Mechanisms of skeletal muscle adaptation in COPD

COPD 中骨骼肌的适应机制

• 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
• 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

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COPD的一种使人衰弱的主要症状，特别是在那些有证据表明 肌肉萎缩（恶病质）。越来越多的证据表明系统性多器官对疾病的贡献 运动不耐受是由于心脏和骨骼肌功能受损，除了原发性 肺结构的破坏。然而，COPD中肺损伤导致 肌肉功能障碍仍不清楚。由于这两种原因，骨骼肌的O2可用性降低 肺和心脏功能受损可能起作用。此外，全身炎症和氧化 应激也发生在COPD中，并有可能限制心脏和骨骼肌血管生成 和收缩性。主要依赖VEGF的骨骼肌毛细血管作用已被报道为 降低，并且已知肺和骨骼肌两者中的VEGF水平在COPD患者中均降低。 降低因此，本项目的总体目标是确定哪些途径（炎症， 氧化应激和/或缺氧），在COPD中改变，导致毛细血管、骨骼肌 表型和功能。中心假设是VEGF的失调是导致许多 COPD患者骨骼肌中发现的结构和功能改变，特别是那些 恶病质表型，这些异常是VEGF不足的结果，以维持 毛细作用和保护骨骼肌免受氧化应激和/或炎症。运动训练是 假设增加肌肉VEGF表达，增加肌肉毛细血管作用和改善运动 容量在项目3提供的人类肌肉活检中，我们将评估炎症，氧化应激， 恶病质和非恶病质骨骼肌中抗氧化平衡和血管生成介质 COPD患者和正常对照。使用四种转基因小鼠模型，我们将特异性靶向 分别评估炎症、氧化应激和氧减少的重要性的途径 在骨骼肌功能障碍的发展中的递送。将评价小鼠COPD模型的 运动诱导的血管生成基因反应、氧化应激和炎性细胞因子的变化 这与毛细血管退化相关，从I型纤维到II型纤维的潜在转变， 锻炼耐力。从这项研究中获得的知识预计将有助于形成两个基础 药理学和运动为基础的治疗策略，可以防止肌肉萎缩， 有助于COPD患者进行更多的体力活动。因此，我们的长远目标是改善 通过恢复肌肉功能改善COPD患者的生活质量。