2009年3月
Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models
HUMAN MOLECULAR GENETICS
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- 巻
- 18
- 号
- 5
- 開始ページ
- 824
- 終了ページ
- 834
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1093/hmg/ddn408
- 出版者・発行元
- OXFORD UNIV PRESS
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.
- リンク情報
- ID情報
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- DOI : 10.1093/hmg/ddn408
- ISSN : 0964-6906
- PubMed ID : 19050039
- Web of Science ID : WOS:000263409100003