Abstract 17989: C-Myc Regulates Substrate Oxidation Patterns During Early Pressure-Overload Hypertrophy
Background: Cardiac hypertrophy alters substrate metabolism towards an increased reliance on glucose utilization. Inactivation of the transcription factor c-Myc (Myc) in the adult myocardium attenuated hypertrophic growth and decreased expression of glycolytic genes in response to aortic constriction. Accordingly, we hypothesize that Myc is an important regulator of substrate utilization for the citric acid cycle during pressure overload hypertrophy.
Methods: We subjected FVB mice with cardiac specific, inducible Myc inactivation (MycKO) and non-transgenic littermates (Myc-intact) to transverse aortic constriction (n=7/group). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketones and unlabeled glucose and insulin.
Results: Cardiac function was similar between the groups although dP/dT, -dP/dt and developed pressure trended towards improvement in the MycKO mice. MycKO had reduced fractional contribution of fatty acids to the citric acid cycle versus Myc-intact (28%±3 vs 37%±2, p<0.05) along with ketones (19%±1 vs 25%±1, p<0.05). Unlabeled, presumably glucose, contribution increased in MycKO (33%±4 vs 19%±2, p<0.05). While MVO2 was similar between the groups, fatty acid and ketone oxidative flux was decreased in MycKO.
Conclusion: Myc regulates substrate oxidation preferences during pressure overload cardiac hypertrophy. Further, our data indicates that the change in substrate utilization pattern during hypertrophy is not necessary to maintain cardiac function during this hemodynamic stress.
- © 2013 by American Heart Association, Inc.