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

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abstract

  • 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.

authors

  • Zordoky, Beshay NM
  • Nagendran, Jeevan
  • Pulinilkunnil, Thomas
  • Kienesberger, Petra C
  • Masson, Grant
  • Waller, Terri J
  • Kemp, Bruce E
  • Steinberg, Gregory
  • Dyck, Jason RB

publication date

  • August 15, 2014

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