Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy

Scott M Ebert; Michael C Dyle; Steven D Kunkel; Steven A Bullard; Kale S Bongers; Daniel K Fox; Jason M Dierdorff; Eric D Foster; Christopher M Adams

doi:10.1074/jbc.M112.374777

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Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy

Journal article

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Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy

Scott M Ebert, Michael C Dyle, Steven D Kunkel, Steven A Bullard, Kale S Bongers, Daniel K Fox, Jason M Dierdorff, Eric D Foster and Christopher M Adams

The Journal of biological chemistry, Vol.287(33), pp.27290-27301

08/10/2012

DOI: 10.1074/jbc.M112.374777

PMCID: PMC3431665

PMID: 22692209

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Abstract

Background: In skeletal muscle, diverse stresses induce the transcription factor ATF4, which promotes muscle atrophy by an unknown mechanism. Results: ATF4 causes muscle atrophy by inducing Gadd45a, which reprograms myonuclear gene expression to repress anti-atrophy mechanisms and induce pro-atrophy mechanisms. Conclusion: Gadd45a is a critical stress-induced mediator of muscle atrophy. Significance: The ATF4/Gadd45a pathway is a potential therapeutic target in atrophic muscle. 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.

Molecular Bases of Disease

Transcription Regulation

Skeletal Muscle

Skeletal Muscle Metabolism

Stress Response

Gadd45a

Muscle Atrophy

ATF4

Details

Title: Subtitle: Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy
Creators: Scott M Ebert - From the
Michael C Dyle - From the
Steven D Kunkel - From the
Steven A Bullard - From the
Kale S Bongers - From the
Daniel K Fox - From the
Jason M Dierdorff - From the
Eric D Foster - From the
Christopher M Adams - From the
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.287(33), pp.27290-27301
DOI: 10.1074/jbc.M112.374777
PMID: 22692209
PMCID: PMC3431665
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: 1R01AR059115-01; T32 GM07361 / National Institutes of Health
Alternative title: Gadd45a Induces Skeletal Muscle Atrophy
Language: English
Date published: 08/10/2012
Academic Unit: Molecular Physiology and Biophysics; College of Public Health; Internal Medicine
Record Identifier: 9984025354802771

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