Journal Article

Dominant-negative inhibition of Ca<sup>2+</sup> influx via TRPV2 ameliorates muscular dystrophy in animal models

Yuko Iwata, Yuki Katanosaka, Yuji Arai, Munekazu Shigekawa and Shigeo Wakabayashi

in Human Molecular Genetics

Volume 18, issue 5, pages 824-834
Published in print March 2009 | ISSN: 0964-6906
Published online December 2008 | e-ISSN: 1460-2083 | DOI:
Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models

Show Summary Details


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 δ-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.

Journal Article.  6739 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.