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) 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.
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Authors | Fumiaki Saito, Motoi Kanagawa, Miki Ikeda, Hiroki Hagiwara, Toshihiro Masaki, Hidehiko Ohkuma, Yuki Katanosaka, Teruo Shimizu, Masahiro Sonoo, Tatsushi Toda, Kiichiro Matsumura |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 23
Issue 17
Pg. 4543-58
(Sep 01 2014)
ISSN: 1460-2083 [Electronic] England |
PMID | 24722207
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]. |
Chemical References |
- Proteins
- Dystroglycans
- Insulin-Like Growth Factor I
- Fcmd protein, mouse
- Transferases
- Large1 protein, mouse
- N-Acetylglucosaminyltransferases
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Topics |
- Animals
- Cell Fusion
- Cell Line
- Down-Regulation
- Dystroglycans
(metabolism)
- Glycosylation
- Humans
- Insulin-Like Growth Factor I
(metabolism)
- Mice
- Mice, Transgenic
- Muscle Fibers, Skeletal
(metabolism, pathology)
- Muscle, Skeletal
(physiopathology)
- Muscular Dystrophy, Animal
(metabolism, physiopathology)
- Myoblasts
(metabolism, pathology)
- N-Acetylglucosaminyltransferases
(metabolism)
- Phenotype
- Proteins
(metabolism)
- Regeneration
- Transfection
- Transferases
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