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

被引:185
作者
Ebert, Scott M. [1 ,2 ,3 ]
Dyle, Michael C. [1 ,2 ,3 ]
Kunkel, Steven D. [1 ,2 ,3 ,4 ]
Bullard, Steven A. [1 ,2 ,3 ,4 ]
Bongers, Kale S. [1 ,2 ,3 ]
Fox, Daniel K. [1 ,2 ,3 ]
Dierdorff, Jason M. [1 ,2 ,3 ]
Foster, Eric D. [1 ,2 ,3 ]
Adams, Christopher M. [1 ,2 ,3 ,4 ]
机构
[1] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Mol Physiol, Iowa City, IA 52242 USA
[2] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Biophys, Iowa City, IA 52242 USA
[3] Univ Iowa, Roy J & Lucille A Carver Coll Med, Fraternal Order Eagles Diabet Res Ctr, Iowa City, IA 52242 USA
[4] Iowa City Vet Affairs Med Ctr, Iowa City, IA 52246 USA
基金
美国国家卫生研究院;
关键词
FOXO TRANSCRIPTION FACTORS; GENE-EXPRESSION; UBIQUITIN LIGASES; PATHWAY; PROTEIN; COACTIVATORS; DEGRADATION; PGC-1-ALPHA; ACTIVATION; GENERATION;
D O I
10.1074/jbc.M112.374777
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
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-1 alpha, 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.
引用
收藏
页码:27290 / 27301
页数:12
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