humans with COPD, in mouse muscle single fibers and in several intact transgenic mouse lines to address mechanisms by which hypoxia and oxidative stress affect muscle structure, function and responses to exercise in health and in COPD. In humans, the sources and importance of oxidative stress will be studied in COPD patients with normal and reduced lean body mass (cachectic phenotype). In mice, the possible roles of oxidative stress, inflammation and apoptosis in the exercise response will be investigated using four specially created transgenic lines. Two of these produce an emphysematous phenotype with muscle wasting based on a) inflammation (pulmonary TNF-a overexpression) and b) apoptosis (pulmonary VEGF deletion). The other two deplete VEGF in c) heart and d) skeletal muscle, which is relevant because reduced muscle VEGF levels are found in COPD. Studies will be performed in both isolated single muscle fibers and intact animals. This research program will elucidate the effects of lung damage in COPD on skeletal muscle, and also will address interactions among potential comorbid conditions common in COPD - cardiac and muscle dysfunction. Overarching hypotheses are that while muscle adaptive responses may be in part signaled by oxidative stress, excessive oxidative stress interferes with muscle contractile and vascular function and also the expression of genes important in adaptation, especially VEGF. Project 1 (Wagner) uses muscle biopsy samples from COPD patients studied in Project 3 to assess the roles of inflammation and oxidative stress on muscle function and VEGF expression and action. It also studies the above four transgenic lines to explore possible pathways to muscle dysfunction in COPD and to understand interactions among impaired lungs, skeletal muscle and heart. Project 2 (Hogan) uses mouse single muscle fibers to elucidate the mechanisms by which hypoxia and oxidative stress impair muscle contractile function, using both normal mice and the same transgenic line overexpressing TNF-a in the lung as Project 1. Project 3 (Richardson) examines sources and importance of oxidative stress to acute exercise and to training in patients with COPD. The program is supported by tissue imaging and administrative cores. Elucidating mechanisms of adaptive response to exercise - in particular the role of oxidative stress - and the mechanisms relating lung disease to muscle dysfunction, should lead to specific, rational strategies for improving exercise capacity and quality of life in patients with COPD.

描述（由申请人提供）： 这项多学科提案的目的是了解健康时，特别是慢性阻塞性肺病中肌肉适应运动的关键机制。慢性阻塞性肺病患者的运动能力会受损，并且骨骼肌和心血管功能障碍也越来越多。据报道，氧化应激增加和肌肉毛细血管减少，这将是该应用的一个主要主题。将对患有慢性阻塞性肺病的人类、小鼠肌肉单纤维和几个完整的转基因小鼠品系进行研究，以解决缺氧和氧化应激影响健康和慢性阻塞性肺病患者的肌肉结构、功能和运动反应的机制。在人类中，氧化应激的来源和重要性将在具有正常和去脂体重减少（恶病质表型）的慢性阻塞性肺病患者中进行研究。在小鼠中，将使用四种专门创建的转基因品系来研究氧化应激、炎症和细胞凋亡在运动反应中的可能作用。其中两种产生肺气肿表型并伴有肌肉萎缩，其原因是 a) 炎症（肺 TNF-a 过度表达）和 b) 细胞凋亡（肺 VEGF 缺失）。另外两种会消耗 c) 心脏和 d) 骨骼肌中的 VEGF，这是相关的，因为在慢性阻塞性肺病 (COPD) 中发现肌肉 VEGF 水平降低。研究将在分离的单肌纤维和完整的动物中进行。该研究计划将阐明慢性阻塞性肺病（COPD）肺损伤对骨骼肌的影响，还将解决慢性阻塞性肺病（COPD）常见的潜在合并症（心脏和肌肉功能障碍）之间的相互作用。总体假设是，虽然肌肉适应性反应可能部分由氧化应激发出信号，但过度的氧化应激会干扰肌肉收缩和血管功能，以及对适应很重要的基因（尤其是 VEGF）的表达。项目 1 (Wagner) 使用项目 3 中研究的 COPD 患者的肌肉活检样本来评估炎症和氧化应激对肌肉功能以及 VEGF 表达和作用的作用。它还研究上述四种转基因系，以探索慢性阻塞性肺病肌肉功能障碍的可能途径，并了解受损的肺、骨骼肌和心脏之间的相互作用。项目 2 (Hogan) 使用小鼠单肌纤维来阐明缺氧和氧化应激损害肌肉收缩功能的机制，使用正常小鼠和与项目 1 相同的肺部过表达 TNF-a 的转基因系。项目 3 (Richardson)研究了氧化应激的来源及其对慢性阻塞性肺病患者急性运动和训练的重要性。该计划得到组织成像和管理核心的支持。阐明运动适应性反应的机制——特别是氧化应激的作用——以及肺部疾病与肌肉功能障碍的相关机制，应该可以制定出具体、合理的策略来提高慢性阻塞性肺病患者的运动能力和生活质量。