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2 but not AMPK1
,31Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom; 2Division of Cardiology, School of Medicine, Université catholique de Louvain, Brussels, Belgium; 3Maternal and Child Health Sciences, Tayside Institute of Child Health, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom; 4The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom; and 5Division of Cell Biology and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
Submitted 13 September 2005 ; accepted in final form 29 November 2005
Recent studies indicate that the LKB1 is a key regulator of the AMP-activated protein kinase (AMPK), which plays a crucial role in protecting cardiac muscle from damage during ischemia. We have employed mice that lack LKB1 in cardiac and skeletal muscle and studied how this affected the activity of cardiac AMPK
1/2 under normoxic, ischemic, and anoxic conditions. In the heart lacking cardiac muscle LKB1, the basal activity of AMPK2 was vastly reduced and not increased by ischemia or anoxia. Phosphorylation of AMPK2 at the site of LKB1 phosphorylation (Thr172) or phosphorylation of acetyl-CoA carboxylase-2, a downstream substrate of AMPK, was ablated in ischemic heart lacking cardiac LKB1. Ischemia was found to increase the ADP-to-ATP (ADP/ATP) and AMP-to-ATP ratios (AMP/ATP) to a greater extent in LKB1-deficient cardiac muscle than in LKB1-expressing muscle. In contrast to AMPK2, significant basal activity of AMPK1 was observed in the lysates from the hearts lacking cardiac muscle LKB1, as well as in cardiomyocytes that had been isolated from these hearts. In the heart lacking cardiac LKB1, ischemia or anoxia induced a marked activation and phosphorylation of AMPK1, to a level that was only moderately lower than observed in LKB1-expressing heart. Echocardiographic and morphological analysis of the cardiac LKB1-deficient hearts indicated that these hearts were not overtly dysfunctional, despite possessing a reduced weight and enlarged atria. These findings indicate that LKB1 plays a crucial role in regulating AMPK2 activation and acetyl-CoA carboxylase-2 phosphorylation and also regulating cellular energy levels in response to ischemia. They also provide genetic evidence that an alternative upstream kinase can activate AMPK1 in cardiac muscle.
cellular energy metabolism; hypoxia; cardiovascular physiology; AMP-activated protein kinase
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