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首页> 外文期刊>Biology Open >Conditional over-expression of PITX1 causes skeletal muscle dystrophy in mice
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Conditional over-expression of PITX1 causes skeletal muscle dystrophy in mice

机译：PITX1的条件过度表达导致小鼠骨骼肌营养不良

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Paired-like homeodomain transcription factor 1 ( PITX1 ) was specifically up-regulated in patients with facioscapulohumeral muscular dystrophy (FSHD) by comparing the genome-wide mRNA expression profiles of 12 neuromuscular disorders. In addition, it is the only known direct transcriptional target of the double homeobox protein 4 (DUX4) of which aberrant expression has been shown to be the cause of FSHD. To test the hypothesis that up-regulation of PITX1 contributes to the skeletal muscle atrophy seen in patients with FSHD, we generated a tet-repressible muscle-specific Pitx1 transgenic mouse model in which expression of PITX1 in skeletal muscle can be controlled by oral administration of doxycycline. After PITX1 was over-expressed in the skeletal muscle for 5 weeks, the mice exhibited significant loss of body weight and muscle mass, decreased muscle strength, and reduction of muscle fiber diameters. Among the muscles examined, the tibialis anterior, gastrocnemius, quadricep, bicep, tricep and deltoid showed significant reduction of muscle mass, while the soleus, masseter and diaphragm muscles were not affected. The most prominent pathological change was the development of atrophic muscle fibers with mild necrosis and inflammatory infiltration. The affected myofibers stained heavily with NADH-TR with the strongest staining in angular-shaped atrophic fibers. Some of the atrophic fibers were also positive for embryonic myosin heavy chain using immunohistochemistry. Immunoblotting showed that the p53 was up-regulated in the muscles over-expressing PITX1. The results suggest that the up-regulation of PITX1 followed by activation of p53-dependent pathways may play a major role in the muscle atrophy developed in the mouse model.
机译：通过比较12种神经肌肉疾病的全基因组mRNA表达谱，成对的类同种异型域转录因子1（PITX1）在患有面肩肱型肌营养不良症（FSHD）的患者中被特异性上调。此外，它是双同源异形盒蛋白4（DUX4）唯一已知的直接转录靶标，其异常表达已被证明是FSHD的原因。为了检验关于FSHD患者中见到的PITX1上调有助于骨骼肌萎缩的假说，我们建立了一种tet可抑制的肌肉特异性Pitx1转基因小鼠模型，其中可以通过口服PITX1来控制其在骨骼肌中的表达强力霉素。在骨骼肌中过表达PITX1 5周后，小鼠表现出体重和肌肉量的显着减少，肌肉强度降低和肌肉纤维直径减小。在所检查的肌肉中，胫前肌，腓肠肌，四头肌，二头肌，三头肌和三角肌显示出明显的肌肉质量减少，而比目鱼肌，咬肌和diaphragm肌没有受到影响。最突出的病理变化是萎缩性肌纤维的发展，轻度坏死和炎性浸润。受影响的肌纤维被NADH-TR染色严重，角形萎缩纤维染色最强。使用免疫组织化学方法，某些萎缩纤维对胚胎肌球蛋白重链也呈阳性。免疫印迹表明，过度表达PITX1的肌肉中p53上调。结果表明，PITX1的上调，然后激活p53依赖性途径，可能在小鼠模型中出现的肌肉萎缩中起主要作用。

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