Abstract 9772: Caloric Restriction Enhances Cardiomyocyte Autophagy via AMPK and ULK1 Pathways and Mitigates Postinfarction Cardiac Remodeling and Dysfunction
We previously reported that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodeling. In the present study, we hypothesized that caloric restriction (CR), a potent inducer of autophagy, enhances cardiomyocyte authophagy and mitigates post-infarction cardiac remodeling and dysfunction.Myocardial infarction (MI) was induced in mice by ligating the left coronary artery. After one week of MI, mice were randomly divided into the following four groups. The control group was fed ad libitum (100%; n=6). Others were fed restricted diet respectively 80%, 60%, and 40% of the control mice’s total calorie (n=6 each). Three weeks later, we evaluated the left ventricular (LV) function. The dilatation and hypofunction of the LV were apparent in the control group: LV diastolic dimension (LVDd) = 4.9±0.1 mm; LV ejection fraction (LVEF) = 27±3.3%; and +dP/dt = 4677±277 mmHg/s. However, both dilatation and hypofunction were significantly mitigated in groups undergoing CR: in 80%, 60%, and 40%CR, respectively, LVDd = 4.0±0.1 mm, 3.4±0.2 mm and 4.0±0.1 mm; LVEF = 36±2.8%, 51±4.3% and 43±1.5%; and +dP/dt = 6849±221 mmHg/s, 7758±638 mmHg/s and 6923±553mmHg/s, among which the 60% CR group showed the strongest therapeutic effect on postinfarction cardiac remodeling (control vs. 60% CR: p<0.001). Cardiomyocyte autophagy was markedly activated in CR groups as evidenced by the overexpressed microtubule-associated protein 1 light chain 3-II (LC3-II) and specific ultrastructural findings including autophagosome formation. Myocardial ATP contents were found significantly increased in the 60% CR group compared with other groups. The activities of AMP-activated protein kinase (AMPK), ULK1 (a homolog of yeast Atg1) and silent information regulator-1 (Sirt1) were enhanced in hearts of the CR groups. Chloroquine, an inhibitor of autophagy, brought about deleterious outcomes, accompanying inactivation of AMPK-ULK1 but not influencing Sirt1 activity.In conclusion, caloric restriction enhances cardiomyocyte autophagy via AMPK-ULK1 pathway to enhance energy status and ameliorates left ventricular remodeling in the postinfarction heart; the optimal caloric restriction is suggested to be 60%.
- © 2013 by American Heart Association, Inc.