Research on muscular dystrophy using mouse developmental biotechnology

利用小鼠发育生物技术研究肌营养不良症

基本信息

批准号：
10670150
负责人：
SASAOKA Toshikuni
金额：
$ 2.05万
依托单位：
National Center of Neurology and Psychiatry
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Sarcoglycanopathy (SGP) is similar to Duchenne muscular dystrophy (DMD) with respect to clinical features and muscle pathology, except for its mode of inheritance, slightly later onset in most cases, less frequent cardiac involvement, absence of mental impairment, and slightly slower progression. The four sarcoglycan subunits (α-, β-, γ-, and δ-SG) of the sarcoglycan complex (SGC) have been shown in four respective forms of SGP.To analyze the physiological roles of the individual subunits of SGC and elucidate the pathogenetic mechanisms of muscle hypertrophy and degeneration, we generated γ-SG-deficient (GSG-/-) mice by gene targeting. The limb, shoulder, and pelvic muscles of the GSG-/- mice exhibited progressive muscle hypertrophy and weakness with age, and findings were similar to those seen in other mouse models for limb girdle and DMD.While calf muscle hypertrophy is a striking diagnostic finding in DMD and SGP, its pathogenetic mechanism remains unknown. We found that the number of muscle fibers in tibialis anterior muscle increased with age, and most of the fibers in the hypertrophic muscle were centrally nucleated regenerating fibers. Fiber branching was seen in hypertrophied muscle. Therefore, muscle hypertrophy may represent a consequence of extensive fiber branching and an increase of muscle fibers. Muscle hypertrophy is not due to fibrous and fat tissue replacement, as has been shown to be the case in the so-called pseudohypertrophy in muscle diseases in humans. The muscle pathology became more "dystrophic" in mice over one year of age when there was a marked variation in fiber size with interstitial fibrosis.

Sarcoglycan Pathy（SGP）类似于临床特征和肌肉病理学的Duchenne肌肉营养不良（DMD），除了其遗传模式，在大多数情况下稍后发作，在大多数情况下稍后发作，心脏受累，缺乏精神损伤的频率较低，进展略有慢。萨果聚糖复合物（SGC）的四个肌肉聚糖亚基（α-，β-，γ-和δ-SG）以四种相对形式显示了SGP。分析SGC单个亚基的生理作用，并阐明了Muscle Mytroghy-SG-SG-SG-SG-DEFIFFICTIFFICTIFFIFFIFFIFFICATIFFIFFICTACTAIF-DEF-DEF-DEF-DEC-DEC-DEC-DEC-DEC-DEF-DEC-DE的生理作用，我们基因靶向。 GSG - / - 小鼠的肢体，肩膀和骨盆肌肉随着年龄的增长而暴露了进行性肌肉肥大和虚弱，发现与肢体girly和DMD的其他小鼠模型中看到的发现相似。当DMD和SGP中，Calf Limb Girly和DMD中的其他小鼠模型中的诊断是一种惊人的诊断。我们发现，胫骨前肌的肌肉纤维数量随着年龄的增长而增加，而肥大肌肉中的大多数纤维是中心核化的再生纤维。在肥大的肌肉中可以看到纤维分支。因此，肌肉肥大可能代表了广泛的纤维分支和肌肉纤维增加的结果。肌肉肥大不是由于纤维组织和脂肪组织的替代而引起的，正如人类肌肉疾病中所谓的伪内植物中所致。当纤维尺寸明显变化并与间隙纤维化发生明显变化时，肌肉病理学变得更加“营养不良”。