Before lung transplant (LTx), exercise limitation in emphysema is predominantly due to ventilatory impairment and muscle detraining. Maximum O2 uptake and lactate threshold are substantially reduced: about 30 percent of predicted. It is, therefore, stunningly disappointing that after LTx, and in spite of normalization of lung function, exercise capacity is no better than about 50 percent of normal. Mechanisms of this impairment may include: disuse atrophy, myopathy from corticosteroid use, mitochondrial myopathy, or a result of immunosuppressive therapy. The true potential of the muscles often goes untested using whole-body exercise as the lung disease limits muscle O2 delivery. Therefore, we will exercise only a small muscle-mass: single-leg knee-extensors. Muscle function will be assessed by a multidisciplinary array including: muscle blood flow, O2 utilization, intramuscular magnetic resonance spectroscopy, and structural, biochemical and molecular analysis of biopsies. Assessment will be made both before and after knee-extensor training and before and after LTx. We hypothesize that: 1) pre-LTx, muscle dysfunction is due to disuse and will be restored to the normal range by training, even as emphysema persists; and 2) post-LTx, immunosuppressive therapy results in muscle myopathy such that similar training will not result in normalization of function. Parallel animal studies of the regulation of angiogenic and hypertrophic genes during immunosuppression will also be made.
