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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670150/
• 关键词: Mouse; Developmental biotechnology; Muscular dystrophy; Muscle hypertrophy; Sarcoglycan; Dystrophin; Dystroglycan; Model animal; エバンスブルー

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.

肉糖病(SGP)与Duchenne肌营养不良症(DMD)在临床特征和肌肉病理方面相似，不同之处在于它的遗传方式，大多数病例起病稍晚，较少发生心脏损害，无智力障碍，进展略慢。肌聚糖复合体的四个亚基(α-，β-，γ-和δ-SG)分别存在于四种不同形态的SGP中。为了分析各个亚基的生理作用，阐明肌肉肥大和退变的发病机制，我们通过基因打靶的方法建立了γ-SG缺陷(GSG-/-)小鼠。GSG-/-小鼠的四肢、肩部和骨盆肌肉随着年龄的增长表现为进行性肌肉肥大和肌肉无力，其结果与其他四肢腰带和DMD小鼠模型相似。尽管小腿肌肉肥大是DMD和SGP的显著诊断结果，但其发病机制尚不清楚。我们发现，胫前肌的肌纤维数量随着年龄的增长而增加，肥大肌中的大部分纤维是中央有核的再生纤维。在肥厚的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肉纤维增加的结果。肌肉肥大不是由于纤维和脂肪组织的替代，而是人类肌肉疾病中所谓的假性肥大的情况。在一岁以上的小鼠中，当纤维大小与间质纤维化有显著差异时，肌肉病理变得更加“营养不良”。

项目成果

Araishi, Kenji: "Loss of the sarcoglycan complex and sarcospan leads to muscular dystrophy in beta-sarcoglycan-deficient mice"Human Molecular Genetics. 8. 1589-1598 (1999)

Araishi, Kenji：“肌聚糖复合物和肌跨的丢失会导致β-肌聚糖缺陷小鼠的肌营养不良”《人类分子遗传学》。

Mikiharu Yoshida et al.: "Biochemical evidence for association of dystrobrevin with the sarcoglycansarcospan complex as a basis for understanding sarcoglycanopathy."Human Molecular Genetics. Vol.9(7). 1033-1040 (2000)

Mikiharu Yoshida 等人：“dystrobrevin 与肌聚糖sarcospan 复合物关联的生化证据，作为了解肌聚糖病的基础。”人类分子遗传学。

Yanyan Wang et al.: "Dopamine D2Long receptor-deficient mice display hypolocomotion and reduced level of haloperidol-induced catalepsy."Journal of Neuroscience. Vol.20(22). 8305-8314 (2000)

Yanyan Wang 等人：“多巴胺 D2Long 受体缺陷的小鼠表现出运动减退和氟哌啶醇诱导的僵直状态降低。”神经科学杂志。

Hagiwara, Y, Sasaoka, T, Araishi K, Imamura M, Yorifuji, H, Nonaka, I, Ozawa E, and Kikuchi, T: "Caveolin-3 deficiency causes muscle degeneration in mice."Human Molecular Genetics.. Vol. 9 (20). 3047-3054 (2000)

Hagiwara, Y, Sasaoka, T, Araishi K, Imamura M, Yorifuji, H, Nonaka, I, Ozawa E, and Kikuchi, T：“Caveolin-3 缺乏导致小鼠肌肉退化。”人类分子遗传学..卷。

Yasuko Hagiwara et al.: "Caveolin-3 deficiency causes muscle degeneration in mice."Human Molecular Genetics. Vol.9(20). 3047-3054 (2000)

Yasuko Hagiwara 等人：“Caveolin-3 缺乏会导致小鼠肌肉退化。”人类分子遗传学。