Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy
Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy
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DOI：
10.1074/jbc.m112.374777
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发表时间：
2012-08-10
影响因子：
4.8
通讯作者：
Adams, Christopher M.
中科院分区：
文献类型：
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作者：
Ebert, Scott M.;Dyle, Michael C.;Adams, Christopher M.
包括饥饿和肌肉废用在内的各种压力导致骨骼肌萎缩。然而，肌肉萎缩的分子机制是复杂的，并没有得到很好的理解。在这里，我们证明生长阻滞和DNA损伤诱导的45a蛋白（Gadd45a）是肌肉萎缩的关键介质。我们通过对应激诱导的促萎缩转录因子ATF4的潜在下游介质的无偏搜索确定了Gadd45a。我们发现Gadd45a是由三种不同的骨骼肌应激引起的骨骼肌萎缩所必需的：禁食、肌肉固定和肌肉去神经支配。相反，在没有上游应激的情况下，肌肉或培养的肌管中被迫表达Gadd45a会诱导萎缩。我们发现，肌肉特异性ATF4敲除小鼠在应激反应中诱导Gadd45a mRNA的能力降低，因此，它们在禁食或肌肉固定反应中经历较少的萎缩。有趣的是，Gadd45a是一种肌核蛋白，可诱导肌核重塑和肌萎缩的综合程序。Gadd45a抑制参与合成代谢信号和能量产生的基因，并诱导促萎缩基因。因此，Gadd45a降低了肌肉萎缩的多种障碍（包括PGC-1 α、Akt活性和蛋白质合成），并刺激了促萎缩机制（包括自噬和caspase介导的蛋白质水解）。这些结果阐明了一个关键的应激诱导途径，重编程肌肉基因表达导致萎缩。
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.