Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner.
Abstract
Recent evidence has identified the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) 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-1alpha. Expression of the PGC-1alpha transgene in this system (tet-on PGC-1alpha) is cardiac-specific in the presence of doxycycline (dox) and is not leaky in the absence of dox. Overexpression of PGC-1alpha in tet-on PGC-1alpha 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-1alpha 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-1alpha mice is characterized by an increase in ventricular mass and chamber dilatation. Surprisingly, removal of dox and cessation of PGC-1alpha overexpression in adult mice results in complete reversal of cardiac dysfunction within 4 weeks. These results indicate that PGC-1alpha 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.
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In adults, PGC-1α induction led to a more modest mitochondrial proliferation, which was nevertheless accompanied by cardiomyopathy.
“In adults, PGC-1␣ induction led to a more modest mitochondrial proliferation, which was nevertheless surprisingly accompanied by cardiomyopathy.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [266]
When higher levels of PGC-1α overexpression are restricted to heart during early life, increased neonatal mitochondrial proliferation is observed, but it is accompanied by myofibrillar displacement.
“When higher levels of PGC-1␣ overexpression are restricted to heart during early life (266), increased neonatal mitochondrial proliferation is observed, but it is accompanied by myofibrillar displacement.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [266]
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- Authors
- Russell, L. K., Mansfield, C. M., Lehman, J. J., Kovacs, A., Courtois, M., Saffitz, J. E., Medeiros, D. M., Valencik, M. L., McDonald, J. A., & Kelly, D. P.
- Affiliations
- Kansas State University (US)
- 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.
- Venue
- Circulation Research
- Published
- 2004-03-05
- Volume
- 94
- Issue
- 4
- Pages
- 525-533
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2099281097
- Cited by
- 402
- References
- 35
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 11 · 2023: 18 · 2022: 17 · 2021: 16 · 2020: 22 · 2019: 12 · 2018: 21 · 2017: 20 · 2016: 16 · 2015: 22 · 2014: 21 · 2013: 13 · 2012: 32
- FWCI
- 6.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01-HL-58493, T32 HL 07275, R01HL058493, T32HL007275)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK-52574, R01 DK45416, R01DK045416, P30-DK56341, P30DK056341, P30DK052574)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- PGC-1α, cardiac-specific overexpression, mitochondrial biogenesis, cardiomyopathy, developmental stage dependence, neonatal heart development, mitochondrial ultrastructure, myocardial energy metabolism, reversible cardiomyopathy, transgenic mouse model
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adenosine Triphosphate, Age Factors, Animals, Animals, Newborn, Cardiomyopathy, Dilated, Disease Models, Animal, Doxycycline, Energy Metabolism, Genes, Synthetic, Mice, Transgenic, Mitochondria, Heart, Organ Specificity, Promoter Regions, Genetic, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Transcription Factors, Trans-Activators, Gene Expression Regulation, Developmental, Myosin Heavy Chains, Transgenes, Myocytes, Cardiac, Mice
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