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PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription
Open accessAbstract
Maintaining muscle size and fiber composition requires contractile activity. Increased activity stimulates expression of the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), which promotes fiber-type switching from glycolytic toward more oxidative fibers. In response to disuse or denervation, but also in fasting and many systemic diseases, muscles undergo marked atrophy through a common set of transcriptional changes. FoxO family transcription factors play a critical role in this loss of cell protein, and when activated, FoxO3 causes expression of the atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 and profound loss of muscle mass. To understand how exercise might retard muscle atrophy, we investigated the possible interplay between PGC-1α and the FoxO family in regulation of muscle size. Rodent muscles showed a large decrease in PGC-1α mRNA during atrophy induced by denervation as well as by cancer cachexia, diabetes, and renal failure. Furthermore, in transgenic mice overexpressing PGC-1α, denervation and fasting caused a much smaller decrease in muscle fiber diameter and a smaller induction of atrogin-1 and MuRF-1 than in control mice. Increased expression of PGC-1α also increased mRNA for several genes involved in energy metabolism whose expression decreases during atrophy. Transfection of PGC-1α into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter. Thus, the high levels of PGC-1α in dark and exercising muscles can explain their resistance to atrophy, and the rapid fall in PGC-1α during atrophy should enhance the FoxO-dependent loss of muscle mass.
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In the citing paper
“PPARGC1A, the gene that encodes PGC‐1α, is most well‐known for its role in mitochondrial biogenesis but has been reported to protect muscle mass in the context of muscle atrophy triggered by aging (Yang et al., 2020), chronic heart failure, and various other muscle wasting conditions (Sandri et al., 2006).”
From Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging ( SOMMA ) (2024) · cites this paper as Sandri et al., 2006
Experimental — accuracy not yet measuredIn the citing paper
“PGC-1α is a transcriptional coactivator that has reduced gene expression in muscles of patients with type 2 diabetes,55 and might have a role in preventing muscle atrophy.53,56”
From Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases (2014) · cites this paper as [53]
In the citing paper
“Myofibre size in skeletal muscle is also reduced in people with type 2 diabetes.53”
From Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases (2014) · cites this paper as [53]
In the citing paper
“First, skeletal muscles are heterogeneous with respect to fiber type and metabolic properties and therefore they vary, often drastically, in their response to the same stimulus.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [2]
In the citing paper
“For instance, slow muscles, such as the soleus, are less sensitive to starvation compared to fast muscles2, while during disuse such as that induced by hind limb suspension, the soleus atrophies faster than glycolytic (fast) muscles3.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [2]
In the citing paper
“For instance, JunB, PGC1α, and PGC1β all inhibit FoxO activity in skeletal muscles2,67,68, while the glucocorticoid receptor and β−catenin synergize with FoxOs to promote muscle wasting69.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [2]
In the citing paper
“With aging, PGC-1α levels dramatically fall in the skeletal muscle [86], while the maintenance of PGC-1α expression preserves muscle mass during sarcopenia, cachexia, denervation, and fasting [85,87].”
From Role of Age-Related Mitochondrial Dysfunction in Sarcopenia (2020) · cites this paper as [85]
In the citing paper
“This phenomenon seems to be mediated by the promotion of mitochondrial turnover and quality control [85,87].”
From Role of Age-Related Mitochondrial Dysfunction in Sarcopenia (2020) · cites this paper as [85]
In the citing paper
“PGC-1α may also prevent muscle atrophy through the regulation of autophagy [85].”
From Role of Age-Related Mitochondrial Dysfunction in Sarcopenia (2020) · cites this paper as [85]
In the citing paper
“Because exercise and ApN share similar signaling pathways [75,76] and the potential of counteracting several facets of this metabolic syndrome, numerous studies attempted to establish relationships between exercise and ApN parameters.”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [75]
In the citing paper
“The transcriptional activity of FoxO3 is inhibited, on one hand, by PGC-1α and on the other hand, by the insulin/IGF1 signaling pathway, which also activates protein synthesis [75].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [75]
In the citing paper
“Forkhead box O (FoxO) family TF play a critical role in protein breakdown by activating the expression of atrogenes (which include two muscle-specific ubiquitin ligases, atrogin-1 and MuRF1) responsible for profound loss of muscle mass [75].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [75]
In the citing paper
“PGC-1α reduces muscle protein degradation by the UPS via blocking nuclear factor κB (NF-κB) and FoxO3 activity (16, 124).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [124]
In the citing paper
“Thus, high-level expression of PGC-1 may actually cause accumulation of lipids and/or incomplete oxidation products, leading to reduced insulin sensitivity, as observed in PGC-1␣ transgenic mice (267-269).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [269]
In the citing paper
“When PGC-1␣ overexpression is restricted to skeletal muscle but overexpressed throughout development by the use of the creatine kinase gene promoter, very large increases in mitochondrial mass, OXPHOS, and fatty acid oxidation genes are observed (267-269).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [269]
In the citing paper
“Despite these effects, insulin sensitivity is normal in PGC-1␣ transgenic mice fed a chow diet and, surprisingly, is reduced during high-fat feeding.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [269]
In the citing paper
“In this model, ATP synthesis rate and exercise performance are increased, and fatty acid oxidation is also enhanced.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [269]
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Metadata
- Authors
- Sandri, M., Lin, J., Handschin, C., Yang, W., Arany, Z. P., Lecker, S. H., Goldberg, A. L., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-10-31
- Volume
- 103
- Issue
- 44
- Pages
- 16260-16265
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1637570
- OpenAlex
- W1977548231
- Cited by
- 974
- References
- 53
- Citations by year
- 2026: 20 · 2025: 38 · 2024: 44 · 2023: 51 · 2022: 56 · 2021: 42 · 2020: 66 · 2019: 64 · 2018: 54 · 2017: 40 · 2016: 51 · 2015: 57 · 2014: 65 · 2013: 68 · 2012: 52
- FWCI
- 13.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- edoc (University of Basel) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- edoc (University of Basel)
- Funders
- Muscular Dystrophy Association
- Compagnia di San Paolo
- National Institutes of Health (DK6230701)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-6230701, R01DK062307, R56DK054477, P30DK040561)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- PGC-1α, skeletal muscle atrophy, FOXO3, atrogin-1, MuRF1, ubiquitin ligase, denervation, cancer cachexia, diabetes mellitus, renal failure, fasting, physical activity, muscle fiber diameter, energy metabolism, transcriptional coactivator, muscle fiber type shift
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Gene Expression Regulation, Mice, Transgenic, Muscular Atrophy, Nerve Tissue Proteins, Transcription Factors, Transcription, Genetic, Biomarkers, Trans-Activators, Muscle, Skeletal, Mice, Forkhead Transcription Factors
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