Transcriptional coactivators PGC-lα and PGC-lβ control overlapping programs required for perinatal maturation of the heart

Ling Lai, Teresa C. Leone, Christoph Zechner, Paul J. Schaeffer, Sean M. Kelly, Daniel P. Flanagan, Denis M. Medeiros, Attila Kovacs, Daniel P. Kelly

Research output: Contribution to journalArticle

188 Citations (Scopus)

Abstract

Oxidative tissues such as heart undergo a dramatic perinatal mitochondrial biogenesis to meet the high-energy demands after birth. PPARγ coactivator-1 (PGC-1) α and β have been implicated in the transcriptional control of cellular energy metabolism. Mice with combined deficiency of PGC-1α and PGC-1β (PGC-1αp-/- mice) were generated to investigate the convergence of their functions in vivo. The phenotype of PGC-1β-/- mice was minimal under nonstressed conditions, including normal heart function, similar to that of PGC-1αα-/- mice generated previously. In striking contrast to the singly deficient PGC-1 lines, PGC-1αp-/- mice died shortly after birth with small hearts, bradycardia, intermittent heart block, and a markedly reduced cardiac output. Cardiac-specific ablation of the PGC-1β gene on a PGC-1α-deficient background phenocopied the generalized PGC-1αp-/- mice. The hearts of the PGC-1αp-/- 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-1αp-/- mice also exhibited a severe abnormality in function and mitochondrial density. We conclude that PGC-1α and PGC-1β share roles that collectively are necessary for the postnatal metabolic and functional maturation of heart and BAT.

Original languageEnglish (US)
Pages (from-to)1948-1961
Number of pages14
JournalGenes and Development
Volume22
Issue number14
DOIs
StatePublished - Jul 15 2008

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Brown Adipose Tissue
Organelle Biogenesis
Parturition
Peroxisome Proliferator-Activated Receptors
Heart Block
Bradycardia
Cardiac Output
Energy Metabolism
Phenotype
Gene Expression
Growth
Genes

Keywords

  • Energy metabolism
  • Heart development
  • Mitochondria
  • Transcriptional regulation

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Transcriptional coactivators PGC-lα and PGC-lβ control overlapping programs required for perinatal maturation of the heart. / Lai, Ling; Leone, Teresa C.; Zechner, Christoph; Schaeffer, Paul J.; Kelly, Sean M.; Flanagan, Daniel P.; Medeiros, Denis M.; Kovacs, Attila; Kelly, Daniel P.

In: Genes and Development, Vol. 22, No. 14, 15.07.2008, p. 1948-1961.

Research output: Contribution to journalArticle

Lai, L, Leone, TC, Zechner, C, Schaeffer, PJ, Kelly, SM, Flanagan, DP, Medeiros, DM, Kovacs, A & Kelly, DP 2008, 'Transcriptional coactivators PGC-lα and PGC-lβ control overlapping programs required for perinatal maturation of the heart', Genes and Development, vol. 22, no. 14, pp. 1948-1961. https://doi.org/10.1101/gad.1661708
Lai, Ling ; Leone, Teresa C. ; Zechner, Christoph ; Schaeffer, Paul J. ; Kelly, Sean M. ; Flanagan, Daniel P. ; Medeiros, Denis M. ; Kovacs, Attila ; Kelly, Daniel P. / Transcriptional coactivators PGC-lα and PGC-lβ control overlapping programs required for perinatal maturation of the heart. In: Genes and Development. 2008 ; Vol. 22, No. 14. pp. 1948-1961.
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