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Mechanisms of skeletal muscle adaptation in COPD

COPD 中骨骼肌的适应机制

基本信息

批准号：
7613212
负责人：
PETER D WAGNER
金额：
$ 41.02万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/7613212
关键词：
Acids Acute Address Angiogenic Factor Angiopoietin-2 Animals Antioxidants Apoptosis Architecture Area Attenuated Biopsy Biopsy Specimen Blood Vessels Blood capillaries Blood flow Budgets C-reactive protein Cachexia Capillarity Carbon Dioxide Cardiac Cardiopulmonary Chronic Obstructive Airway Disease Chronic lung disease Citrate (si)-Synthase Comorbidity Complement Coupled Crossbreeding DEXA Data Development Dimensions Dobutamine Dose Echocardiography Environmental air flow Enzymes Equilibrium Exercise Fatigue Fiber Fibroblast Growth Factor 2 Functional disorder Gene Deletion Genes Goals Health Heart Histologic Housing Human Human Resources Hypercapnia Hypoxia Impairment In Situ In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-6 Knee Knowledge Lead Left Leg Lung Magnetic Resonance Imaging Measurement Measures Mediator of activation protein Messenger RNA Metabolic Mitochondria Modeling Molecular Morphology Mus Muscle Muscle Cells Muscle Fibers Muscle function Myocardium Organ Oxidative Stress Oxidative Stress Pathway Pathway interactions Patients Performance Phenotype Physical activity Physiologic intraventricular pressure Physiological Play Plethysmography Process Production Proteins Pulmonary Emphysema Pulmonary Surfactant-Associated Protein C Quality of life Reporting Research Methodology Research Personnel Respiratory Diaphragm Rest Role Running Severity of illness Skeletal Muscle Speed Stratification Structure Study Subject Superoxides Supplementation Symptoms Techniques Testing Therapeutic Thioctic Acid Tidal Volume Time Training Transfer Agreement Transgenic Mice Transgenic Organisms Vascular Endothelial Growth Factors Ventricular Vitamin E Work age difference angiogenesis antioxidant therapy awake base capillary catalase cytokine density exhaustion experience improved in vivo indexing mRNA Expression morphometry mouse Cre recombinase mouse model muscle form overexpression prevent programs promoter protein expression respiratory response restoration sciatic nerve skeletal stem wasting

项目摘要

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.

运动受限是慢性阻塞性肺病的一种使人衰弱的主要症状，特别是在那些有证据表明