Mechanisms of Adaptation to Exercise in Health and COPD

描述(由申请人提供)： 这一多学科建议的目标是了解肌肉适应健康运动的关键机制，特别是在慢性阻塞性肺疾病中。慢性阻塞性肺疾病患者的运动能力受损，骨骼肌和心血管功能障碍的影响越来越大。氧化应激增加和肌肉毛细血管减少已被报道，并将是这一应用的主要主题。将在患有COPD的人类、小鼠肌肉单纤维和几个完整的转基因小鼠品系中进行研究，以解决缺氧和氧化应激影响健康和COPD患者的肌肉结构、功能和对运动的反应的机制。在人类中，将研究瘦体重正常和瘦体重减少(恶病质表型)的COPD患者氧化应激的来源和重要性。在小鼠中，将使用四个专门创建的转基因株系来研究氧化应激、炎症和细胞凋亡在运动反应中的可能作用。其中两种可导致肌肉萎缩的肺气肿表型，其基础是a)炎症(肺组织肿瘤坏死因子-a过表达)和b)细胞凋亡(肺血管内皮生长因子缺失)。另外两个在c)心脏和d)骨骼肌中消耗血管内皮生长因子，这是相关的，因为在慢性阻塞性肺疾病中发现肌肉血管内皮生长因子水平降低。研究将在分离的单一肌肉纤维和完整的动物身上进行。这项研究计划将阐明COPD的肺损伤对骨骼肌的影响，并将解决COPD常见的潜在并存条件与心脏和肌肉功能障碍之间的相互作用。最重要的假设是，虽然肌肉适应性反应可能部分由氧化应激发出信号，但过度的氧化应激干扰肌肉收缩和血管功能，以及与适应有关的重要基因的表达，特别是血管内皮生长因子。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和血管内皮生长因子的表达和作用的作用。它还研究了上述四个转基因株系，以探索COPD患者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)使用小鼠的单个肌肉纤维来阐明低氧和氧化应激损害肌肉收缩功能的机制，使用的是正常小鼠和与项目1相同的在肺中过度表达肿瘤坏死因子-a的转基因系。项目3(Richardson)研究了氧化应激的来源和对COPD患者急性运动和训练的重要性。该计划得到了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机制，应该导致提高COPD患者的运动能力和生活质量的具体、合理的策略。

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.