SKELETAL MUSCLE DYSFUNCTION IN COPD

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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.