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: 7744685
• 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/7744685
• 关键词: Mechanisms; Adaptation; Exercise; Health; COPD

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）： 这项多学科建议的目的是了解肌肉适应健康的关键机制，尤其是在COPD中。 COPD中的运动能力受损，骨骼肌和心血管功能障碍越来越多。据报道，氧化应激增加和肌肉毛细血管降低，将成为此应用中的主要主题。研究将在患有COPD的人类，小鼠肌肉单纤维和几种完整的转基因小鼠系中进行研究，以解决缺氧和氧化应激影响肌肉结构，功能和对健康和COPD运动的反应的机制。在人类中，将在正常和瘦体重降低的COPD患者中研究氧化应激的来源和重要性（缓存表型）。在小鼠中，将使用四种特殊创建的转基因线研究氧化应激，炎症和凋亡在运动反应中的作用。其中两个基于A）炎症（肺TNF-A过表达）和b）凋亡（肺VEGF缺失）产生肌肉浪费的过滤表型。其他两个耗尽的VEGF在c）心脏和d）骨骼肌中，这很重要，因为在COPD中发现了肌肉VEGF水平降低。研究将在孤立的单肌纤维和完整动物中进行。该研究计划将阐明COPD中肺损伤对骨骼肌的影响，并且还将解决COPD常见的潜在合并症 - 心脏和肌肉功能障碍的相互作用。总体假设是，虽然肌肉适应性反应可能部分由氧化应激信号，但过度的氧化应激会干扰肌肉收缩和血管功能，以及基因在适应性中很重要的基因表达，尤其是VEGF。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。它还研究了上述四个转基因线，以探索COPD中肌肉功能障碍的可能途径，并了解肺部受损，骨骼肌和心脏的相互作用。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，同时使用正常小鼠和相同的转基因线，使肺中TNF-A过表达TNF-A的Project1。Project3（Richardson）检查了氧化应激的氧化应激以及对急性运动和培训COPD的氧化压力的重要性。该程序由组织成像和行政核心支持。阐明对运动的适应性反应的机制 - 尤其是氧化应激的作用 - 以及与肺部疾病有关的机制与肌肉功能障碍有关的机制，应提高COPD患者运动能力和生活质量的特定，理性的策略。