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 language | English |
|---|---|
| Article number | ddu168 |
| Pages (from-to) | 4543-4558 |
| Number of pages | 16 |
| Journal | Human Molecular Genetics |
| Volume | 23 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - 2014 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
- Medicine(all)
Cite this
Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice. / Saito, Fumiaki; Kanagawa, Motoi; Ikeda, Miki; Hagiwara, Hiroki; Masaki, Toshihiro; Ohkuma, Hidehiko; Katanosaka, Yuki; Shimizu, Teruo; Sonoo, Masahiro; Toda, Tatsushi; Matsumura, Kiichiro.
In: Human Molecular Genetics, Vol. 23, No. 17, ddu168, 2014, p. 4543-4558.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice
AU - Saito, Fumiaki
AU - Kanagawa, Motoi
AU - Ikeda, Miki
AU - Hagiwara, Hiroki
AU - Masaki, Toshihiro
AU - Ohkuma, Hidehiko
AU - Katanosaka, Yuki
AU - Shimizu, Teruo
AU - Sonoo, Masahiro
AU - Toda, Tatsushi
AU - Matsumura, Kiichiro
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84905668632&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905668632&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu168
DO - 10.1093/hmg/ddu168
M3 - Article
C2 - 24722207
AN - SCOPUS:84905668632
VL - 23
SP - 4543
EP - 4558
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 17
M1 - ddu168
ER -