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

Roth, David A., Cynthia D. White, Deborah A. Podolin, andRobert S. Mazzeo. Alterations in myocardial signal transduction due to aging and chronic dynamic exercise. J. Appl. Physiol.84(1): 177-184, 1998.Normal aging without disease leads todiminished chronotropic and inotropic responses to catecholaminestimulation, resulting in depressed cardiac function with stress. Thepurpose of this study was to determine molecular mechanisms fordecrements in adrenergic responsiveness of the left ventricle (LV) dueto aging and to study the effects of chronic dynamic exercise on signaltransduction. We measured -adrenergic receptor (-AR) density,adenylyl cyclase (AC) activity, and G-protein content and distributionin LV from 66 male Fischer 344 rats from three age groups that wereeither sedentary or treadmill trained (60 min/day, 5 days/wk, 10 wk at75% of the maximal capacity). Final ages were 7 mo(young), 15 mo (middle-age), and 25 mo (old). There was no significantdifference in -AR density among groups as a function of age ortraining. AC production of adenosine 3,5-cyclic monophosphate (cAMP)with the use of five pharmacological stimulations revealed that oldsedentary 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 didincrease G-protein-dependent cAMP production in young myocardium (12-34%). Immunodetectable concentrations of stimulatory andinhibitory G proteins (G_s and G_i, respectively)showed 43% less total G_s with similar G_icontent in hearts from old sedentary compared with middle-age sedentaryrats. When compared with young sedentary animals, G_icontent was 39 and 50% higher in middle-age sedentary and oldsedentary myocardium, respectively. With age, there was a significantshift in the -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 mostsignificant training effect was a decrease in G_i content inhearts from old trained rats (23%), which resulted in values comparable with young sedentary rats and reduced theG_i/G_s ratio by 27% in old-rat LV. We reportthat age-associated reductions in cardiovascular -adrenergicresponsiveness correspond with alterations in postreceptor adrenergicsignaling rather than with a decrease in receptor number. Chronicdynamic exercise partially attenuates these reductions throughalterations in postreceptor elements of cardiac signal transduction.