title: Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha1.
abstract: 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 AMPKalpha1/alpha2 under normoxic, ischemic, and anoxic conditions. In the heart lacking cardiac muscle LKB1, the basal activity of AMPKalpha2 was vastly reduced and not increased by ischemia or anoxia. Phosphorylation of AMPKalpha2 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 AMPKalpha2, significant basal activity of AMPKalpha1 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 AMPKalpha1, 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 AMPKalpha2 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 AMPKalpha1 in cardiac muscle.
authors.affiliation: Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, Univ. of Dundee, Dow St., Dundee DD1 5EH, UK. k.sakamoto@dundee.ac.uk
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Elham
authors.initials: E
authors.lastname: Zarrinpashneh
authors.forename: Grant R
authors.initials: GR
authors.lastname: Budas
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Pouleur
authors.forename: Anindya
authors.initials: A
authors.lastname: Dutta
authors.forename: Alan R
authors.initials: AR
authors.lastname: Prescott
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vanoverschelde
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Jovanović
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D004562:Electrocardiography; D004789:Enzyme Activation; D006321:Heart / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009929:Organ Size; D010477:Perfusion; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D021122:Protein Subunits; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase