title: AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism.
abstract: OBJECTIVE
  AMP-activated protein kinase (AMPK) is thought to be a central player in regulating myocardial metabolism and its activation has been shown to inhibit cardiac hypertrophy. Recently, mice with muscle-specific deletion of AMPK β1/β2 subunits (AMPKβ1β2-deficient mice, β1β2M-KO) have been generated and possess <10% of normal AMPK activity in muscle. However, how/if dramatic AMPK deficiency alters cardiac metabolism, function, or morphology has not been investigated. Therefore, the aim of this study was to determine whether a significant loss of AMPK activity alters cardiac function, metabolism, and hypertrophy, and whether this may play a role in the pathogenesis of heart failure.
  
  
  RESULTS
  β1β2M-KO mice exhibit an approximate 25% reduction in systolic and diastolic function compared with wild-type (WT) littermates. Despite the well-documented role of AMPK in controlling myocardial energy metabolism, there was no difference in basal glucose and fatty acid oxidation rates between β1β2M-KO and WT mice. However, there was reduced AMPK-mediated phosphorylation of troponin I in β1β2M-KO and reduced ventricular cell shortening in the presence of low Ca(2+), which may explain the impaired cardiac function in these mice. Interestingly, β1β2M-KO mice did not display any signs of compensatory cardiac hypertrophy, which could be attributed to impaired activation of p38 MAPK.
  
  
  CONCLUSIONS
  β1β2M-KO mice display evidence of dilated cardiomyopathy. This is the first mouse model of AMPK deficiency that demonstrates cardiac dysfunction in the absence of pathological stress and provides insights into the role of AMPK in regulating myocardial function, metabolism, hypertrophy, and the progression to heart failure.
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, 458 Heritage Medical Research Centre, Edmonton, AB, Canada T6G 2S2.
authors.forename: Miranda M
authors.initials: MM
authors.lastname: Sung
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, 458 Heritage Medical Research Centre, Edmonton, AB, Canada T6G 2S2.
authors.forename: Beshay N
authors.initials: BN
authors.lastname: Zordoky
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Bujak
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: James S V
authors.initials: JS
authors.lastname: Lally
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, 458 Heritage Medical Research Centre, Edmonton, AB, Canada T6G 2S2.
authors.forename: David
authors.initials: D
authors.lastname: Fung
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardio-Vasculaire, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Horman
authors.affiliation: Boston University School of Medicine, Boston, MA, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Miller
authors.affiliation: Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
authors.affiliation: Department of Medicine, St Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, 458 Heritage Medical Research Centre, Edmonton, AB, Canada T6G 2S2 jason.dyck@ualberta.ca.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics*; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics*
chemical_list: D055372:AMP-Activated Protein Kinases
keywords: AMPK; Heart failure; Hypertrophy; Remodelling