Attenuation of age-related declines in glucagon-mediated signal transduction in rat liver by exercise training

This study investigated alterations in glucagon receptor-mediated signal tr ansduction in rat livers from 7- to 25-mo-old animals and examined the effe cts of exercise training on ameliorating these changes. Sixty-six young (4 mo), middle-aged (12 mo), and old (22 mo) male Fischer 344 rats were divide d into sedentary and trained (treadmill running) groups. Isolated hepatic m embranes were combined with [I-125-Tyr(10)]monoiodoglucagon and nine concen trations of glucagon to determine maximal binding capacity (B-max) and diss ociation constant (K-d). No alterations were found in B-max among groups; h owever, middle-aged trained animals had significantly higher glucagon affin ity (lower K-d; 21.1 +/- 1.8 nM) than did their untrained counterparts (50. 2 +/- 7.1 nM). Second messenger studies were performed by measuring adenyly l cyclase (AC) specific activity under basal conditions and with four pharm acological stimulations to assess changes in receptor-dependent, G protein- dependent, and AC catalyst-dependent cAMP production. Age-related declines were observed in the old animals under all five conditions. Training result ed in increased cAMP production in the old animals when AC was directly sti mulated by forskolin. Stimulatory G protein (G(s)) content was reduced with age in the sedentary group; however training offset this decline. We concl ude that age-related declines in glucagon signaling capacity and responsive ness may be attributed, in part, to declines in intrinsic AC activity and c hanges in G protein [inhibitory G protein (G(i))/G(s)] ratios. These age-re lated changes occur in the absence of alterations in glucagon receptor cont ent and appear to involve both G protein- and AC-related changes. Endurance training was able to Significantly offset these declines through restorati on of the G(i)/G(s) ratio and AC activity.