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Overexpression of LARGE suppresses muscle regeneration in model mice of muscular dystrophy

  • P1-321
  • 斉藤 史明 / Fumiaki Saito:1 金川 基 / Motoi Kanagawa:2 池田 美樹 / Miki Ikeda:1 萩原 宏毅 / Hiroki Hagiwara:1,3 真先 敏弘 / Toshihiro Masaki:1,3 大熊 秀彦 / Hidehiko Ohkuma:1 片野坂 友紀 / Yuki Katanosaka:4 清水 輝夫 / Teruo Shimizu:5 園生 雅弘 / Masahiro Sonoo:1 戸田 達史 / Tatsushi Toda:2 松村 喜一郎 / Kiichiro Matsumura:1 
  • 1:帝京大・医・神経内科 / Dept Neurol, Teikyo Univ, Tokyo, Japan 2:神戸大院・医・神経内科/分子脳科学 / Dept of Neurol/Mol Brain Sci, Univ of Kobe, Kobe, Japan 3:帝京科学大・医療技術科学 / Dept of Med Sci, Teikyo Univ of Sci, Uenohara/Tokyo, Japan 4:岡山大院・医歯薬・システム生理 / Dept of Cardiovascul Physiol, Okayama Univ, Okayama, Japan 5:帝京大・医療技術 / Dept of Sport and Med Sci, Teikyo Univ  

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 dy2J 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.

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