ArticleThe Journal of biological chemistry2012
Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 153 papers.
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Who cites it
153 citing papers in PubMed, 232 citations in OpenAlex.
- The PERK-GADD45A axis is a key driver of hepatic stellate cell activation.Hepatology communications · 2026Article
- Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.Muscles (Basel, Switzerland) · 2026Review
- Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.bioRxiv : the preprint server for biology · 2026Article
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- ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.bioRxiv : the preprint server for biology · 2026Article
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- Transcriptional readthrough at Atf4 locus suppresses Rps19bp1 and impairs heart development.Cardiovascular research · 2026Article
- Traditional Chinese Medicine for Diabetic Sarcopenia: A Review and Its Related Mechanisms.Journal of diabetes research · 2026Review
- Autophagy selectively clears ER in TNF-α-induced muscle atrophy.Autophagy reports · 2026Article
- Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size.American journal of physiology. Cell physiology · 2025Article
- Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size.bioRxiv : the preprint server for biology · 2025Article
- FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.Obesity (Silver Spring, Md.) · 2025Article
- Transcriptional Readthrough atbioRxiv : the preprint server for biology · 2025Article
- Emerging roles for integrated stress response signaling in homeostasis.The FEBS journal · 2025Review
- ATF4 in proximal tubules modulates kidney function and modifies the metabolome.Journal of molecular medicine (Berlin, Germany) · 2025Article
- Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma.Neoplasia (New York, N.Y.) · 2025Article
- ATF4 Deletion in Brown Adipocytes Attenuates Diet-Induced Insulin Resistance in Male Mice Independently of Weight Gain.Endocrinology · 2025Article
- PDE10A Inhibition Reduces NLRP3 Activation and Pyroptosis in Sepsis and Nerve Injury.International journal of molecular sciences · 2025Article
- GADD45A suppression contributes to cardiac remodeling by promoting inflammation, fibrosis and hypertrophy.Cellular and molecular life sciences : CMLS · 2025Article
93 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.