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Transcriptional coactivators PGC-1 and PGC-lβ control overlapping programs required for perinatal maturation of the heart

¹ Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Missouri 63110, USA; ² Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA; ³ Department of Zoology, Miami University, Oxford, Ohio 45056, USA; ⁴ Kansas State University, Manhattan, Kansas 66506, USA; ⁵ Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, Missouri 63110, USA; ⁶ Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA

Oxidative tissues such as heart undergo a dramatic perinatal mitochondrial biogenesis to meet the high-energy demands after birth. PPAR coactivator-1 (PGC-1) and β have been implicated in the transcriptional control of cellular energy metabolism. Mice with combined deficiency of PGC-1 and PGC-1β (PGC-1β^–/– 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-1^–/– mice generated previously. In striking contrast to the singly deficient PGC-1 lines, PGC-1β^–/– 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-1-deficient background phenocopied the generalized PGC-1β^–/– mice. The hearts of the PGC-1β^–/– 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-1β^–/– mice also exhibited a severe abnormality in function and mitochondrial density. We conclude that PGC-1 and PGC-1β share roles that collectively are necessary for the postnatal metabolic and functional maturation of heart and BAT.

[Keywords: Transcriptional regulation; heart development; mitochondria; energy metabolism]

Received February 11, 2008; revised version accepted May 16, 2008.

⁸ Corresponding author.

E-MAIL dkelly{at}burnham.org; FAX (407) 745-2001.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1661708.

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