Skeletal muscle dysfunction in lung transplantation
Sleep Apnea Syndromes
Skeletal muscle dysfunction has been documented in patients with chronic lung disease by findings of diminished muscle strength and exercise performance. Several specific skeletal muscle abnormalities were detected. The proportion of type I fibers is decreased, which is similar to findings in deconditioning and immobilization. As decreases in type I fibers persist after transplantation, hypothesis of selective type I cell death has been proposed, possibly involving an increased rate of free radical formation in oxidative fibers that would interfere with full recovery of exercise capacity. A diminished capillary to fiber ratio is also found in healthy elderly subjects and other chronic diseases. Markers of reduced oxidative activity such as lower PCr and ATP levels and increased glycolytic and anaerobic function with early lactic acid accumulation, decreased intracellular pH and reduced oxygen utilization have also been established in chronic lung disease pre- and post-transplant. It is unclear if these findings are linked to a change in capillary bed anatomy resulting in decreased oxygen delivery to oxidative myofibrils. One major methodologic difficulty is the lack of a practical technique to repeatedly measure blood flow and oxygen delivery to exercising muscle. Further more, most pathophysiologic studies investigate small patient series, which makes generalization of findings to all subjects with COPD improbable. Heterogeneity in capillary blood flow and distribution has been demonstrated in exercising muscle. A test of Wagner's theoretical construct, using selected clinical data, predicts that after restoration of ventilatory capacity by lung transplantation, maximal oxygen utilization would fail to increase proportionately. It might be that lower oxygen availability would cause permanent muscle changes with subsequent fiber death. A complex interaction of circulatory, respiratory and musculoskeletal factors impairs our ability to isolate and identify the exact factors involved in this dysfunction. A lack of perfusion may generate cell atrophy and death, but may also be secondary to cellular dysfunction. The exact level where defects exist will be hard to define unless careful microscopic analysis of regional anatomy and physiology are made at different clinical stage sof the disease. If a cellular abnormality is more likely, the differentiation between mitochondrial and non-mitochondrial abnormalities in cellular oxygen utiliation will be difficult to assess. A common factor, such as deconditioning, may trigger a complex chain of events resulting in persistent abnormalities of oxygen utilization that can be only partially improved after physical rehabilitation. The cardiorespiratory system is dramatically improved after thoracic transplantation, and is not a limiting factor during exercise in those patients. Despite this, it appears that an abnormality in peripheral oxygen utilization persists. The bulk of observations is consistent with a myopathy as a factor in exercise limitation, but still can not exclude abnormal microcirculation and reduced oxygen delivery. Examining all of the above factors pre- and post-transplantation can help in distinguishing the pre-existing cardiopulmonary disease from other variables, such as medications, and help determine the contribution of immnosuppressant effects ot the underlying dysfunction and physical deconditioning. There is a tendency among clinicians to strive to identify a single limiting factor responsible for decreases in maximal oxygen utilization in given patients. Accordingly, exercise performances have been classified as 'ventilatory' or circulatory' limited. Such categorizations may be of questionable diagnostic value, as maximal oxygen utilizaton is actually set by an integrative process involving quantitative interactions between all steps in oxygen transportation (Figures 1 and 2). The established dysfunctional oxygen utilization by skeletal muscle is a pertinent problem in clinical practice because of the functional limitation of patients wit chronic lung and heart disease and because of the incomplete recovery of exercise capacity demonstrated after a potential curative procedure, such as organ transplantation. Identifying the determinant factors of such limitation and addressing its treatment will be an important step in the full recovery of those patients. Further research involving a quantitative assessment of the relative importance of each contributing step shall identify the potential sites for intervention and determine the maximal obtainable improvement of exercise capacity in patients iwht lung and heart disease.