Published online before print January 15, 2004, doi: 10.1161/01.RES.0000117088.36577.EB
© 2004 American Heart Association, Inc.
Integrative Physiology |
Cardiac-Specific Induction of the Transcriptional Coactivator Peroxisome Proliferator-Activated Receptor 
Coactivator-1
Promotes Mitochondrial Biogenesis and Reversible Cardiomyopathy in a Developmental Stage-Dependent Manner
From the Department of Medicine (L.K.R., C.M.M., J.J.L., A.K., M.C., J.E.S., D.P.K.), Center for Cardiovascular Research, and Departments of Pathology (J.E.S.), Molecular Biology & Pharmacology (D.P.K.), and Pediatrics (D.P.K.), Washington University School of Medicine, St Louis, Mo; Department of Human Nutrition (D.M.M.), Kansas State University, Manhattan, Kan; and Department of Internal Medicine (M.L.V., J.A.M.), University of Utah, Salt Lake City, Utah.
Correspondence to Daniel P. Kelly, MD, Center for Cardiovascular Research, Washington University School of Medicine, 660 S Euclid, Campus Box 8086, St Louis, MO 63110. E-mail dkelly{at}im.wustl.edu
Recent evidence has identified the peroxisome proliferator-activated receptor 
coactivator-1
(PGC-1) as a regulator of cardiac energy metabolism and mitochondrial biogenesis. We describe the development of a transgenic system that permits inducible, cardiac-specific overexpression of PGC-1. Expression of the PGC-1 transgene in this system (tet-on PGC-1) is cardiac-specific in the presence of doxycycline (dox) and is not leaky in the absence of dox. Overexpression of PGC-1 in tet-on PGC-1 mice during the neonatal stages leads to a dramatic increase in cardiac mitochondrial number and size coincident with upregulation of gene markers associated with mitochondrial biogenesis. In contrast, overexpression of PGC-1 in the hearts of adult mice leads to a modest increase in mitochondrial number, derangements of mitochondrial ultrastructure, and development of cardiomyopathy. The cardiomyopathy in adult tet-on PGC-1 mice is characterized by an increase in ventricular mass and chamber dilatation. Surprisingly, removal of dox and cessation of PGC-1 overexpression in adult mice results in complete reversal of cardiac dysfunction within 4 weeks. These results indicate that PGC-1 drives mitochondrial biogenesis in a developmental stage-dependent manner permissive during the neonatal period. This unique murine model should prove useful for the study of the molecular regulatory programs governing mitochondrial biogenesis and characterization of the relationship between mitochondrial dysfunction and cardiomyopathy and as a general model of inducible, reversible cardiomyopathy.
Key Words: mitochondria • metabolism • transgenic mice • cardiomyopathy • transcription factors
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