AMPK-Dependent Inhibitory Phosphorylation of ACC Is Not Essential for Maintaining Myocardial Fatty Acid Oxidation

• Published in: Circulation research 2014-08, Vol.115 (5), p.518-524
• Main Authors: Zordoky, Beshay N.M, Nagendran, Jeevan, Pulinilkunnil, Thomas, Kienesberger, Petra C, Masson, Grant, Waller, Terri J, Kemp, Bruce E, Steinberg, Gregory R, Dyck, Jason R.B
• Format: Article
• Language: English
• Subjects: Acetyl-CoA Carboxylase - genetics; Acetyl-CoA Carboxylase - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Energy Metabolism; Fatty Acids - metabolism; Female; Gene Knock-In Techniques; Male; Malonyl Coenzyme A - metabolism; Mice, Mutant Strains; Mice, Transgenic; Mutation; Myocardial Contraction; Myocardium - enzymology; Oxidation-Reduction; Phosphorylation; Serine; Time Factors; Ventricular Function, Left
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.115.304538

RATIONALE: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. METHODS AND 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.