Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division.
Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division.
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DOI：
10.1038/nm.3990
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发表时间：
2015-12
期刊：
影响因子：
82.9
通讯作者：
Rudnicki MA
中科院分区：
文献类型：
--
作者：
Dumont NA;Wang YX;von Maltzahn J;Pasut A;Bentzinger CF;Brun CE;Rudnicki MA
肌营养不良蛋白在分化的肌纤维中表达，其中肌膜完整性需要肌营养不良蛋白，并且其基因中的功能缺失突变导致杜氏肌营养不良症（DMD），一种以进行性和严重的骨骼肌变性为特征的疾病。在这里，我们发现抗肌萎缩蛋白也在激活的肌肉干细胞（也称为卫星细胞）中高度表达，在那里它与Ser/Thr激酶Mark 2（也称为Par 1b）相关，这是细胞极性的重要调节因子。在缺乏肌营养不良蛋白的情况下，Mark 2蛋白的表达下调，导致不能将Pard 3转移到细胞的相对侧。因此，在肌营养不良蛋白缺陷的卫星细胞中，不对称分裂的数量显著减少，同时也显示出极性丧失、异常分裂模式，包括中心体扩增、有丝分裂纺锤体取向受损和细胞分裂延长。总而言之，这些内在缺陷强烈减少了适当肌肉再生所需的肌源性祖细胞的产生。因此，我们得出结论，肌营养不良蛋白在卫星细胞极性和不对称分裂的调节中起着至关重要的作用。我们的研究结果表明，DMD中的肌肉萎缩不仅是由肌纤维脆性引起的，而且还因内在卫星细胞功能障碍导致的再生受损而加剧。
Dystrophin is expressed in differentiated myofibers where it is required for sarcolemmal integrity, and loss-of-function mutations in its gene result in Duchenne Muscular Dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells) where it associates with the Ser/Thr kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to polarize Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, while also displaying a loss of polarity, abnormal division patterns including centrosome amplification, impaired mitotic spindle orientation, and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD is not only caused by myofiber fragility, but is also exacerbated by impaired regeneration due to intrinsic satellite cell dysfunction.