Life‐long caloric restriction confers pronounced AMPK‐dependent cardioprotection

Abstract

AIMSTo determine whether myocardial resistance to ischemia/reperfusion (I/R) injury is enhanced in the senescent heart after life‐long caloric restriction, and whether AMP‐activated protein kinase (AMPK) plays a role in that phenotype.METHODS AND RESULTSHearts from ad libitum fed (AL) and life‐long calorically restricted (LCR, 40% restriction) B6D2F1 mice were examined by echocardiography, and 25/90 minute global I/R. AMPK inhibition (AraA) was applied to both groups (AL+AraA, LCR+AraA) prior to I/R. LCR hearts were smaller (AL, 270 ± 7 mg vs. LCR, 185 ± 5 mg, p < 0.001), and had thinner posterior walls (PWTd: AL, 1.07 ± 0.05 mm vs. LCR, 0.84 ± 0.05 mm, p < 0.05), but similar in vivo luminal dimension (LVIDd; LVIDs: AL, 3.8 ± 0.14; 2.0 ± 0.19 mm vs. LCR, 3.5 ± 0.18; 1.8 ± 0.17 mm, both p > 0.2). LCR hearts were protected from infarction (Infarct Size: AL, 28 ± 4 % vs. LCR, 10 ± 1 %, p < 0.01) and post‐ischemic functional deficit (LVDP recovery: AL, 65 ± 8 % vs. LCR, 93 ± 7 %, p < 0.01), and both effects were abolished by AraA (Infarct size: LCR+AraA, 22 ± 4 %; LVDP recovery: LCR+AraA, 82 ± 9 %, both p vs. AL > 0.1). LCR dramatically increased AMPKα phosphorylation (AL, 1.30 ± 0.03 vs. LCR, 1.55 ± 0.03, ratio units, p < 0.001), but not expression (AL, 1.21 ± 0.07 vs. LCR, 1.19 ± 0.01, ratio units, p = 0.8).CONCLUSIONSLife‐long caloric restriction induces powerful AMPK‐dependent I/R resistance, and involves elevated AMPKα phosphorylation.