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

Janice M. Huss, Ken ichi Imahashi, Catherine R. Dufour, Carla J. Weinheimer, Michael Courtois, Atilla Kovacs, Vincent Giguère, Elizabeth Murphy, Daniel P. Kelly

Research output: Contribution to journalArticlepeer-review

209 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)25-37
Number of pages13
JournalCell metabolism
Volume6
Issue number1
DOIs
StatePublished - Jul 11 2007

Keywords

  • DEVBIO
  • HUMDISEASE

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