Alterations in myocardial signal transduction due to aging and chronic dynamic exercise

Normal aging without disease leads to diminished chronotropic and inotropic responses to catecholamine stimulation, resulting in depressed cardiac function with stress. The purpose of this study was to determine molecular mechanisms for decrements in adrenergic responsiveness of the left ventricle (LV) due to aging and to study the effects of chronic dynamic exercise on signal transduction. We measured β-adrenergic receptor (β-AR) density, adenylyl cyclase (AC) activity, and G-protein content and distribution in LV from 66 male Fischer 344 rats from three age groups that were either sedentary or treadmill trained (60 min/day, 5 days/wk, 10 wk at 75% of the maximal capacity). Final ages were 7 mo (young), 15 mo (middle- age), and 25 mo (old). There was no significant difference in β-AR density among groups as a function of age or training. AC production of adenosine 3',5'-cyclic monophosphate (cAMP) with the use of five pharmacological stimulations revealed that old sedentary myocardium had depressed basal, receptor-dependent, G-protein-dependent, and AC catalyst stimulation (30- 43%) compared with hearts from young and middle-age sedentary rats. Training did not alter AC activity in either middle-age or old groups but did increase G-protein-dependent cAMP production in young myocardium (12-34%). Immunodetectable concentrations of stimulatory and inhibitory G proteins (G(s) and G(i), respectively) showed 43% less total G(s) with similar G(i) content in hearts from old sedentary compared with middle-age sedentary rats. When compared with young sedentary animals, G(i) content was 39 and 50% higher in middle-age sedentary and old sedentary myocardium, respectively. With age, there was a significant shift in the α-subunit of G(s) distribution from cytosolic fractions of LV homogenates to membrane-bound fractions (8-12% redistribution in middle-age sedentary vs. old sedentary). The most significant training effect was a decrease in G(i) content in hearts from old trained rats (23%), which resulted in values comparable with young sedentary rats and reduced the G(i)/G(s) ratio by 27% in old-rat LV. We report that age-associated reductions in cardiovascular β-adrenergic responsiveness correspond with alterations in postreceptor adrenergic signaling rather than with a decrease in receptor number. Chronic dynamic exercise partially attenuates these reductions through alterations in postreceptor elements of cardiac signal transduction.