DETERMINANTS OF MAXIMAL O2 TRANSPORT

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Chronic diseases (COPD, heart failure, renal failure) are marked by reduced exercise capacity. There is increasing evidence that skeletal muscle structure and function may be intrinsically abnormal in such conditions. The present proposal continues work from the current cycle to better understand the mechanisms of exercise limitation in both health and disease, in particular the role of skeletal muscle. Physiological approaches already developed under the PPG involving muscle O2 transport analysis (large versus small muscle mass exercise, femoral blood flow, blood gas sampling, magnetic resonance spectroscopy to measure intracellular P02, morphology to assess diffusion distances and capillary surface area) will be combined with molecular-level studies focused on genes associated with muscle angiogenic responses to exercise, since the amount of capillary surface appears critical to O2 transport limitation. This integrated approach will be applied in both animal and human studies, the latter in both health and chronic disease (heart failure, chronic obstructive pulmonary disease). Animal work will use mechanistic interventions not possible in man to complement human experiments, and in both, the molecular approaches will be applied in intact physiological systems. Major goals include: 1) separating O2 transport-based exercise limitation from that due to intrinsic muscle abnormalities in chronic diseases; 2) determining if VEGF is essential to angiogenesis using Cre/loxP targeted knockout strategy, as well as VEGF antagonists such as Suramin, Losartan and Captopril; 3) defining the mechanisms that normally increase VEGF message and protein capillarity in chronic diseases. Our ultimate objective is to identify abnormalities of muscle O2 transport in chronic disease at the level of gene regulation, in the hope of eventual gene-targeted therapy. We hypothesize that these will centrally involve the muscle angiogenic response to exercise.