p53 and ATF4 mediate distinct and additive pathways to skeletal muscle atrophy during limb immobilization
p53 and ATF4 mediate distinct and additive pathways to skeletal muscle atrophy during limb immobilization
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DOI：
10.1152/ajpendo.00010.2014
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发表时间：
2014-08-01
影响因子：
5.1
通讯作者：
Adams, Christopher M.
中科院分区：
文献类型：
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作者：
Fox, Daniel K.;Ebert, Scott M.;Adams, Christopher M.
固定通过尚未被充分理解的复杂信号通路导致骨骼肌萎缩。为了更好地了解这些途径，我们研究了 p53 和 ATF4 的作用，这两种转录因子可介导对各种细胞应激的适应。使用小鼠模型，我们证明 3 天的肌肉固定会诱导肌肉萎缩并增加 p53 和 ATF4 的表达。此外，缺乏p53或ATF4的肌纤维对固定诱导的肌肉萎缩有部分抵抗力，并且p53或ATF4的强制表达在没有固定的情况下诱导肌纤维萎缩。然而，重要的是，p53 和 ATF4 并不需要彼此来促进萎缩，并且 p53 和 ATF4 的共表达比单独任一转录因子诱导更多的萎缩。此外，同时缺乏p53和ATF4的肌纤维比仅缺乏p53或ATF4的肌纤维更能抵抗固定引起的萎缩。有趣的是，p53 和 ATF4 途径的独立和相加性质允许对至少一种下游效应子 p21 进行组合控制。使用全基因组 mRNA 表达阵列，我们将 p21 mRNA 鉴定为骨骼肌转录本，通过 p53 和 ATF4 的联合作用在固定肌肉中高度诱导。另外，在小鼠肌肉中，p21以不需要固定、p53或ATF4的方式诱导萎缩，并且p21对于固定、p53和ATF4诱导的萎缩是必需的。总的来说，这些结果将 p53 和 ATF4 确定为固定诱导的肌肉萎缩的重要且互补的介质，并发现 p21 是 p53 和 ATF4 途径的关键下游效应子。
Immobilization causes skeletal muscle atrophy via complex signaling pathways that are not well understood. To better understand these pathways, we investigated the roles of p53 and ATF4, two transcription factors that mediate adaptations to a variety of cellular stresses. Using mouse models, we demonstrate that 3 days of muscle immobilization induces muscle atrophy and increases expression of p53 and ATF4. Furthermore, muscle fibers lacking p53 or ATF4 are partially resistant to immobilization-induced muscle atrophy, and forced expression of p53 or ATF4 induces muscle fiber atrophy in the absence of immobilization. Importantly, however, p53 and ATF4 do not require each other to promote atrophy, and coexpression of p53 and ATF4 induces more atrophy than either transcription factor alone. Moreover, muscle fibers lacking both p53 and ATF4 are more resistant to immobilization-induced atrophy than fibers lacking only p53 or ATF4. Interestingly, the independent and additive nature of the p53 and ATF4 pathways allows for combinatorial control of at least one downstream effector, p21. Using genome-wide mRNA expression arrays, we identified p21 mRNA as a skeletal muscle transcript that is highly induced in immobilized muscle via the combined actions of p53 and ATF4. Additionally, in mouse muscle, p21 induces atrophy in a manner that does not require immobilization, p53 or ATF4, and p21 is required for atrophy induced by immobilization, p53, and ATF4. Collectively, these results identify p53 and ATF4 as essential and complementary mediators of immobilization-induced muscle atrophy and discover p21 as a critical downstream effector of the p53 and ATF4 pathways.