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Role of the energy sensor AMPK in the heart: lessons learned from an inducible AMPK α1α2-knockout in mouse cardiomyocytes
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Edité par CCSD -
International audience. AMP-activated protein kinase (AMPK) is known as a key sensor and regulator of energy homeostasis in the eukaryotic cell. Especially in the heart, which has high energy requirements and a remarkable metabolic homeostasis, AMPK signaling is supposed to play a key role. While important functions of AMPK have indeed been identified in the pathological heart, very few studies analyzed a non-pathological setting. To address this issue, we used here a novel, cardiomyocyte-specific AMPK α1 and α2 double knockout (KO) in the mouse, induced at the age of 8 weeks [1]. Both AMPK α isoforms were deleted in a large part of cardiomyocytes already two weeks after tamoxifen administration, persisting during the entire study period. At baseline conditions, AMPK KO had no detectable effect on heart function and structure. However, KO mice showed decreased basal metabolic rate (oxygen uptake, energy expenditure) and a trend to lower locomotor activity with increased age (one year after KO induction). Importantly, significant impairment of cardiac function occurred under an increased workload that was induced by dobutamine. This was consistent with lower endurance exercise capacity of KO mice, suggesting that cardiac output became limiting. Loss of AMPK also resulted in multiple alterations of cardiac mitochondria, including reduced respiration of isolated mitochondria with complex I substrates, reduced activity of complexes I and IV, and a shift in cristae morphology from lamellar to mixed lamellar-tubular. A strong tendency to diminished ATP and glycogen level was observed in older animals, one year after KO induction. In summary, our data suggest important physiological roles of cardiomyocyte AMPK at increased cardiac workload. They can potentially limit exercise performance, and involve impaired mitochondrial functions and bioenergetics that further deteriorate with age.
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