title: AMPK-dependent inhibitory phosphorylation of ACC is not essential for maintaining myocardial fatty acid oxidation.
abstract: BACKGROUND
  The energy sensor AMP-activated protein kinases (AMPK) is thought to play an important role in regulating myocardial fatty acid oxidation (FAO) via its phosphorylation and inactivation of acetyl coenzyme A carboxylase (ACC). However, studies supporting this have not directly assessed whether the maintenance of FAO rates and subsequent cardiac function requires AMPK-dependent inhibitory phosphorylation of ACC.
  
  
  OBJECTIVE
  To determine whether preventing AMPK-mediated inactivation of ACC influences myocardial FAO or function.
  
  
  RESULTS
  A double knock-in (DKI) mouse (ACC-DKI) model was generated in which the AMPK phosphorylation sites Ser79 on ACC1 and Ser221 (Ser212 mouse) on ACC2 were mutated to prevent AMPK-dependent inhibitory phosphorylation of ACC. Hearts from ACC-DKI mice displayed a complete loss of ACC phosphorylation at the AMPK phosphorylation sites. Despite the inability of AMPK to regulate ACC activity, hearts from ACC-DKI mice displayed normal basal AMPK activation and cardiac function at both standard and elevated workloads. In agreement with the inability of AMPK in hearts from ACC-DKI mice to phosphorylate and inhibit ACC, there was a significant increase in cardiac malonyl-CoA content compared with wild-type mice. However, cardiac FAO rates were comparable between wild-type and ACC-DKI mice at baseline, during elevated workloads, and after a more stressful condition of myocardial ischemia that is known to robustly activate AMPK.
  
  
  CONCLUSIONS
  Our findings show AMPK-dependent inactivation of ACC is not essential for the control of myocardial FAO and subsequent cardiac function during a variety of conditions involving AMPK-independent and AMPK-dependent metabolic adaptations.
authors.affiliation: From the Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (B.N.M.Z., J.N., T.P., P.C.K., G.M., T.J.W., J.R.B.D.); Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Victoria, Australia (B.E.K.); and Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (G.R.S.).
authors.forename: Beshay N M
authors.initials: BN
authors.lastname: Zordoky
authors.affiliation: From the Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (B.N.M.Z., J.N., T.P., P.C.K., G.M., T.J.W., J.R.B.D.); Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Victoria, Australia (B.E.K.); and Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (G.R.S.).
authors.forename: Jeevan
authors.initials: J
authors.lastname: Nagendran
authors.affiliation: From the Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (B.N.M.Z., J.N., T.P., P.C.K., G.M., T.J.W., J.R.B.D.); Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Victoria, Australia (B.E.K.); and Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (G.R.S.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
authors.affiliation: From the Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (B.N.M.Z., J.N., T.P., P.C.K., G.M., T.J.W., J.R.B.D.); Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Victoria, Australia (B.E.K.); and Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (G.R.S.).
authors.forename: Petra C
authors.initials: PC
authors.lastname: Kienesberger
authors.affiliation: From the Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (B.N.M.Z., J.N., T.P., P.C.K., G.M., T.J.W., J.R.B.D.); Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Victoria, Australia (B.E.K.); and Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (G.R.S.).
authors.forename: Grant
authors.initials: G
authors.lastname: Masson
authors.affiliation: From the Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (B.N.M.Z., J.N., T.P., P.C.K., G.M., T.J.W., J.R.B.D.); Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Victoria, Australia (B.E.K.); and Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (G.R.S.).
authors.forename: Terri J
authors.initials: TJ
authors.lastname: Waller
authors.affiliation: From the Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (B.N.M.Z., J.N., T.P., P.C.K., G.M., T.J.W., J.R.B.D.); Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Victoria, Australia (B.E.K.); and Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (G.R.S.).
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: From the Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (B.N.M.Z., J.N., T.P., P.C.K., G.M., T.J.W., J.R.B.D.); Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Victoria, Australia (B.E.K.); and Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (G.R.S.).
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.affiliation: From the Department of Pediatrics, Faculty of Medicine and Dentistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (B.N.M.Z., J.N., T.P., P.C.K., G.M., T.J.W., J.R.B.D.); Department of Medicine, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Victoria, Australia (B.E.K.); and Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (G.R.S.). jason.dyck@ualberta.ca.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D055879:Gene Knock-In Techniques; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D012694:Serine; D013997:Time Factors; D016277:Ventricular Function, Left
chemical_list: D005227:Fatty Acids; D012694:Serine; D008316:Malonyl Coenzyme A; D055372:AMP-Activated Protein Kinases; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase
keywords: AMP-activated protein kinase; acetyl-CoA carboxylase