Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice.
Although a diminished ability of tissues and organisms to tolerate stress is a clinically important hallmark of normal aging, little is known regarding its biochemical basis. Our goal was to determine whether age-associated changes in AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism during the stress response, might contribute to the poor stress tolerance of aged cardiac and skeletal muscle. Basal AMPK activity and the degree of activation of AMPK by AMP and by in vivo hypoxemia (arterial Po2 of 39 mmHg) were measured in cardiac and skeletal muscle (gastrocnemius) from 5- and 24-mo-old C57Bl/6 mice. In the heart, neither basal AMPK activity nor its allosteric activation by AMP was affected by age. However, after 10 min of hypoxemia, the activity of alpha2-AMPK, but not alpha1-AMPK, was significantly higher in the hearts from old than from young mice (P < 0.005), this difference being due to differences in phosphorylation of alpha2-AMPK. Significant activation of AMPK in the young hearts did not occur until 30 min of hypoxemia (P < 0.01), stress that was poorly tolerated by the old mice (mortality = 67%). In contrast, AMPK activity in gastrocnemius muscle was unaffected by age or hypoxemia. We conclude that the age-associated decline in hypoxic tolerance in cardiac and skeletal muscle is not caused by changes in basal AMPK activity or a blunted AMPK response to hypoxia. Activation of AMPK by in vivo hypoxia is slower and more modest than might be predicted from in vitro and ex vivo experiments.
Department ofMedicine, University of Wisconsin, Madison 53706, USA.
Asensio A
AA
Gonzalez
Reetu
R
Kumar
Jacob D
JD
Mulligan
Ashley J
AJ
Davis
Kurt W
KW
Saupe
D055372:AMP-Activated Protein Kinases; D000375:Aging / Q000502:physiology*; D000818:Animals; D001784:Blood Gas Analysis; D006019:Glycolysis / Q000502:physiology; D006321:Heart / Q000254:growth & development*; D000860:Hypoxia / Q000201:enzymology*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000254:growth & development*; D009206:Myocardium / Q000201:enzymology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000097:blood; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016019:Survival Analysis
D007527:Isoenzymes; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D010100:Oxygen