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

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

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)824-834
Number of pages11
JournalHuman Molecular Genetics
Volume18
Issue number5
DOIs
Publication statusPublished - Feb 25 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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