AMPK-Dependent Inhibitory Phosphorylation of ACC Is Not Essential for Maintaining Myocardial Fatty Acid Oxidation
Rationale: The energy sensor adenosine monophosphate-activated protein kinase (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 the prevention of 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 to wild-type (WT) mice. However, cardiac FAO rates were comparable between WT and ACC-DKI mice at baseline, during elevated workloads and following 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 dependent metabolic adaptations.
- Fatty acid oxidation
- AMP-activated protein kinase signal transduction
- myocardial metabolism
- fatty acid
- Received June 5, 2014.
- Revision received July 2, 2014.
- Accepted July 7, 2014.