Abstract 12092: AMP Activated Protein Kinase is Indispensable for Maintaining Normal Cardiac Function during Caloric Restriction
Caloric restriction (CR) is a robust dietary intervention known to enhance cardiovascular health and delay age-related diseases. AMP activated protein kinase (AMPK) has been suggested to mediate the cardioprotective effects of CR. However, this hypothesis remains untested by using definitive loss-of-function animal models. Here, we investigated the specific role of AMPK in CR-induced cardiac effects using mice lacking AMPKα2 gene (knockout, KO). Wild-type (WT) mice and AMPK α2-KO mice were randomly assigned to a group fed ad libitum (AL) or a group with restricted calorie intake (CR, 20% less food than AL for 2 weeks, then 40% less for another 2 weeks). CR activated cardiac AMPK signaling in WT mice, but not in AMPKα2 KO mice. This CR regimen caused a roughly 20% decrease in heart weight in both WT and AMPK α2 KO mice, suggesting that AMPK is not required for CR to reduce heart size. However, compared with WT mice, cardiac function in AMPKα2 KO mice was markedly deteriorated during CR as indicated by decreased fractional shortening (AL 39.9±4.9 vs CR 29.9±2.6, p<0.01) and ejection fraction (AL 71.4±5.6 vs CR 57.8±4.0, p<0.05). Hemodynamic measurements revealed that CR did not produce any effect on Left ventricular dP/dt-max and dP/dt-min in WT mice, but CR led to reduced absolute values of dP/dt-max and dP/dt-min in AMPKα2 KO mice, suggesting the necessity of AMPK in maintaining normal cardiac function during CR. Moreover, CR decreased endoplasmic reticulum (ER) stress in WT mice, but not in AMPKα2 KO mice, as assessed by the levels of CHOP, BiP, PDI, PERK and IRE1α, suggesting that AMPK mediates the ability of CR to inhibit ER stress. Additionally, CR induced cardiac oxidative injury and apoptotic cell death in AMPKα2 KO mice but not in WT mice. These findings demonstrate that in the absence of AMPK signaling CR is unable to provide cardioprotection; instead, CR triggers adverse effects that ultimately lead to cardiac dysfunction. Thus, our results indicate that an intact AMPK signaling pathway is absolutely required for maintaining cardiac homeostasis during CR, a dietary intervention that normally protects the heart from stressful stimuli.
- © 2012 by American Heart Association, Inc.