AMP Activated Protein Kinase Is Indispensable for Myocardial Adaptation to Caloric Restriction in Mice

作者：Chen Kai; Kobayashi Satoru; Xu Xianmin; Viollet Benoit; Liang Qiangrong^*

来源：PLos One, 2013, 8(3): e59682.

DOI：10.1371/journal.pone.0059682

Caloric restriction (CR) is a robust dietary intervention known to enhance cardiovascular health. AMP activated protein kinase (AMPK) has been suggested to mediate the cardioprotective effects of CR. However, this hypothesis remains to be tested by using definitive loss-of-function animal models. In the present study, we subjected AMPK alpha 2 knockout (KO) mice and their wild type (WT) littermates to a CR regimen that reduces caloric intake by 20%-40% for 4 weeks. CR decreased body weight, heart weight and serum levels of insulin in both WT and KO mice to the same degree, indicating the effectiveness of the CR protocol. CR activated cardiac AMPK signaling in WT mice, but not in AMPK alpha 2 KO mice. Correspondingly, AMPK alpha 2 KO mice had markedly reduced cardiac function during CR as determined by echocardiography and hemodynamic measurements. The compromised cardiac function was associated with increased markers of oxidative stress, endoplasmic reticulum stress and myocyte apoptosis. Mechanistically, CR down-regulated the expression of ATP5g2, a subunit of mitochondrial ATP synthase, and reduced ATP content in AMPK alpha 2 KO hearts, but not in WT hearts. In addition, CR accelerated cardiac autophagic flux in WT mice, but failed to do so in AMPK alpha 2 KO mice. These results demonstrated that without AMPK, CR triggers adverse effects that can lead to cardiac dysfunction, suggesting that AMPK signaling pathway is indispensible for energy homeostasis and myocardial adaptation to CR, a dietary intervention that normally produces beneficial cardiac effects.

• 出版日期2013-3-19