Skeletal muscle transcriptional coactivator PGC-1α mediates mitochondrial, but not metabolic, changes during calorie restriction
Open accessAbstract
Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation, and reactive oxygen species (ROS) scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1α is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1α activity. To test this model, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1α (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1α is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy (EM) demonstrated that PGC-1α is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1α is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1α nor mitochondrial biogenesis in skeletal muscle are required for the whole-body metabolic benefits of CR.
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Reductions in muscle function/respiratory capacity associated with decline in NOX4 might create a vicious cycle, further compromising exercise-induced antioxidant defense and contributing to age-associated decline in insulin sensitivity.
“Moreover, although defective mitochondrial biogenesis per se does not promote insulin resistance (52, 53), any reductions in muscle function/respiratory capacity associated with the decline in NOX4 might be expected to create a vicious cycle, further compromising exercise-induced antioxidant defense and contributing to the age-associated decline in insulin sensitivity.”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [52]
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- Authors
- Finley, L. W. S., Lee, J., Souza, A., Desquiret-Dumas, V., Bullock, K., Rowe, G. C., Procaccio, V., Clish, C. B., Arany, Z., & Haigis, M. C.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- Department of Biochemistry and Genetics, Angers University Hospital School of Medicine and Unité Mixte de Recherche Institut National de la Santé et de la Recherche Médicale, U771-CNRS6214, 49045 Angers, France; and
- Beth Israel Deaconess Medical Center (US)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-02-03
- Volume
- 109
- Issue
- 8
- Pages
- 2931-2936
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3286952
- OpenAlex
- W2106978702
- Cited by
- 102
- References
- 38
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 3 · 2022: 9 · 2021: 4 · 2020: 9 · 2019: 5 · 2018: 6 · 2017: 11 · 2016: 8 · 2015: 10 · 2014: 12 · 2013: 12 · 2012: 10
- FWCI
- 9.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Science Foundation
- Ellison Medical Foundation
- Richard and Susan Smith Family Foundation
- Glenn Foundation for Medical Research
- Fondation pour la Recherche Médicale
- National Institutes of Health
- National Institute on Aging (R01AG032375, AG032375)
- National Heart, Lung, and Blood Institute
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- PGC-1α, caloric restriction, skeletal muscle, mitochondrial biogenesis, mitochondrial density, glucose homeostasis, transcriptional coactivator, lifespan extension, mitochondrial gene expression
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Homeostasis, Mice, Inbred C57BL, Mitochondria, Oxidation-Reduction, Transcription Factors, Transcription, Genetic, Trans-Activators, Mice, Knockout, Muscle, Skeletal, Muscle Fibers, Skeletal, Caloric Restriction, Genes, Mitochondrial, Mice, Metabolomics
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