SKELETAL MUSCLE DYSFUNCTION IN COPD

慢性阻塞性肺病患者的骨骼肌功能障碍

• 批准号: 6476711
• 负责人: DAVID M SYSTROM
• 金额: $ 11.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476711
• 关键词: chronic obstructive pulmonary disease; clinical research; corticosteroids; exercise; hormone therapy; human subject; magnetic resonance imaging; medical rehabilitation related tag; microcirculation; mitochondrial disease /disorder; muscle function; muscle metabolism; musculoskeletal disorder therapy; nuclear magnetic resonance spectroscopy; oxygen transport; plethysmography; rehabilitation; respiratory gas level; smoking; statistics /biometry; stop flow technique; striated muscles

Chronic obstructive pulmonary disease (COPD) affects 14 million people in the United States, is a major source of morbidity and mortality and drains increasing scarce health care resources. The overall aim of this project is to better understand reduced exertional tolerance in COPD, which in turn, is related to its morbidity and mortality. Recent published and pilot data from our laboratories suggest a major reason for reduced aerobic capacity in COPD is not abnormal lung function per se, but decreased oxidative capacity of peripheral skeletal muscle itself. Using classic measures of oxygen delivery and utilization during exercise, we have demonstrated a clinically relevant problem with systemic O2 uptake in COPD, which does not improve with ventilatory muscle unloading, after volume reduction surgery or after lung transplantation. These data are consistent with an abnormality of either microcirculatory matching of blood flow and metabolism in the limb muscle or to an inherent defect in the muscle mitochondrion. Our laboratories have developed a new magnetic resonance imaging plethysmographic and T1-weighted measurements of both global and regional peripheral muscle perfusion, which have demonstrated abnormalities in congestive heart failure patients. We have also utilized state of the art 31P magnetic resonance spectroscopy techniques and found abnormal pHi regulation during exercise in the lung transplant recipient's skeletal myocyte, suggestive of an oxidative myopathy. The specific propose of this project is to identify patients with severe COPD and abnormal systemic O2 extraction and to then differentiate between abnormalities of skeletal muscle perfusion and an intrinsic mitochondrial defect as an explanation for their limit to exercise. {Through statistical analysis, we will determine associations among abnormal O2 extraction and smoking history, nutrition, hypoxemia and corticosteroid use.} Having identified patients with abnormal skeletal muscle O2 extraction, we will seek to differentiate disorders of regional blood flow to the exercising limb from intrinsic abnormalities of the muscle mitochondrion as a cause and {determine whether such abnormalities are related to detraining}. Better understanding of the skeletal muscle oxidative abnormality in COPD will provide a rational basis for new therapies in this devastating disease.

慢性阻塞性肺疾病（COPD）影响美国1400万人，是发病率和死亡率的主要来源，并且消耗越来越稀缺的卫生保健资源。该项目的总体目标是更好地了解COPD患者劳力耐受性降低，这反过来又与其发病率和死亡率相关。 我们实验室最近发表的和初步的数据表明，COPD患者有氧能力降低的主要原因不是肺功能本身异常，而是外周骨骼肌本身的氧化能力降低。 使用经典的氧输送和利用的措施，在运动中，我们已经证明了一个临床相关的问题，全身O2摄取的COPD，这并没有改善与肌肉卸载，减容手术后或肺移植后。 这些数据与肢体肌肉中血流和代谢的微循环匹配异常或肌肉线粒体的固有缺陷一致。 我们的实验室已经开发出一种新的磁共振成像体积描记和T1加权测量的全球和区域外周肌肉灌注，这表明在充血性心力衰竭患者的异常。 我们还利用了最先进的31 P磁共振波谱技术，发现肺移植受者的骨骼肌细胞在运动过程中pHi调节异常，提示氧化性肌病。 该项目的具体建议是识别患有严重COPD和异常全身O2提取的患者，然后区分骨骼肌灌注异常和内在线粒体缺陷，作为其运动限制的解释。 {通过统计分析，我们将确定异常O2提取与吸烟史、营养、低氧血症和皮质类固醇使用之间的关联。} 在确定骨骼肌O2提取异常的患者后，我们将寻求区分运动肢体的局部血流障碍与肌肉线粒体的内在异常作为原因，并{确定此类异常是否与停止训练有关}。 更好地了解COPD骨骼肌氧化异常将为这种毁灭性疾病的新疗法提供合理的基础。