MASTR directs MyoD-dependent satellite cell differentiation during skeletal muscle regeneration
MASTR directs MyoD-dependent satellite cell differentiation during skeletal muscle regeneration
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DOI：
10.1101/gad.179663.111
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发表时间：
2012-01-15
影响因子：
10.5
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
--
作者：
Mokalled, Mayssa H.;Johnson, Aaron N.;Olson, Eric N.
为了应对骨骼肌损伤，卫星细胞（作为肌源干细胞群）被激活，通过增殖扩大，最终相互融合并与受损的肌纤维融合，以促进肌肉再生。在这里，我们发现转录共激活因子心肌素家族的成员 MASTR 和 MRTF-A 在骨骼肌损伤和肌营养不良时在卫星细胞中上调。小鼠体内 MASTR 的整体和卫星细胞特异性缺失会损害骨骼肌再生。当 MRTF-A 也被删除时，这种损害会更大，这是由于卫星细胞的异常分化和过度增殖造成的。这些异常类似于与 MyoD 基因缺失相关的异常，MyoD 是肌生成的主要调节因子，在 MASTR 和 MRTF-A 缺失的情况下，MyoD 的表达下调。与 MASTR 在 MyoD 表达转录调节中的重要作用一致，MASTR 通过与 MEF2 和 Myocardin 家族成员的关联来激活肌肉特异性的出生后 MyoD 增强子。我们的结果为肌肉再生的遗传回路提供了新的见解，并将 MASTR 确定为该过程的中央调节器。
In response to skeletal muscle injury, satellite cells, which function as a myogenic stem cell population, become activated, expand through proliferation, and ultimately fuse with each other and with damaged myofibers to promote muscle regeneration. Here, we show that members of the Myocardin family of transcriptional coactivators, MASTR andMRTF-A, are up-regulated in satellite cells in response to skeletal muscle injury andmuscular dystrophy. Global and satellite cell-specific deletion of MASTR in mice impairs skeletal muscle regeneration. This impairment is substantially greater when MRTF-A is also deleted and is due to aberrant differentiation and excessive proliferation of satellite cells. These abnormalities mimic those associated with genetic deletion of MyoD, a master regulator of myogenesis, which is down-regulated in the absence of MASTR and MRTF-A. Consistent with an essential role of MASTR in transcriptional regulation of MyoD expression, MASTR activates a muscle-specific postnatal MyoD enhancer through associations with MEF2 and members of the Myocardin family. Our results provide new insights into the genetic circuitry of muscle regeneration and identify MASTR as a central regulator of this process.