期刊
HUMAN MOLECULAR GENETICS
卷 18, 期 5, 页码 824-834出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddn408
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [18077015, 19390080, 17659241]
- Promotion of Fundamental Studies in Health Sciences of National Institute of Biomedical Innovation (NIBIO)
- Cardiovascular Diseases [17A-1]
- Ministry of Health, Labor, and Welfare [16B-2, 19A-7]
- Takeda Science Foundation
- Salt Science Research Foundation [0737]
- Grants-in-Aid for Scientific Research [19390080, 17659241, 18077015] Funding Source: KAKEN
Muscular dystrophy is a severe degenerative disorder of skeletal muscle characterized by progressive muscle weakness. One subgroup of this disease is caused by a defect in the gene encoding one of the components of the dystrophin-glycoprotein complex, resulting in a significant disruption of membrane integrity and/or stability and, consequently, a sustained increase in the cytosolic Ca2+ concentration ([Ca2+](i)). In the present study, we demonstrate that muscular dystrophy is ameliorated in two animal models, dystrophin-deficient mdx mice and delta-sarcoglycan-deficient BIO14.6 hamsters by dominant-negative inhibition of the transient receptor potential cation channel, TRPV2, a principal candidate for Ca2+-entry pathways. When transgenic (Tg) mice expressing a TRPV2 mutant in muscle were crossed with mdx mice, the [Ca2+](i) increase in muscle fibers was reduced by dominant-negative inhibition of endogenous TRPV2. Furthermore, histological, biochemical and physiological indices characterizing dystrophic pathology, such as an increased number of central nuclei and fiber size variability/fibrosis/apoptosis, elevated serum creatine kinase levels, and reduced muscle performance, were all ameliorated in the mdx/Tg mice. Similar beneficial effects were also observed in the muscles of BIO14.6 hamsters infected with adenovirus carrying mutant TRPV2. We propose that TRPV2 is a principal Ca2+-entry route leading to a sustained [Ca2+](i) increase and muscle degeneration, and that it is a promising therapeutic target for the treatment of muscular dystrophy.
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