ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart.
At birth, the heart undergoes a critical metabolic switch from a predominant dependence on carbohydrates during fetal life to a greater dependence on postnatal oxidative metabolism. This remains the principle metabolic state throughout life, although pathologic conditions such as heart failure and cardiac hypertrophy reactivate components of the fetal genetic program to increase carbohydrate utilization. Disruption of the ERRgamma gene (Esrrg), which is expressed at high levels in the fetal and postnatal mouse heart, blocks this switch, resulting in lactatemia, electrocardiographic abnormalities, and death during the first week of life. Genomic ChIP-on-chip and expression analysis identifies ERRgamma as both a direct and an indirect regulator of a nuclear-encoded mitochondrial genetic network that coordinates the postnatal metabolic transition. These findings reveal an unexpected and essential molecular genetic component of the oxidative metabolic gene program in the heart and highlight ERRgamma in the study of cardiac hypertrophy and failure.
Alaynick
William A
WA
Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Kondo
Richard P
RP
Xie
Wen
W
He
Weimin
W
Dufour
Catherine R
CR
Downes
Michael
M
Jonker
Johan W
JW
Giles
Wayne
W
Naviaux
Robert K
RK
Giguère
Vincent
V
Evans
Ronald M
RM
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D004562:Electrocardiography; D004579:Electron Transport / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D050259:Genes, Mitochondrial / Q000502:physiology*; D006321:Heart / Q000196:embryology* / Q000503:physiopathology; D007773:Lactates / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac; D020411:Oligonucleotide Array Sequence Analysis; D018408:Patch-Clamp Techniques; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D016276:Ventricular Function
C490916:Esrrg protein, mouse; D007773:Lactates; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D012964:Sodium