AMPK Activation Is Indispensable for the Protective Effects of Caloric Restriction on Left Ventricular Function in Postinfarct Myocardium

SIMPLE SUMMARY: Impaired coronary blood flow induces cardiac ischemia and can lead to myocardial infarction. Although revascularization therapy and medical treatment potentially restore cardiac function in ischemic hearts, loss of cardiomyocytes and replacement of the dead myocardium by a scar can lead to ischemic heart disease with impaired cardiac output, a condition called heart failure. Medical treatment of heart failure includes drugs such as ACE-inhibitors, beta-blockers, diuretics, mineralocorticoid receptor antagonists, and SGLT (sodium-glucose cotransporter) 2 inhibitors. In addition, dietary interventions may provide further benefits to slow down disease progression. Caloric restriction, the decrease in calorie intake without malnutrition, is a strategy for improving health and increasing lifespan. Caloric restriction reduces the risk factors for cardiovascular diseases, and it improves heart function in animals and humans. Our study investigated the impact of caloric restriction on heart failure progression in mice and rats with myocardial infarction. We show that caloric restriction inhibits progressive loss of heart function, even when started after heart failure is already established. Together, the findings help to deepen our understanding of the complex mechanisms involved in the cardioprotective effects of caloric restriction and how they could be therapeutically utilized to prevent disease progression. ABSTRACT: Background: Caloric restriction (CR) extends lifespan in many species, including mammals. CR is cardioprotective in senescent myocardium by correcting pre-existing mitochondrial dysfunction and apoptotic activation. Furthermore, it confers cardioprotection against acute ischemia-reperfusion injury. Here, we investigated the role of AMP-activated protein kinase (AMPK) in mediating the cardioprotective CR effects in failing, postinfarct myocardium. Methods: Ligation of the left coronary artery or sham operation was performed in rats and mice. Four weeks after surgery, left ventricular (LV) function was analyzed by echocardiography, and animals were assigned to different feeding groups (control diet or 40% CR, 8 weeks) as matched pairs. The role of AMPK was investigated with an AMPK inhibitor in rats or the use of alpha 2 AMPK knock-out mice. Results: CR resulted in a significant improvement in LV function, compared to postinfarct animals receiving control diet in both species. The improvement in LV function was accompanied by a reduction in serum BNP, decrease in LV proapoptotic activation, and increase in mitochondrial biogenesis in the LV. Inhibition or loss of AMPK prevented most of these changes. Conclusions: The failing, postischemic heart is protected from progressive loss of LV systolic function by CR. AMPK activation is indispensable for these protective effects.