Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart (original) (raw)

  1. Ling Lai1,2,7,
  2. Teresa C. Leone1,2,7,
  3. Christoph Zechner1,2,
  4. Paul J. Schaeffer1,2,3,
  5. Sean M. Kelly1,2,
  6. Daniel P. Flanagan1,2,
  7. Denis M. Medeiros4,
  8. Attila Kovacs1,2, and
  9. Daniel P. Kelly1,2,5,6,8
  10. 1 Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Missouri 63110, USA;
  11. 2 Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA;
  12. 3 Department of Zoology, Miami University, Oxford, Ohio 45056, USA;
  13. 4 Kansas State University, Manhattan, Kansas 66506, USA;
  14. 5 Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, Missouri 63110, USA;
  15. 6 Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA
  16. ↵7 These authors contributed equally to this work.

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-1αβ−/− 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-1α−/− mice generated previously. In striking contrast to the singly deficient PGC-1 lines, PGC-1αβ−/− 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-1αβ−/− mice. The hearts of the PGC-1αβ−/− 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-1αβ−/− 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.

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