The Transcription Factor ATF4 Promotes Skeletal Myofiber Atrophy during Fasting
The Transcription Factor ATF4 Promotes Skeletal Myofiber Atrophy during Fasting
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DOI：
10.1210/me.2009-0345
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发表时间：
2010-04-01
影响因子：
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通讯作者：
Adams, Christopher M.
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文献类型：
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作者：
Ebert, Scott M.;Monteys, Alex Mas;Adams, Christopher M.
长时间禁食会改变骨骼肌基因表达，从而促进肌纤维萎缩，但其潜在机制尚不完全清楚。在这里，我们研究了激活转录因子 4 (ATF4) 的潜在作用，这种转录因子在细胞对饥饿的反应中发挥着进化上古老的作用。在小鼠骨骼肌中，禁食会增加 ATF4 mRNA 的水平。为了确定肌纤维萎缩是否需要增加 ATF4 表达，我们用靶向 ATF4 的抑制性 RNA 降低了 ATF4 表达，并发现它可以减少禁食期间的肌纤维萎缩。同样，用抗磷酸化形式的真核起始因子 2 α 降低 ATF4 mRNA 的空腹水平可减少肌纤维萎缩。为了确定 ATF4 是否足以减少肌纤维尺寸，我们过表达 ATF4，并发现它在不禁食的情况下减少了肌纤维尺寸。相比之下，转录失活的 ATF4 构建体不会减少肌纤维大小，表明需要 ATF4 介导的转录调节。为了开始确定 ATF4 介导的肌纤维萎缩的机制，我们比较了禁食和 ATF4 过表达对整体骨骼肌 mRNA 表达的影响。有趣的是，ATF4 的表达增加了一小部分 5 种禁食反应性 mRNA，其中包括 15 种 mRNA 中受禁食诱导程度最高的 4 种。这五种 mRNA 编码先前与生长抑制（p21(Cip1/Waf1)、GADD45 α 和 PW1/Peg3）或基于肌联蛋白的应激信号传导有关的蛋白质 [肌肉 LIM 蛋白 (MLP) 和心脏锚蛋白重复蛋白 (CARP)]。综上所述，这些数据表明 ATF4 是饥饿期间骨骼肌纤维萎缩的新型介质。 （分子内分泌学24：790-799，2010）
Prolonged fasting alters skeletal muscle gene expression in a manner that promotes myofiber atrophy, but the underlying mechanisms are not fully understood. Here, we examined the potential role of activating transcription factor 4 (ATF4), a transcription factor with an evolutionarily ancient role in the cellular response to starvation. In mouse skeletal muscle, fasting increases the level of ATF4 mRNA. To determine whether increased ATF4 expression was required for myofiber atrophy, we reduced ATF4 expression with an inhibitory RNA targeting ATF4 and found that it reduced myofiber atrophy during fasting. Likewise, reducing the fasting level of ATF4 mRNA with a phosphorylation-resistant form of eukaryotic initiation factor 2 alpha decreased myofiber atrophy. To determine whether ATF4 was sufficient to reduce myofiber size, we overexpressed ATF4 and found that it reduced myofiber size in the absence of fasting. In contrast, a transcriptionally inactive ATF4 construct did not reduce myofiber size, suggesting a requirement for ATF4-mediated transcriptional regulation. To begin to determine the mechanism of ATF4-mediated myofiber atrophy, we compared the effects of fasting and ATF4 overexpression on global skeletal muscle mRNA expression. Interestingly, expression of ATF4 increased a small subset of five fasting-responsive mRNAs, including four of the 15 mRNAs most highly induced by fasting. These five mRNAs encode proteins previously implicated in growth suppression (p21(Cip1/Waf1), GADD45 alpha, and PW1/Peg3) or titin-based stress signaling [muscle LIM protein (MLP) and cardiac ankyrin repeat protein (CARP)]. Taken together, these data identify ATF4 as a novel mediator of skeletal myofiber atrophy during starvation. (Molecular Endocrinology 24: 790-799, 2010)