Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, TX 75390, USA.
Genes Dev. 2012 Jan 15;26(2):190-202. doi: 10.1101/gad.179663.111.
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 and MRTF-A, are up-regulated in satellite cells in response to skeletal muscle injury and muscular 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.
针对骨骼肌损伤，卫星细胞作为一种肌源性干细胞群被激活，通过增殖而扩增，最终彼此融合，并与受损的肌纤维融合，从而促进肌肉再生。在这里，我们发现肌细胞生成素家族的转录共激活因子 MASTR 和 MRTF-A 在受到骨骼肌损伤和肌肉疾病的刺激时在卫星细胞中上调。在小鼠中，对 MASTR 进行全局和卫星细胞特异性敲除会损害骨骼肌再生。当同时敲除 MRTF-A 时，损害会更大，这是由于卫星细胞的异常分化和过度增殖所致。这些异常与 MyoD 的基因缺失相关，MyoD 是肌生成的主要调节因子，在缺乏 MASTR 和 MRTF-A 时其表达下调。与 MASTR 在 MyoD 表达的转录调控中的重要作用一致，MASTR 通过与 MEF2 和肌细胞生成素家族成员的结合，激活了一个肌肉特异性的出生后 MyoD 增强子。我们的研究结果为肌肉再生的遗传调控提供了新的见解，并确定 MASTR 是这一过程的核心调节因子。
