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

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 Ca(2+) concentration ([Ca(2+)](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 Ca(2+)-entry pathways. When transgenic (Tg) mice expressing a TRPV2 mutant in muscle were crossed with mdx mice, the [Ca(2+)](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 Ca(2+)-entry route leading to a sustained [Ca(2+)](i) increase and muscle degeneration, and that it is a promising therapeutic target for the treatment of muscular dystrophy.

• Authors: Yuko Iwata, Yuki Katanosaka, Yuji Arai, Munekazu Shigekawa, Shigeo Wakabayashi
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 18 Issue 5 Pg. 824-34 (Mar 01 2009) ISSN: 1460-2083 [Electronic] England
• PMID: 19050039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels
• TRPV Cation Channels
• Trpv2 protein, mouse
• Calcium

Topics

• Adenoviridae (genetics, metabolism)
• Animals
• Calcium (metabolism)
• Calcium Channels (genetics, metabolism)
• Cell Line
• Cricetinae
• Disease Models, Animal
• Down-Regulation
• Genetic Vectors (genetics, metabolism)
• Humans
• Mice
• Mice, Inbred mdx
• Mice, Transgenic
• Muscle, Skeletal (metabolism)
• Muscular Dystrophies (genetics, metabolism)
• TRPV Cation Channels (genetics, metabolism)