ALTERATIONS IN MYOCARDIAL SIGNAL-TRANSDUCTION DUE TO AGING AND CHRONIC DYNAMIC EXERCISE

Normal aging without disease leads to diminished chronotropic and inot ropic responses to catecholamine stimulation, resulting in depressed c ardiac function with stress. The purpose of this study was to determin e molecular mechanisms for decrements in adrenergic responsiveness of the left ventricle (LV) due to aging and to study the effects of chron ic dynamic exercise on signal transduction. We measured beta-adrenergi c receptor (beta-AR) density, adenylyl cyclase (AC) activity, and G-pr otein content and distribution in LV from 66 male Fischer 344 rats fro m 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 s ignificant difference in beta-AR density among groups as a function of age or training. AC production of adenosine 3',5'-cyclic monophosphat e (cAMP) with the use of five pharmacological stimulations revealed th at 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 alte r AC activity in either middle-age or old groups but did increase G-pr otein-dependent cAMP production in young myocardium (12-34%). Immunode tectable 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 sedentar y rats. When compared with young sedentary animals, G(i) content was 3 9 and 50% higher in middle-age sedentary and old sedentary myocardium, respectively. With age, there was a significant shift in the uc-subun it 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 decrea se in G(i) content in hearts from old trained rats (23%), which result ed 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 reduct ions in cardiovascular beta-adrenergic responsiveness correspond with alterations in postreceptor adrenergic signaling rather than with a de crease in receptor number. Chronic dynamic exercise partially attenuat es these reductions through alterations in postreceptor elements of ca rdiac signal transduction.