Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart.
Oxidative tissues such as heart undergo a dramatic perinatal mitochondrial biogenesis to meet the high-energy demands after birth. PPARgamma coactivator-1 (PGC-1) alpha and beta have been implicated in the transcriptional control of cellular energy metabolism. Mice with combined deficiency of PGC-1alpha and PGC-1beta (PGC-1alphabeta(-/-) mice) were generated to investigate the convergence of their functions in vivo. The phenotype of PGC-1beta(-/-) mice was minimal under nonstressed conditions, including normal heart function, similar to that of PGC-1alpha(-/-) mice generated previously. In striking contrast to the singly deficient PGC-1 lines, PGC-1alphabeta(-/-) mice died shortly after birth with small hearts, bradycardia, intermittent heart block, and a markedly reduced cardiac output. Cardiac-specific ablation of the PGC-1beta gene on a PGC-1alpha-deficient background phenocopied the generalized PGC-1alphabeta(-/-) mice. The hearts of the PGC-1alphabeta(-/-) mice exhibited signatures of a maturational defect including reduced growth, a late fetal arrest in mitochondrial biogenesis, and persistence of a fetal pattern of gene expression. Brown adipose tissue (BAT) of PGC-1alphabeta(-/-) mice also exhibited a severe abnormality in function and mitochondrial density. We conclude that PGC-1alpha and PGC-1beta share roles that collectively are necessary for the postnatal metabolic and functional maturation of heart and BAT.
Lai
Ling
L
Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Missouri 63110, USA
Leone
Teresa C
TC
Zechner
Christoph
C
Schaeffer
Paul J
PJ
Kelly
Sean M
SM
Flanagan
Daniel P
DP
Medeiros
Denis M
DM
Kovacs
Attila
A
Kelly
Daniel P
DP
D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D015139:Blotting, Southern; D005260:Female; D020869:Gene Expression Profiling; D006321:Heart / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016133:Polymerase Chain Reaction; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C045073:Cre recombinase; D019426:Integrases