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 [(125)I-Tyr(10)]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(s)] 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.
Podolin
D A
DA
University of Colorado, Boulder, CO 80303, USA. dpodolin@mailbox.une.edu
Wills
B K
BK
Wood
I O
IO
Lopez
M
M
Mazzeo
R S
RS
Roth
D A
DA
D000262:Adenylyl Cyclases / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D001345:Autoradiography; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000032:analysis / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000032:analysis / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D005934:Glucagon / Q000378:metabolism*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D015151:Immunoblotting; D007457:Iodine Radioisotopes; D008099:Liver / Q000378:metabolism*; D008297:Male; D010807:Physical Endurance; D005082:Physical Exertion / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D018027:Receptors, Glucagon / Q000502:physiology; D015398:Signal Transduction
D007457:Iodine Radioisotopes; D018027:Receptors, Glucagon; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D005934:Glucagon; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases