Role of the α2-isoform of AMP-activated protein kinase in the metabolic response of the heart to no-flow ischemia

Abstract

AMP-activated protein kinase (AMPK) is a major sensor and regulator of the energetic state of the cell. Little is known about the specific role of AMPKα₂, the major AMPK isoform in the heart, in response to global ischemia. We used AMPKα₂-knockout (AMPKα₂^−/−) mice to evaluate the consequences of AMPKα₂ deletion during normoxia and ischemia, with glucose as the sole substrate. Hemodynamic measurements from echocardiography of hearts from AMPKα₂^−/− mice during normoxia showed no significant modification compared with wild-type animals. In contrast, the response of hearts from AMPKα₂^−/− mice to no-flow ischemia was characterized by a more rapid onset of ischemia-induced contracture. This ischemic contracture was associated with a decrease in ATP content, lactate production, glycogen content, and AMPKβ₂ content. Hearts from AMPKα₂^−/− mice were also characterized by a decreased phosphorylation state of acetyl-CoA carboxylase during normoxia and ischemia. Despite an apparent worse metabolic adaptation during ischemia, the absence of AMPKα₂ does not exacerbate impairment of the recovery of postischemic contractile function. In conclusion, AMPKα₂ is required for the metabolic response of the heart to no-flow ischemia. The remaining AMPKα₁ cannot compensate for the absence of AMPKα₂.