The Nuclear Receptor ERRα Is Required for the Bioenergetic and Functional Adaptation to Cardiac Pressure Overload

Downregulation and functional deactivation of the transcriptional coactivator PGC-1α has been implicated in heart failure pathogenesis. We hypothesized that the estrogen-related receptor α (ERRα), which recruits PGC-1α to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERRα^-/- mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. ³¹P-NMR studies revealed abnormal phosphocreatine depletion in ERRα^-/- hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERRα^-/- hearts. Cardiac ERRα target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERRα^-/- mice at baseline or with pressure overload. These results demonstrate that the nuclear receptor ERRα is required for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure.