Abstract P058: Necessity of mTOR Inhibition and Autophagy Induction for Maintaining Cardiac Homeostasis During Caloric Restriction
Caloric restriction (CR) is a robust dietary intervention known to delay age-related heart disease. CR is able to antagonize cardiac remodeling in animal and human under various pathological conditions. However, the direct effect of CR on the heart at basal physiological state is not well characterized. In this study, we examined the impact of CR on cardiac homeostasis and explored the signaling mechanisms that mediate the cardiac effect of CR. Male C57BL/6J mice underwent 20% CR, i.e. 20% less food than ad libitum (AL), for 2 weeks and 40% CR for another 2 weeks. This CR regimen caused a roughly 20% decrease in heart weight and myocyte cross-sectional area. CR diminished the activity of the mammalian target of rapamycin (mTOR) and accelerated autophagic flux. To determine the functional role of mTOR inhibition in CR-induced heart size reduction, we used transgenic mice that express a constitutively active mTOR (mTORca) in the heart. CR did not inhibit cardiac mTOR signaling in mTORca mice as it did in wild type (WT) mice. As a result, the ability of CR to reduce heart size in WT mice was severely impaired in mTORca mice. Specifically, CR reduced the heart weight by 23.1% in WT mice (p<0.01 vs AL), but only tended to reduce it in mTORca mice (13.1%, p>0.05 vs AL). Strikingly, when animals were treated with the mTOR inhibitor rapamycin, CR decreased heart weight in both WT and mTORca mice to the same extent, strongly suggesting that mTOR inhibition is required for CR to exert its cardiac effect. Autophagy is a cellular degradation pathway that may contribute to CR-induced heart size reduction. Surprisingly, CR can still decrease heart weight in 2 different autophagy-deficient mouse models, namely, beclin 1 heterozygous knockout mice and ATG16L1 hypomorphic mice. Nonetheless, cardiac function in these mice was markedly deteriorated during CR as indicated by decreased fractional shortening (Beclin 1+−: AL 37.9±2.8 vs CR 29.6±2.1, p<0.01; ATG16L1-HM: AL 36.8±1.8 vs CR 30.1±2.1, p<0.05). This was accompanied by increased oxidative injury, suggesting that autophagy is indispensible for a normal cardiac function during CR. In conclusion, both mTOR inhibition and autophagy induction are essential for maintaining cardiac homeostasis in response to CR-triggered mild stress.
- © 2011 by American Heart Association, Inc.