Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle
Open accessAbstract
Skeletal and cardiac muscle depend on high turnover of ATP made by mitochondria in order to contract efficiently. The transcriptional coactivator PGC-1alpha has been shown to function as a major regulator of mitochondrial biogenesis and respiration in both skeletal and cardiac muscle, but this has been based only on gain-of-function studies. Using genetic knockout mice, we show here that, while PGC-1alpha KO mice appear to retain normal mitochondrial volume in both muscle beds, expression of genes of oxidative phosphorylation is markedly blunted. Hearts from these mice have reduced mitochondrial enzymatic activities and decreased levels of ATP. Importantly, isolated hearts lacking PGC-1alpha have a diminished ability to increase work output in response to chemical or electrical stimulation. As mice lacking PGC-1alpha age, cardiac dysfunction becomes evident in vivo. These data indicate that PGC-1alpha is vital for the heart to meet increased demands for ATP and work in response to physiological stimuli.
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Whole-body PGC-1α-null mice consistently display 30-60% reductions in OXPHOS gene expression in muscle, normal to decreased mitochondrial density in skeletal muscle, and decreased cristae density in heart.
“These mice consistently display 30 -60% reductions in OXPHOS gene expression in muscle, normal to decreased mitochondrial density in skeletal muscle, and decreased cristae density in heart.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [68]
Muscle is significantly more insulin sensitive in both whole-body and muscle-specific PGC-1α null mice.
“Interestingly, muscle is significantly more insulin sensitive in both whole-body and muscle-specific PGC-1␣ null mice.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [68]
Functionally, whole-body PGC-1α-null mice show decreases in ATP levels, state 3 respiration, and metabolic efficiency, and cardiac and skeletal muscle performance is reduced in response to stress.
“Functionally, decreases in ATP levels, state 3 respiration, and metabolic efficiency are seen, and cardiac and skeletal muscle performance is reduced in response to stress.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [68]
The paradoxical finding of increased insulin sensitivity in PGC-1α null mice may be explained by leanness and hyperactivity noted in one of the whole-body knockout lines.
“This apparently paradoxical finding-where decreased oxidative function is not paralleled by insulin resistance-may be explained by the leanness and hyperactivity noted in one of the whole-body knockout lines (68, 69).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [68]
PGC-1α whole-body knockout results in normal mitochondrial DNA but reduced OXPHOS mRNA by 30-60% and cytochrome C protein by 50% (Lin, 2004; Arany, 2005).
“Lin, 2004 (69); PGC-1␣ whole-body KO Normal 30 -60% 2 mRNA; | Arany, 50% 2 CytC | 2005 (68) protein”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [68]
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References 64 · Cited by 694
Research works printed but not linked: 1
- Angiography, and Intervention (Philadelphia: Lippincott, Williams & Wilkins).
- Authors
- Arany, Z., He, H., Lin, J., Hoyer, K., Handschin, C., Toka, O., Ahmad, F., Matsui, T., Chin, S., Wu, P.-H., Rybkin, I. I., Shelton, J. M., Manieri, M., Cinti, S., Schoen, F. J., Bassel-Duby, R., Rosenzweig, A., Ingwall, J. S., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Spiegelman, Bruce M.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2005-04
- Volume
- 1
- Issue
- 4
- Pages
- 259-271
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2160909177
- Cited by
- 694
- References
- 64
- Citations by year
- 2026: 28 · 2025: 26 · 2024: 25 · 2023: 23 · 2022: 35 · 2021: 38 · 2020: 37 · 2019: 30 · 2018: 30 · 2017: 36 · 2016: 30 · 2015: 43 · 2014: 33 · 2013: 26 · 2012: 51
- FWCI
- 17.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- edoc (University of Basel) (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, other-oa)
- edoc (University of Basel)
- Funders
- National Institutes of Health (5k01dk065584-05)
- National Heart, Lung, and Blood Institute (HL06296, R01HL063985, HL063985, HL07604, HL052320, P50HL052320, T32HL007604)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK54477, DK065584, R01DK061562, DK 61562)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- PGC-1α, transcriptional coactivator, myocardium, mitochondrial biogenesis, oxidative phosphorylation, ATP production, cardiac contractile function, energy metabolism, cardiac dysfunction, mitochondrial respiration
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Mitochondria, Myocardium, Transcription Factors, Trans-Activators, Mice, Knockout, Muscle, Skeletal, Muscle Fibers, Skeletal, Mice
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