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

doi:10.1093/hmg/ddu168

Cited by 23 publications

(19 citation statements)

References 64 publications

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“…For example, because glycosylation levels of α-DG and the expression levels of LARGE change during muscle differentiation and regeneration 36 , excess glycosylation may disturb cellular homeostasis and tissue regeneration. In fact, LARGE overexpression in C2C12 myoblasts impairs differentiation 42 . Furthermore, there may be situations or cells in which glycosylation is physiologically unnecessary even in wild-type tissues 34 .…”

Section: Discussionmentioning

confidence: 98%

“…However, LARGE overexpression in cells lacking GTDC2 expression or POMT1 activity did not induce hyperglycosylation of α-DG 9 40 . Moreover, some studies have shown the beneficial effects of LARGE overexpression in POMGnT1 - or FKRP -mutant mice 38 39 , but others showed a deterioration in FKRP - or fukutin -mutant mice crossed with LARGE-overexpressing transgenic mice 41 42 . Thus, it remains unclear whether LARGE could be a target molecule for α-DGP treatment.…”

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confidence: 99%

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Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression

Ohtsuka

Kanagawa

et al. 2015

Sci Rep

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α-Dystroglycanopathy (α-DGP) is a group of muscular dystrophy characterized by abnormal glycosylation of α-dystroglycan (α-DG), including Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease, Walker-Warburg syndrome, and congenital muscular dystrophy type 1D (MDC1D), etc. LARGE, the causative gene for MDC1D, encodes a glycosyltransferase to form [-3Xyl-α1,3GlcAβ1-] polymer in the terminal end of the post-phosphoryl moiety, which is essential for α-DG function. It has been proposed that LARGE possesses the great potential to rescue glycosylation defects in α-DGPs regardless of causative genes. However, the in vivo therapeutic benefit of using LARGE activity is controversial. To explore the conditions needed for successful LARGE gene therapy, here we used Large-deficient and fukutin-deficient mouse models for MDC1D and FCMD, respectively. Myofibre-selective LARGE expression via systemic adeno-associated viral gene transfer ameliorated dystrophic pathology of Large-deficient mice even when intervention occurred after disease manifestation. However, the same strategy failed to ameliorate the dystrophic phenotype of fukutin-conditional knockout mice. Furthermore, forced expression of Large in fukutin-deficient embryonic stem cells also failed to recover α-DG glycosylation, however coexpression with fukutin strongly enhanced α-DG glycosylation. Together, our data demonstrated that fukutin is required for LARGE-dependent rescue of α-DG glycosylation, and thus suggesting new directions for LARGE-utilizing therapy targeted to myofibres.

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression

Ohtsuka

Kanagawa

et al. 2015

Sci Rep

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“…Numerous emerging therapeutic questions in the CMD to be addressed in the shorter term were discussed and led to the following conclusions:

In the dystroglycanopathies prednisone seems to be ready for a clinical trial, and should be tested in fukutin and FKRP mouse models. Further questions to address are the applicability of LARGE upregulation, as well as its limitations since its transgenic upregulation on disease backgrounds has been shown to be deleterious [58,59], modeling cardiac disease in the mouse model, and the question whether the CNS diseases can be influenced by therapeutic interventions. The applicability of AAV-mediated gene transfer therapy could be assessed in various genetic models.

For LAMA2 -CMD, the critical question remaining unanswered is to identify the different driving mechanisms at different stages of the disease.

…”

Section: Translational Link To the Clinicmentioning

confidence: 99%

“…Further questions to address are the applicability of LARGE upregulation, as well as its limitations since its transgenic upregulation on disease backgrounds has been shown to be deleterious [58,59], modeling cardiac disease in the mouse model, and the question whether the CNS diseases can be influenced by therapeutic interventions. The applicability of AAV-mediated gene transfer therapy could be assessed in various genetic models.…”

Section: Translational Link To the Clinicmentioning

confidence: 99%

212th ENMC International Workshop:

Durbeej

Allamand

Bonaldo³

et al. 2016

Neuromuscular Disorders

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“…Overexpression of LARGE via an adenoviral vector is capable of hyperglycosylating skeletal muscle α-DG in vivo [19]. Although LARGE overexpression by transgenic approach exacerbates muscular dystrophy in FKRP knock-down mice [20] and fukutin knockout mice [21] thought to be caused by inhibition of regeneration from satellite cells, we have shown that LARGE expression ameliorates muscular dystrophy in LARGE mutant and POMGnT1 knockout mice when delivered systemically by an adeno-associated viral vector 9 (AAV9) after birth [22]. Furthermore, AAV-mediated expression of LARGE, fukutin-related protein, or B4GALNT2 (GALGT2) ameliorates muscular dystrophic phenotype in FKRP mutant mice [23,24,25] and in a mouse model bearing a pathogenic human FKRP mutation [26].…”

Section: Introductionmentioning

confidence: 99%

Postnatal Gene Therapy Improves Spatial Learning Despite the Presence of Neuronal Ectopia in a Model of Neuronal Migration Disorder

Liu

Bampoe

et al. 2016

Genes

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Patients with type II lissencephaly, a neuronal migration disorder with ectopic neurons, suffer from severe mental retardation, including learning deficits. There is no effective therapy to prevent or correct the formation of neuronal ectopia, which is presumed to cause cognitive deficits. We hypothesized that learning deficits were not solely caused by neuronal ectopia and that postnatal gene therapy could improve learning without correcting the neuronal ectopia formed during fetal development. To test this hypothesis, we evaluated spatial learning of cerebral cortex-specific protein O-mannosyltransferase 2 (POMT2, an enzyme required for O-mannosyl glycosylation) knockout mice and compared to the knockout mice that were injected with an adeno-associated viral vector (AAV) encoding POMT2 into the postnatal brains with Barnes maze. The data showed that the knockout mice exhibited reduced glycosylation in the cerebral cortex, reduced dendritic spine density on CA1 neurons, and increased latency to the target hole in the Barnes maze, indicating learning deficits. Postnatal gene therapy restored functional glycosylation, rescued dendritic spine defects, and improved performance on the Barnes maze by the knockout mice even though neuronal ectopia was not corrected. These results indicate that postnatal gene therapy improves spatial learning despite the presence of neuronal ectopia.

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

Cited by 23 publications

References 64 publications

Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression

Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression

212th ENMC International Workshop:

Postnatal Gene Therapy Improves Spatial Learning Despite the Presence of Neuronal Ectopia in a Model of Neuronal Migration Disorder

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