AMPK-Dependent Inhibitory Phosphorylation of ACC is not Essential for Maintaining Myocardial Fatty Acid Oxidation. Zordoky BN, Nagendran J, Pulinilkunnil T, Kienesberger PC, Masson G, Waller TJ, Kemp BE, Steinberg GR, Dyck JR. Circ Res. 2014 Aug 15;115(5):518-24.
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.
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