We have recently demonstrated an extremely close relationship (r=0.99) between beta adrenergic receptor density and myocyte fiber type population of rat skeletal muscle. Alpha and beta receptor density, agonist responsiveness, and myocyte fiber type are known to be modulated in a variety of tissues by common physiologic and pathophysiologic states such as aging, endurance exercise-training, beta blockade, congestive heart failure (CHF), and altered thyroid status. However, the density, distribution, and agonist responsiveness of these receptors have not been defined in human skeletal muscle, an important target organ for expression of physiologic effects. Our long-term objective is to characterize the distribution of alpha1 and beta receptors in human skeletal muscle and define their role in physiologic and pathophysiologic processes.
Specific aims of this project are: 1) to characterize alpha1 and beta receptor subtype density and distribution in vascular and myocyte components of skeletal muscle of healthy young and older humans, 2) to characterize effects of endurance exercise- training, beta-blockade, chronic CHF, and hyperthyroidism on adrenergic receptor density and distribution and myocyte fiber type population, 3) to determine whether these conditions alter adrenergic receptor density independent of or in conjunction with changes in fiber type population, and 4) to delineate the relationship between differences or effects on receptor density and agonist responsiveness, plasma catecholamine levels at rest and during exercise, skeletal muscle oxidative capacity, and exercise capacity. For these studies, skeletal muscle tissue samples 75- 100 mg in size will be obtained by percutaneous biopsy. Alpha1 and beta adrenergic receptor characteristics will be quantified in thin slices of skeletal muscle tissue by radioligand binding and light microscopic autoradiography. Myocyte fiber type will be delineated by myofibrillar ATPase staining. Beta adrenergic agonist responsiveness will be evaluated in terms of basal- and isoproterenol stimulated adenylate cyclase activity in skeletal muscle and vascular conductance of the distal lower extremity. Skeletal muscle oxidative capacity will be defined by assay of mitochondrial marker enzyme activity. Exercise capacity will be quantified in terms of maximal oxygen uptake by respiratory gas analysis. Data analysis will emphasize evaluation of relationships between alpha1 and beta adrenergic receptor characteristics and agonist responsiveness, plasma catecholamine concentrations, skeletal muscle oxidative capacity.
