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Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart
Open accessAbstract
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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“Previous work has established that repression of either or both co-activators (PGC-1α or PGC-1β) decreases mitochondrial biogenesis and function, elicits cardiomyopathy and impairs de novo glucose production23-25.”
From Telomere dysfunction induces metabolic and mitochondrial compromise (2011) · cites this paper as [25]
In the citing paper
“The existence of compensation for PGC-1 deficiency by PGC-1␣ and vice versa is evidenced by the phenotype of double PGC-1␣ and PGC-1 muscle-specific knockout mice (62).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [62]
In the citing paper
“PGC-1-null mice (59, 62, 65, 66) display phenotypes similar to, but not identical to, those of PGC-1␣ knockouts, including reduced expression of OXPHOS genes, reduced ATP synthesis, reduced exercise capacity, and impaired thermogenesis (59,62).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [62]
In the citing paper
“These animals display normal mitochondrial biogenesis during development but die early after birth due to failure of perinatal mitochondrial proliferation and consequent cardiac failure (62).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [62]
In the citing paper
“Insulin sensitivity in these animals is reported to be normal.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [62]
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“Lai, 2008 (62) PGC-1␣ and PGC-1 2 60%, heart | muscle-specific KO”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [62]
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Metadata
- Authors
- Lai, L., Leone, T. C., Zechner, C., Schaeffer, P. J., Kelly, S. M., Flanagan, D. P., Medeiros, D. M., Kovacs, A., & Kelly, D. P.
- Affiliations
- Washington University in St. Louis (US)
- Kansas State University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-07-15
- Volume
- 22
- Issue
- 14
- Pages
- 1948-1961
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2492740
- OpenAlex
- W2146878987
- Cited by
- 326
- References
- 59
- Citations by year
- 2026: 15 · 2025: 8 · 2024: 14 · 2023: 18 · 2022: 17 · 2021: 31 · 2020: 16 · 2019: 20 · 2018: 16 · 2017: 14 · 2016: 17 · 2015: 19 · 2014: 18 · 2013: 21 · 2012: 26
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- American Heart Association
- Alvin J. Siteman Cancer Center (CA91842, #P30 CA91842)
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (5p60dk020579-35, DK-052574, DK56341, DK020579, CA91842)
- National Heart, Lung, and Blood Institute (R01HL058427)
- National Cancer Institute (P30CA091842)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK045416, P60-DK-020579, P30DK056341, P30DK052574)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- PGC-1α, PGC-1β, mitochondrial biogenesis, cardiac output, atrioventricular block, brown adipose tissue, fetal gene expression, postnatal heart development, energy metabolism
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Adipose Tissue, Brown, Female, Heart, Male, Mice, Inbred C57BL, Mitochondria, Heart, Transcription Factors, Blotting, Southern, Trans-Activators, Polymerase Chain Reaction, Mice, Knockout, Integrases, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Mice
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