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 transduction in rat livers from 7- to 25-mo-old animals and examined the effects 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 divided into sedentary and trained (treadmill running) groups. Isolated hepatic membranes were combined with [¹²⁵I-Tyr¹⁰]monoiodoglucagon and nine concentrations of glucagon to determine maximal binding capacity (B_max) and dissociation constant (K_d). No alterations were found in B_max among groups; however, middle-aged trained animals had significantly higher glucagon affinity (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 adenylyl cyclase (AC) specific activity under basal conditions and with four pharmacological 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 resulted in increased cAMP production in the old animals when AC was directly stimulated by forskolin. Stimulatory G protein (G_s) content was reduced with age in the sedentary group; however, training offset this decline. We conclude that age-related declines in glucagon signaling capacity and responsiveness may be attributed, in part, to declines in intrinsic AC activity and changes in G protein [inhibitory G protein (G_i)/G_sJ ratios. These age-related changes occur in the absence of alterations in glucagon receptor content and appear to involve both G protein-and AC-related changes. Endurance training was able to significantly offset these declines through restoration of the G_i/G_s ratio and AC activity.