Mechanisms of skeletal muscle adaptation in COPD

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Exercise limitation is a debilitating, major symptom of COPD, especially in those who show evidence of muscle wasting (cachexia). There is increasing evidence of systemic multi-organ contributions to exercise intolerance due to impaired cardiac and skeletal muscle function in addition to primary destruction of lung architecture. However, the mechanisms by which lung damage in COPD leads to muscle dysfunction remain unclear. Reduced availability of 02 to skeletal muscle as a result of both impaired lung and cardiac function may play a role. In addition systemic inflammation and oxidative stress also occur in COPD and have the potential to limit both heart and skeletal muscle angiogenesis and contractility. Skeletal muscle capillarity, which is largely VEGF-dependent, has been reported as reduced in patients with COPD, and it is known that VEGF levels in both lungs and skeletal muscle are decreased. Thus, the overall objective of this project is to determine which pathways (inflammation, oxidative stress, and/or hypoxia), altered in COPD, lead to changes in capillarity, skeletal muscle phenotype and function. The central hypothesis is that dysregulation of VEGF is responsible for many of the structural and functional alterations found in skeletal muscle of patients with COPD, especially those with a cachectic phenotype, and that these abnormalities are the result of insufficient VEGF to maintain capillarity and protect skeletal muscle from oxidative stress and/or inflammation. Exercise training is hypothesized to augment muscle VEGF expression, increase muscle capillarity and improve exercise capacity. In human muscle biopsies provided by Project 3, we will assess inflammation, oxidative stress, antioxidant balance and mediators of angiogenesis in skeletal muscle of cachectic and non-cachectic COPD patients and normal controls. Using four transgenic murine models, we will specifically target pathways to separately evaluate the importance of inflammation, oxidative stress and reduced O2 delivery in the development of skeletal muscle dysfunction. Mouse COPD models will be evaluated for changes in exercise-induced angiogenic gene responses, oxidative stress and inflammatory cytokines that correlate with capillary regression, a potential transition from type I to type II fibers, and impaired exercise endurance. The knowledge gained from this study is expected to help form the basis for both pharmacological and exercise-based therapeutic strategies that could prevent muscle wasting and facilitate greater physical activity in patients with COPD. Thus, our long-term goal is to improve the quality of life in patients with COPD through the restoration of muscle function.