The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy
Open accessAbstract
Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1α, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy.
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“Gadd45α induces the remodeling of chromatin to repress genes involved in anabolic signaling and energy production and to activate pro-atrophy genes including autophagy and caspase-related genes74.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [74]
In the citing paper
“Importantly, the overexpression of ATF4 and GADD45 is sufficient to induce muscle loss [19, 20].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [20]
In the citing paper
“Genes encoding for glycolysis and oxidative phosphorylation enzymes are coordinately suppressed in atrophying muscles during denervation, disuse, diabetes, cancer, fasting, and chronic kidney disease [10, 11, 13, 20].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [20]
In the citing paper
“In fact, the overexpression of either Atf4 [27], Gadd45 [26], or Fgf21 [23] in muscles is sufficient to induce muscle atrophy.”
From Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles (2019) · cites this paper as [26]
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Metadata
- Authors
- Ebert, S. M., Dyle, M. C., Kunkel, S. D., Bullard, S. A., Bongers, K. S., Fox, D. K., Dierdorff, J. M., Foster, E. D., & Adams, C. M.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Adams, Christopher M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 287
- Issue
- 33
- Pages
- 27290-27301
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3431665
- OpenAlex
- W2059083151
- Cited by
- 221
- References
- 63
- Citations by year
- 2026: 14 · 2025: 12 · 2024: 25 · 2023: 16 · 2022: 19 · 2021: 22 · 2020: 25 · 2019: 14 · 2018: 12 · 2017: 13 · 2016: 12 · 2015: 16 · 2014: 12 · 2013: 7 · 2012: 2
- FWCI
- 4.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000976)
- National Heart, Lung, and Blood Institute (HL-007121, T32HL007121)
- National Institute of General Medical Sciences (T32 GM07361, T32GM007337)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR059115)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Keywords
- GADD45A, skeletal muscle atrophy, ATF4, muscle stress, fasting, muscle immobilization, muscle denervation, PGC-1α, Akt signaling, autophagy, protein synthesis, gene expression reprogramming
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, GADD45 Proteins, Animals, Cell Line, Cell Nucleus, Energy Metabolism, Gene Expression Regulation, Muscle Proteins, Muscular Atrophy, Nuclear Proteins, RNA, Messenger, Stress, Physiological, Transcription Factors, Protein Biosynthesis, Signal Transduction, Trans-Activators, Mice, Knockout, Muscle, Skeletal, Cell Cycle Proteins, Proto-Oncogene Proteins c-akt, Mice, Activating Transcription Factor 4
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