SKELETAL MUSCLE DYSFUNCTION IN COPD

慢性阻塞性肺病 (COPD) 影响着美国 1400 万人，是发病率和死亡率的主要来源，并消耗着日益稀缺的医疗资源。该项目的总体目标是更好地了解慢性阻塞性肺病患者的体力耐受力降低，而这又与其发病率和死亡率相关。 我们实验室最近发表的试验数据表明，慢性阻塞性肺病患者有氧能力降低的主要原因并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。 使用运动过程中氧气输送和利用的经典措施，我们证明了慢性阻塞性肺病患者全身氧气摄取的临床相关问题，在减容手术后或肺移植后，通气肌减负荷并不能改善这一问题。 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。 我们的实验室开发了一种新的磁共振成像体积描记法和 T1 加权测量方法，可测量整体和区域外周肌肉灌注，已证明充血性心力衰竭患者存在异常。 我们还利用最先进的 31P 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出现异常 pHi 调节，提示存在氧化性肌病。 该项目的具体建议是识别患有严重慢性阻塞性肺病和全身氧气提取异常的患者，然后区分骨骼肌灌注异常和内在线粒体缺陷，作为他们运动受限的解释。 {通过统计分析，我们将确定异常吸氧量与吸烟史、营养、低氧血症和皮质类固醇使用之间的关联。}在确定了骨骼肌吸氧量异常的患者后，我们将设法区分运动肢体的局部血流紊乱与肌肉线粒体的内在异常，并{确定此类异常是否与训练不足有关}。 更好地了解慢性阻塞性肺病中的骨骼肌氧化异常将为这种破坏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.