Metabolic and Non-Metabolic Effects of Cardiac-Specific and Inducible Deletion of the AMPKalpha2 in Female and Male Mice

Mitochondrial dysfunction plays a major role in the Heart Failure (HF) pathophysiology. The AMP activated protein kinase (AMPK) is activated by a high AMP-ADP/ATP ratio and regulates a number of metabolic pathways. Many studies have highlighted a protective role of AMPK in HF, but its relevance to cardiac tissue, its metabolic part and its sex-specificity are not well established. The aim of this study is to determine the role of AMPK in the healthy and failing heart in male and female mice. We developed and validated a mouse strain with an adult-inducible cardiac-specific deletion of AMPKα2, the major cardiac isoform, using the Cre-Lox system (40 mg/kg tamoxifen injection on two consecutive days at adult age). At four months after the deletion, cardiac contractility, morphology and metabolism were studied in control and KO mice from both sexes. We observed only in male KO mice a decrease of left ventricular ejection fraction (− 10%), an increase of the total fibrosis (+ 64%) and defects in mitochondrial structures. Male KO mice also showed a reduced (− 28%) mitochondrial respiration via complex I associated with a different cardiolipin species distribution. Our results reveal in adult healthy hearts, a sex-specificity in the effects of AMPKα2 deletion, leading to impaired contractile function related to metabolic and non-metabolic alterations only in male mice.