Impaired viability of muscle precursor cells in muscular dystrophy with glycosylation defects and amelioration of its severe phenotype by limited gene expression
| Autor: | Chiyomi Ito, Tatsushi Toda, So-ichiro Fukada, Kanoko Sato, Chih Chieh Yu, Masako Hozoji-Inada, Takahito Ito, Megumi Matsuo, Motoi Kanagawa, Tomoko Chiyo, Kazuhiro Kobayashi, Yuki Katanosaka, Keiji Naruse, Yuko Miyagoe-Suzuki, Masahiko Yamaguchi, Takashi Okada, Shin'ichi Takeda, Atsushi Kuga, Yoshihisa Ohtsuka |
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| Rok vydání: | 2013 |
| Předmět: |
Glycosylation
Cell Survival Genetic enhancement Gene Expression Biology Muscular Dystrophies Myoblasts Mice Transferases Precursor cell Fukuyama congenital muscular dystrophy Genetics medicine Dystroglycan Myocyte Animals Muscular dystrophy Dystroglycans Muscle Skeletal Molecular Biology Genetics (clinical) Mice Knockout Proteins General Medicine medicine.disease Fukutin Disease Models Animal Phenotype Cancer research biology.protein Myogenic Regulatory Factor 5 ITGA7 |
| Zdroj: | Human molecular genetics. 22(15) |
| ISSN: | 1460-2083 |
| Popis: | A group of muscular dystrophies, dystroglycanopathy is caused by abnormalities in post-translational modifications of dystroglycan (DG). To understand better the pathophysiological roles of DG modification and to establish effective clinical treatment for dystroglycanopathy, we here generated two distinct conditional knock-out (cKO) mice for fukutin, the first dystroglycanopathy gene identified for Fukuyama congenital muscular dystrophy. The first dystroglycanopathy model-myofiber-selective fukutin-cKO [muscle creatine kinase (MCK)-fukutin-cKO] mice-showed mild muscular dystrophy. Forced exercise experiments in presymptomatic MCK-fukutin-cKO mice revealed that myofiber membrane fragility triggered disease manifestation. The second dystroglycanopathy model-muscle precursor cell (MPC)-selective cKO (Myf5-fukutin-cKO) mice-exhibited more severe phenotypes of muscular dystrophy. Using an isolated MPC culture system, we demonstrated, for the first time, that defects in the fukutin-dependent modification of DG lead to impairment of MPC proliferation, differentiation and muscle regeneration. These results suggest that impaired MPC viability contributes to the pathology of dystroglycanopathy. Since our data suggested that frequent cycles of myofiber degeneration/regeneration accelerate substantial and/or functional loss of MPC, we expected that protection from disease-triggering myofiber degeneration provides therapeutic effects even in mouse models with MPC defects; therefore, we restored fukutin expression in myofibers. Adeno-associated virus (AAV)-mediated rescue of fukutin expression that was limited in myofibers successfully ameliorated the severe pathology even after disease progression. In addition, compared with other gene therapy studies, considerably low AAV titers were associated with therapeutic effects. Together, our findings indicated that fukutin-deficient dystroglycanopathy is a regeneration-defective disorder, and gene therapy is a feasible treatment for the wide range of dystroglycanopathy even after disease progression. |
| Databáze: | OpenAIRE |
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