Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice.
Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice.
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DOI：
10.1093/hmg/ddu168
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发表时间：
2014-09
影响因子：
3.5
通讯作者：
F. Saito;M. Kanagawa;M. Ikeda;H. Hagiwara;T. Masaki;Hidehiko Ohkuma;Y. Katanosaka;Teruo Shimizu;M. Sonoo;T. Toda;K. Matsumura
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文献类型：
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作者：
F. Saito;M. Kanagawa;M. Ikeda;H. Hagiwara;T. Masaki;Hidehiko Ohkuma;Y. Katanosaka;Teruo Shimizu;M. Sonoo;T. Toda;K. Matsumura
几种类型的肌营养不良症是由α-DG(α-DG)和层粘连蛋白之间的连接缺陷引起的。其中，糖营养不良症，包括福山型先天性肌营养不良症，是由α-DG糖基化异常引起的。最近的研究表明，类-乙酰氨基葡萄糖基转移酶(LIG)强烈增强α-DG的层粘连蛋白结合活性。因此，大规模恢复α-DG-层粘连蛋白连接被认为是治疗肌营养不良症最有前景的可能疗法之一。在这项研究中，我们建立了过表达大(大TG)的转基因小鼠，并将它们分别与Dy(2J)小鼠和Fukutin条件性基因敲除小鼠(层粘连蛋白α2缺陷型先天性肌营养不良症和FCMD模型)杂交。值得注意的是，在这两个菌株中，转基因的Large基因的过度表达导致了肌肉营养不良的加重。通过形态计量学分析，我们发现肌肉病理的恶化是由于肌肉再生受到抑制所致。在C2C12细胞中过表达的Large进一步表明肌管形成存在缺陷。有趣的是，胰岛素样生长因子1(IGF-1)的表达在大型TG小鼠和大量过度表达C2C12肌管中都被证实降低。补充IGF-1的C2C12细胞修复了有缺陷的肌管形成。综上所述，我们的研究结果表明，大蛋白的过度表达通过抑制肌肉再生来加重肌营养不良，这种不利影响是通过减少IGF-1的表达来实现的。
Several types of muscular dystrophy are caused by defective linkage between α-dystroglycan (α-DG) and laminin. Among these, dystroglycanopathy, including Fukuyama-type congenital muscular dystrophy (FCMD), results from abnormal glycosylation of α-DG. Recent studies have shown that like-acetylglucosaminyltransferase (LARGE) strongly enhances the laminin-binding activity of α-DG. Therefore, restoration of the α-DG-laminin linkage by LARGE is considered one of the most promising possible therapies for muscular dystrophy. In this study, we generated transgenic mice that overexpress LARGE (LARGE Tg) and crossed them with dy(2J) mice and fukutin conditional knockout mice, a model for laminin α2-deficient congenital muscular dystrophy (MDC1A) and FCMD, respectively. Remarkably, in both the strains, the transgenic overexpression of LARGE resulted in an aggravation of muscular dystrophy. Using morphometric analyses, we found that the deterioration of muscle pathology was caused by suppression of muscle regeneration. Overexpression of LARGE in C2C12 cells further demonstrated defects in myotube formation. Interestingly, a decreased expression of insulin-like growth factor 1 (IGF-1) was identified in both LARGE Tg mice and LARGE-overexpressing C2C12 myotubes. Supplementing the C2C12 cells with IGF-1 restored the defective myotube formation. Taken together, our findings indicate that the overexpression of LARGE aggravates muscular dystrophy by suppressing the muscle regeneration and this adverse effect is mediated via reduced expression of IGF-1.