Research on muscular dystrophy using mouse developmental biotechnology

肌糖病（SGP）在临床特征和肌肉病理方面与杜氏肌营养不良（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，无精神损害，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）已经在四种不同形式的SGP中显示出来。为了分析SGC各亚基的生理作用，阐明肌肉肥大和变性的发病机制，我们采用基因靶向法培养了γ- sg缺陷（GSG-/-）小鼠。GSG-/-小鼠的肢体、肩部和骨盆肌肉随着年龄的增长表现出进行性肌肉肥大和无力，结果与其他四肢束带和DMD小鼠模型相似。虽然小腿肌肉肥大是DMD和SGP的显著诊断发现，但其发病机制尚不清楚。我们发现胫骨前肌的肌纤维数量随着年龄的增长而增加，肥厚肌中大部分纤维为中央有核再生纤维。肥大肌肉中可见纤维分支。因此，肌肉肥大可能是广泛的纤维分支和肌纤维增加的结果。肌肉肥大并不是由于纤维组织和脂肪组织的替代，正如在人类肌肉疾病中所谓的假性肥大所显示的那样。一岁以上小鼠的肌肉病理变得更加“营养不良”，纤维大小出现明显变化，伴有间质纤维化。

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.