Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity.
Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity.
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DOI：
10.1016/j.celrep.2016.06.095
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发表时间：
2016-08-02
期刊：
影响因子：
8.8
通讯作者：
Schneider RJ
中科院分区：
文献类型：
--
作者：
Chenette DM;Cadwallader AB;Antwine TL;Larkin LC;Wang J;Olwin BB;Schneider RJ
骨骼肌损伤后，肌肉干细胞（卫星细胞）被激活，增殖和分化形成肌纤维。我们发现，mRNA衰变蛋白AUF 1通过靶向降解含有3′ AU富集元件（战神）的特定mRNA来调节卫星细胞功能。Auf 1 −/−小鼠随着年龄增长骨骼肌萎缩加速，损伤后骨骼肌修复受损。卫星细胞mRNA分析和再生研究表明，auf 1 −/−卫星细胞自我更新受损是由于ARE-mRNA的稳定性增加和过表达，包括基质金属蛋白酶MMP 9的细胞自主过表达。分泌的MMP 9降解骨骼肌基质，阻止卫星细胞介导的再生并恢复静止。在auf 1 −/−小鼠中阻断MMP 9活性可恢复骨骼肌修复和卫星细胞群的维持。AUF 1对ARE-mRNA衰减的控制代表了成体干细胞调节的机制，并与人类骨骼肌萎缩性疾病有关。
Following skeletal muscle injury, muscle stem cells (satellite cells) are activated, proliferate, and differentiate to form myofibers. We show that mRNA decay protein AUF1 regulates satellite cell function through targeted degradation of specific mRNAs containing 3′ AU-rich elements (AREs). Auf1−/− mice undergo accelerated skeletal muscle wasting with age and impaired skeletal muscle repair following injury. Satellite cell mRNA analysis and regeneration studies demonstrate that auf1−/− satellite cell self-renewal is impaired due to increased stability and overexpression of ARE-mRNAs, including cell-autonomous overexpression of matrix metalloprotease MMP9. Secreted MMP9 degrades the skeletal muscle matrix, preventing satellite cell-mediated regeneration and return to quiescence. Blocking MMP9 activity in auf1−/− mice restores skeletal muscle repair and maintenance of the satellite cell population. Control of ARE-mRNA decay by AUF1 represents a mechanism for adult stem cell regulation and is implicated in human skeletal muscle wasting diseases.