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.

肌聚糖病 (SGP) 在临床特征和肌肉病理学方面与杜氏肌营养不良症 (DMD) 相似，但其遗传方式不同，大多数病例发病稍晚，心脏受累较少，无精神障碍，进展稍慢肌聚糖复合物 (SGC) 的四个肌聚糖亚基（α-、β-、γ- 和 δ-SG）已在 SGP 的四种不同形式中显示。为了研究SGC各个亚基的生理作用并阐明肌肉肥大和退化的致病机制，我们通过基因靶向GSG-/的四肢、肩部和骨盆肌肉产生了γ-SG缺陷（GSG-/-）小鼠。 - 随着年龄的增长，小鼠表现出进行性肌肉肥大和无力，其结果与其他小鼠模型的肢带和 DMD 相似。虽然小腿肌肉肥大是 DMD 和 SGP 的一个惊人的诊断发现，我们发现，胫骨前肌的肌纤维数量随着年龄的增长而增加，并且肥大的肌肉中大部分纤维是中心有核的再生纤维，因此肥大的肌肉可能出现纤维分支。代表广泛的纤维分支的结果，肌肉肥大并不是由于纤维和脂肪组织的替代，正如所谓的情况所示。人类肌肉疾病中的假性肥大，在一岁以上的小鼠中，当纤维尺寸因间质纤维化而发生明显变化时，肌肉病理学变得更加“营养不良”。