Overexpression of peroxisome proliferator-activated receptor γ co-activator-1α leads to muscle atrophy with depletion of ATP.
Open accessAbstract
Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) is a key nuclear receptor co-activator for mitochondrial biogenesis. Here we report that overexpression of PGC-1alpha in skeletal muscles increased mitochondrial number and caused atrophy of skeletal muscle, especially type 2B fiber-rich muscles (gastrocnemius, quadriceps, and plantaris). Muscle atrophy became evident at 25 weeks of age, and a portion of the muscle was replaced by adipocytes. Mice showed increased energy expenditure and reduced body weight; thyroid hormone levels were normal. Mitochondria exhibited normal respiratory chain activity per mitochondrion; however, mitochondrial respiration was not inhibited by an ATP synthase inhibitor, oligomycin, clearly indicating that oxidative phosphorylation was uncoupled. Accordingly, ATP content in gastrocnemius was markedly reduced. A similar phenotype is observed in Luft's disease, a mitochondrial disorder that involves increased uncoupling of respiration and muscle atrophy. Our results indicate that overexpression of PGC-1alpha in skeletal muscle increases not only mitochondrial biogenesis but also uncoupling of respiration, resulting in muscle atrophy.
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Higher levels of PGC-1α overexpression through actin promoter-driven expression in transgenic animals display a strikingly different phenotype.
“Higher levels of overexpression of PGC-1␣ achieved through actin promoter-driven expression in transgenic animals display a strikingly different phenotype (263,264).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [264]
In these animals, mitochondrial density and OXPHOS gene expression are more than double basal levels, and large increases in UCP2 gene expression are observed.
“In these animals, mitochondrial density and OXPHOS gene expression are more than double basal levels, and large increases in UCP2 gene expression are also observed.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [264]
Mitochondrial energetics are impaired in these animals, with 60% decreases in ATP levels in muscle homogenates and concomitant increases in AMP kinase activation.
“Mitochondrial energetics are impaired, with 60% decreases in ATP levels in muscle homogenates and concomitant increases in AMP kinase activation, probably as a compensatory response to decreased mitochondrial functionality.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [264]
Muscle function appears compromised in these animals, as evidenced by decreased voluntary exercise, muscle atrophy, and decreased insulin sensitivity.
“Muscle function appears compromised, as evidenced by decreased voluntary exercise, muscle atrophy, and decreased insulin sensitivity.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [264]
PGC-1α transgenic expression increases OXPHOS mRNA and protein levels, with increases ranging from 130% to 500% across transgenic models.
“180% 1 COXIV | protein | 130% 1 mRNA | | 150 -200% | 1 mRNA | | | 150 -250% | 1 mRNA | | | | 170 -300% | 1 mRNA | 200 -500% | 1 mRNA and | protein”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [264]
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- Authors
- Miura, S., Tomitsuka, E., Kamei, Y., Yamazaki, T., Kai, Y., Tamura, M., Kita, K., Nishino, I., & Ezaki, O.
- Affiliations
- National Institute of Health and Nutrition (JP)
- The University of Tokyo (JP)
- Tokyo Medical and Dental University (JP)
- National Center of Neurology and Psychiatry (JP)
- Corresponding author
- Miura, Shinji
- Ezaki, Osamu
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 169
- Issue
- 4
- Pages
- 1129-1139
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1780180
- OpenAlex
- W2131523552
- Cited by
- 107
- References
- 45
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 7 · 2019: 3 · 2018: 1 · 2017: 8 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 7 · 2012: 6
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- National Institute of Biomedical Innovation
- National Center of Neurology and Psychiatry
- National Institutes of Health
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- PGC-1α, skeletal muscle atrophy, mitochondrial biogenesis, mitochondrial uncoupling, ATP depletion, mitochondrial respiratory chain, energy expenditure
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adenosine Triphosphate, Animals, Body Weight, Female, Male, Mice, Transgenic, Mitochondria, Muscle, Muscular Atrophy, Oxidative Phosphorylation, Transcription Factors, Transcriptional Activation, Trans-Activators, Adipocytes, Muscle, Skeletal, Cell Respiration, Cell Proliferation, Mice
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