Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice.
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.
Department of Neurology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan, f-saito@med.teikyo-u.ac.jp.
Fumiaki
F
Saito
Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Motoi
M
Kanagawa
Department of Neurology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Miki
M
Ikeda
Department of Neurology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan, Department of Medical Science, Teikyo University of Science, Uenohara Campus, Uenohara-shi 409-0193, Japan.
Hiroki
H
Hagiwara
Department of Neurology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan, Department of Medical Science, Teikyo University of Science, Senju Campus, Tokyo 120-0045, Japan.
Toshihiro
T
Masaki
Department of Neurology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Hidehiko
H
Ohkuma
Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8558, Japan and.
Yuki
Y
Katanosaka
Department of Sport and Medical Science, Teikyo University Faculty of Medical Technology, Tokyo 173-8605, Japan.
Teruo
T
Shimizu
Department of Neurology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Masahiro
M
Sonoo
Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Tatsushi
T
Toda
Department of Neurology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Kiichiro
K
Matsumura
D000818:Animals; D002459:Cell Fusion; D002460:Cell Line; D015536:Down-Regulation; D049030:Dystroglycans / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000503:physiopathology*; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D010641:Phenotype; D011506:Proteins / Q000378:metabolism; D012038:Regeneration; D014162:Transfection; D014166:Transferases
D011506:Proteins; D049030:Dystroglycans; D007334:Insulin-Like Growth Factor I; C491879:Fcmd protein, mouse; D014166:Transferases; C502747:Large1 protein, mouse; D017351:N-Acetylglucosaminyltransferases