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Human Molecular Genetics Advance Access originally published online on December 2, 2008
Human Molecular Genetics 2009 18(5):824-834; doi:10.1093/hmg/ddn408
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models

Yuko Iwata1,*, Yuki Katanosaka1, Yuji Arai2, Munekazu Shigekawa1,{dagger} and Shigeo Wakabayashi1

1 Department of Molecular Physiology 2 Department of Bioscience, National Cardiovascular Center Research Institute Suita, Osaka 565-8565, Japan

* To whom correspondence should be addressed at: Department of Molecular Physiology, National Cardiovascular Center Research Institute, Fujishiro-dai 5-7, Suita, Osaka 565-8565, Japan. Tel: +81 668335012; Fax: +81 668355314; Email: yukoiwat{at}ri.ncvc.go.jp

Received August 19, 2008; Accepted December 1, 2008

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.

{dagger} Present address: Department of Human Life Science, Senri Kinran University, Suita, Osaka 565-0873, Japan.


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 Proc. Natl. Acad. Sci. USAHome page
D. P. Millay, S. A. Goonasekera, M. A. Sargent, M. Maillet, B. J. Aronow, and J. D. Molkentin
Calcium influx is sufficient to induce muscular dystrophy through a TRPC-dependent mechanism
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[Abstract] [Full Text] [PDF]


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