Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice

Abstract

. Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice. Am J Physiol Regul Integr Comp Physiol 287: R1270 -R1275, 2004. First published July 29, 2004 doi:10.1152/ajpregu.00409.2004.-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 ␣2-AMPK, but not ␣1-AMPK, was significantly higher in the hearts from old than from young mice (P Ͻ 0.005), this difference being due to differences in phosphorylation of ␣2-AMPK. Significant activation of AMPK in the young hearts did not occur until 30 min of hypoxemia (P Ͻ 0.01), stress that was poorly tolerated by the old mice (mortality ϭ 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.

Reduced skeletal muscle AMPK and mitochondrial markers do not promote age-induced insulin resistance

“…Skeletal muscle AMPK is reduced with aging in some (22,25) but not all studies (11) and has been shown to be vital for maintaining mitochondrial content [for review, see O'Neill et al (27)]. To establish whether a reduction in AMPK and mitochondrial content causes the development of aging-induced insulin resistance, we studied mice with undetectable levels of skeletal muscle AMPK and reduced mitochondrial function (28).…”

“…An important regulator of mitochondrial content in skeletal muscle is the AMP-activated protein kinase (AMPK), and many studies have found AMPK protein or activity levels to be lower in aged vs. young humans (22,25) and rodents (12,33,34), although it should be noted this is not observed in all studies (11,35). AMPK is a heterotrimer composed of ␣-, ␤-, and ␥-subunits (44).…”

AMPK in Health and Disease

“…In higher organisms, the role of AMPK in the regulation of aging is not clear, with some reports demonstrating a significant reduction in AMPK signaling in muscle (399,408) while others report no change (169,379) or even increased AMPK activity (494,495). The effects of metabolic stress such as hypoxia, caloric restriction, or muscle contraction on AMPK signaling in aging are equally equivocal with some studies reporting increased activation (169,379), while others have reported a reduction (349,408).…”

“…The effects of metabolic stress such as hypoxia, caloric restriction, or muscle contraction on AMPK signaling in aging are equally equivocal with some studies reporting increased activation (169,379), while others have reported a reduction (349,408). Interestingly, resveratrol (3,5,4Ј-trihydroxystilbene), which extends the life span of organisms through Sir2, a conserved deacetylase, proposed to underlie the beneficial effects of caloric restriction, activates AMPK (121, 220,384,575).…”

Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice

“…The tolerance to multiple stresses is diminished with aging, and an impaired tolerance is also observed in isolated hearts (43). To test whether FAK gene deletion influences heart morphology and function in old mice, we performed echocardiography to examine CFKO and control mice at 9 months of age.…”