Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.
Open accessAbstract
Skeletal muscle atrophy is a debilitating response to fasting, disuse, cancer, and other systemic diseases. In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy. Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. When Foxo activation is blocked by a dominant-negative construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented. Thus, forkhead factor(s) play a critical role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting.
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Two muscle-specific E3 ubiquitin ligases, MuRF1 and MAFbx, are key regulators of proteasomal proteolysis in skeletal muscle, especially under atrophy-inducing conditions.
“Two muscle-specific E3 ubiquitin ligases, muscle RING finger 1 (MuRF1, also known as TRIM63) and muscle atrophy F-Box (MAFbx, also known as atrogin-1 or FBXO32), are thought to be key regulators of proteasomal proteolysis in skeletal muscle, especially under atrophy-inducing conditions (Cai et al., 2004; Sandri et al., 2004; Stitt et al., 2004).”
From Proteasome dysfunction induces muscle growth defects and protein aggregation (2014) · cites this paper as Sandri et al., 2004
In “IGF-1 and Insulin Suppress an Atrophy Program” (page unavailable), the paper links atrogin-1 and MuRF1 expression to catabolic conditions and muscle wasting. It also says their precise functions in wasting remain unclear. The copy therefore supports their proposed role in atrophy, but does not establish the more specific claim that both regulate proteasomal proteolysis. (LLM, conf=0.81)
Experimental — accuracy not yet measuredTwo muscle-specific E3 ubiquitin ligases, MuRF1 and Atrogin1, are thought to be key regulators of proteasomal proteolysis in skeletal muscle, especially under atrophy-inducing conditions.
“Two muscle-specific E3 ubiquitin ligases, MuRF1 and Atrogin1, are thought to be key regulators of proteasomal proteolysis in skeletal muscle, especially under atrophy-inducing conditions (Cai et al., 2004; Sandri et al., 2004).”
From Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy (2020) · cites this paper as Sandri et al., 2004
In “IGF-1 and Insulin Suppress an Atrophy Program” (page unavailable), the paper links atrogin-1 and MuRF1 expression to catabolic conditions and muscle wasting, and associates atrophy-related ubiquitin ligases with protein breakdown. It also says their precise functions in muscle wasting remain unclear; the available body-text passages do not establish that both are key regulators specifically of proteasomal proteolysis. (LLM, conf=0.78)
Experimental — accuracy not yet measuredAtrogin-1 plays a key role in muscle atrophy as muscle specific ubiquitin ligase.
“Atrogin-1 plays a key role in muscle atrophy as muscle specific ubiquitin ligase.”
From GLP-1RA Liraglutide and Semaglutide Improves Obesity-Induced Muscle Atrophy via SIRT1 Pathway (2023) · cites this paper as [48]
FoxO family transcription factors (FoxO1, FoxO3, FoxO4) are critical mediators of the catabolic response during atrophy.
“FoxO family of transcription factors (FoxO1, FoxO3, and FoxO4) are critical mediators of the catabolic response during atrophy [9, 15, 16].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [9]
The IGF1-AKT-mTOR axis increases protein synthesis by stimulating the translational machinery and simultaneously blocks FoxO transcription factors and protein degradation.
“The IGF1–AKT-–mTOR axis increases protein synthesis by stimulating the translational machinery and simultaneously blocks FoxOs transcription factors and protein degradation [9].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [9]
Alterations in mPTP function contribute to the aging-related loss of muscle mass and function.
“Alterations in mPTP function are undoubtedly contributing to the aging-related loss of muscle mass and function, since mPTP opening can trigger several atrophy-regulating pathways.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [17]
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- Authors
- Sandri, M., Sandri, C., Gilbert, A., Skurk, C., Calabria, E., Picard, A., Walsh, K., Schiaffino, S., Lecker, S. H., & Goldberg, A. L.
- Affiliations
- Harvard University (US)
- Veneto Institute of Molecular Medicine (IT)
- Beth Israel Deaconess Medical Center (US)
- Boston University (US)
- Corresponding author
- Lecker, Stewart H
- Goldberg, Alfred L
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 117
- Issue
- 3
- Pages
- 399-412
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3619734
- OpenAlex
- W2033797333
- Cited by
- 3,012
- References
- 41
- Citations by year
- 2026: 129 · 2025: 122 · 2024: 121 · 2023: 118 · 2022: 141 · 2021: 153 · 2020: 165 · 2019: 159 · 2018: 151 · 2017: 117 · 2016: 134 · 2015: 171 · 2014: 176 · 2013: 177 · 2012: 150
- FWCI
- 33.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- National Space Biomedical Research Institute
- European Commission (QLRT-2000-00530)
- National Institutes of Health (DK02707, DK62307)
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Agenzia Spaziale Italiana
- Muscular Dystrophy Association
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- FOXO transcription factors, atrogin-1, skeletal muscle atrophy, ubiquitin ligase, PI3K/Akt signaling, insulin-like growth factor I, FOXO3, forkhead transcription factor, starvation, glucocorticoids, myotubes, muscle atrophy, transcriptional regulation
- MeSH terms
- Adenoviridae, Animals, Cells, Cultured, Cloning, Molecular, Fasting, Gene Expression Regulation, Genetic Vectors, Glucocorticoids, Insulin-Like Growth Factor I, Ligases, Models, Biological, Muscle Proteins, Muscular Atrophy, Promoter Regions, Genetic, Proto-Oncogene Proteins, Transcription Factors, Signal Transduction, Protein Serine-Threonine Kinases, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Muscle Cells, RNA Interference, Ubiquitin-Protein Ligases, SKP Cullin F-Box Protein Ligases, Proto-Oncogene Proteins c-akt, Mice
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