Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice

Fumiaki Saito, Motoi Kanagawa, Miki Ikeda, Hiroki Hagiwara, Toshihiro Masaki, Hidehiko Ohkuma, Yuki Katanosaka, Teruo Shimizu, Masahiro Sonoo, Tatsushi Toda, Kiichiro Matsumura

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19 Citations (Scopus)

Abstract

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)stronglyenhancesthe 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 inanaggravation ofmuscular dystrophy. Usingmorphometric analyses,wefound 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.

Original languageEnglish
Article numberddu168
Pages (from-to)4543-4558
Number of pages16
JournalHuman Molecular Genetics
Volume23
Issue number17
DOIs
Publication statusPublished - Sep 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Saito, F., Kanagawa, M., Ikeda, M., Hagiwara, H., Masaki, T., Ohkuma, H., Katanosaka, Y., Shimizu, T., Sonoo, M., Toda, T., & Matsumura, K. (2014). Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice. Human Molecular Genetics, 23(17), 4543-4558. [ddu168]. https://doi.org/10.1093/hmg/ddu168