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