Skeletal myopathy in mice over-expressing the human myotonic dystrophy protein kinase (DMPK) gene

Monica A. Narang, James D. Waring, Luc A. Sabourin, Evica Rajcan-Separovic, David Parry, Frank Jirik, Robert G. Korneluk
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引用次数: 1

Abstract

Myotonic dystrophy (DM) is caused by the expansion of a trinucleotide repeat located in the 3’-untranslated region of a serine-threonine kinase (DMPK), such that repeat size corresponds with severity of disease and age of onset. The mechanism by which this mutation causes DM remains unclear. Recent reports indicate that over-expression of DMPK in murine C2C12 myoblasts inhibits myogenesis, reminiscent of the marked immaturity observed in DM patient muscle. Accordingly, we generated transgenic mice over-expressing the human DMPK gene with expression enhancing matrix attachment region (MAR) sequences. These mice show substantial over-expression of human DMPK transcript and protein in brain, skeletal muscle, tongue, and eye - tissues typically affected in DM. Cryostat sections of skeletal muscle from these transgenic animals revealed diagnostic hallmarks of DM including increased centronucleation, type 1 fiber atrophy and ringed fibers. Additionally, primary myoblasts established from these mice showed reduced fusion potential indicating a delay or defect in myoblast differentiation. These results suggest that over-expression of the human DMPK gene in these mice confers a skeletal muscle pathology similar to that seen in DM patients.

过度表达人肌强直性营养不良蛋白激酶(DMPK)基因的小鼠骨骼肌病
肌强直性营养不良(DM)是由位于丝氨酸-苏氨酸激酶(DMPK) 3 ' -非翻译区的三核苷酸重复扩增引起的,重复大小与疾病的严重程度和发病年龄相对应。这种突变导致糖尿病的机制尚不清楚。最近的报道表明,DMPK在小鼠C2C12成肌细胞中的过度表达抑制了肌肉的发生,这让人想起了在糖尿病患者肌肉中观察到的明显不成熟。因此,我们构建了具有表达增强基质附着区(MAR)序列的过表达人DMPK基因的转基因小鼠。这些小鼠的大脑、骨骼肌、舌头和眼睛组织中显示了大量的人类DMPK转录物和蛋白的过度表达,这些组织是糖尿病的典型影响。这些转基因动物的骨骼肌低温切片显示了糖尿病的诊断特征,包括核中心化增加、1型纤维萎缩和环状纤维。此外,从这些小鼠中建立的原代成肌细胞显示融合电位降低,表明成肌细胞分化延迟或缺陷。这些结果表明,这些小鼠中人类DMPK基因的过度表达导致骨骼肌病理与糖尿病患者相似。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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