SKELETAL MUSCLE DYSFUNCTION IN COPD

慢性阻塞性肺疾病（COPD）在美国影响了1400万人，是发病率和死亡率的主要来源，并消耗了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患者的运动耐受性降低，这反过来又与COPD的发病率和死亡率有关。我们实验室最近发表的和试点数据表明，COPD患者有氧能力下降的主要原因不是肺功能本身异常，而是外周骨骼肌本身氧化能力下降。通过经典的运动过程中氧气输送和利用的测量，我们已经证明了慢性阻塞性肺病患者的系统性氧气摄取的临床相关问题，在减容手术或肺移植后，通气肌卸载并没有改善。这些数据与肢体肌肉中血液流动和代谢的微循环匹配异常或肌肉线粒体固有缺陷相一致。我们的实验室已经开发了一种新的磁共振成像体积脉搏图和t1加权测量全球和区域外周肌肉灌注，这已经证明了充血性心力衰竭患者的异常。我们还利用最先进的31P磁共振波谱技术，在肺移植受体的骨骼肌细胞运动期间发现异常的pHi调节，提示氧化性肌病。该项目的具体建议是识别严重COPD患者和异常的全身氧提取，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，我们将确定异常氧提取与吸烟史、营养、低氧血症和皮质类固醇使用之间的关系。在确定了骨骼肌氧提取异常的患者后，我们将试图区分运动肢体的局部血流障碍与肌肉线粒体的内在异常，并确定这种异常是否与去训练有关。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。

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.