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.

运动受限是慢性阻塞性肺疾病的一种主要症状，尤其是在那些表现出 肌肉萎缩(恶病质)。有越来越多的证据表明系统性多器官对 除原发性外，由于心肌和骨骼肌功能受损而导致的运动不耐受 肺部结构遭到破坏。然而，慢性阻塞性肺疾病肺损伤导致 肌肉功能障碍仍不清楚。由于这两种情况，骨骼肌对02的可利用性降低 肺和心功能受损可能起到一定作用。此外，全身炎症和氧化 慢性阻塞性肺病患者也会出现应激，并有可能限制心脏和骨骼肌血管生成 和可伸缩性。骨骼肌毛细血管在很大程度上依赖于血管内皮生长因子，据报道 COPD患者体内血管内皮生长因子水平降低，已知肺和骨骼肌中的血管内皮生长因子水平 减少了。因此，该项目的总体目标是确定哪些途径(炎症、 氧化应激和/或低氧)，在COPD中改变，导致毛细血管、骨骼肌改变 表型和功能。中心假说是血管内皮生长因子的失调导致了许多 慢性阻塞性肺疾病患者骨骼肌结构和功能的变化 有恶病质表型，这些异常是血管内皮生长因子不足维持的结果 毛细作用，保护骨骼肌免受氧化应激和/或炎症的伤害。运动训练是 假想是增加肌肉血管内皮生长因子的表达，增加肌肉毛细血管和改善运动 容量。在Project 3提供的人体肌肉活检中，我们将评估炎症、氧化应激、 恶病质与非恶病质骨骼肌抗氧化平衡及血管生成介质的研究 COPD患者和正常对照组。使用四种转基因小鼠模型，我们将专门针对 分别评估炎症、氧化应激和氧气减少的重要性的途径 分娩过程中骨骼肌功能障碍的发展。将评估小鼠COPD模型 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 与毛细血管退缩相关，即从I型纤维到II型纤维的潜在转变，并受损 锻炼耐力。从这项研究中获得的知识有望为这两项研究奠定基础 以药物和运动为基础的治疗策略，可以防止肌肉萎缩和 促进COPD患者更多的体力活动。因此，我们的长期目标是改善 通过肌肉功能的恢复提高COPD患者的生活质量。