Metabolic Reprograming Driven by Interaction AMP-activated Protein Kinase and Coactivator SRC-2 Regulate Cardiac Stress Response

Flexibility in fuel source for the heart is necessary to meet ATP demands during a high and variable workload such as transaortic constriction (TAC). During such chronic metabolic and hemodynamic stresses, shifts occur in substrate utilization in the heart based on magnitude of the demand, oxygen and nutrient availability. These shifts directly affect the amount of ATP available for other stress responsive pathways and therefore their efficacy. Communication from metabolic changes to these other pathways is crucial. As a result, it is important understand the molecular communication between metabolic and hypertrophic pathways under stress. We have found that chronic loss of cardiomyocyte SRC-2 and transient activation of AMPK both effect metabolic inputs prior to TAC and result in a blunted hypertrophic response. We hypothesized that SRC-2 and AMPK are critical upstream regulators of the cardiac stress response controlling metabolic changes translating into altered hypertrophy. Furthermore, we proposed that they could be regulating each other to control both the temporal changes to the metabolic machinery through AMPK and long-term genetic changes through SRC-2. We identified AMPK as a coregulator of SRC-2 activity and confirmed a direct interaction between them in cardiac cells. We have identified putative AMPK phosphorylation sites on SRC-2 that control SRC-2 stability and activity. Conversely, we found by ChIP that SRC-2 localized to AMPK subunit genes. Additionally, we performed co-immunoprecipitation and luciferase reporters and found that SRC-2 can interact with AMPK subunits and regulate its activity. We believe that disruption of these interactions is a main determinant in efficient hypertrophy in response to metabolic changes. Our results suggest the basis of a mechanism whereby energetic changes are sensed via AMPK and translated to transcriptional machinery of diverse targets via SRC-2 which allows AMPK to effect multiple cardiac transcription pathways. This mechanism provides insights into the role of AMPK-SRC-2 interaction in regulating myocardial function, metabolism, hypertrophy, and the progression to heart failure.