title: 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.affiliation: Department of Molecular Physiology, National Cardiovascular Center Research Institute Suita, Osaka 565-8565, Japan. yukoiwat@ri.ncvc.go.jp
authors.forename: Yuko
authors.initials: Y
authors.lastname: Iwata
authors.forename: Yuki
authors.initials: Y
authors.lastname: Katanosaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.forename: Munekazu
authors.initials: M
authors.lastname: Shigekawa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Wakabayashi
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004195:Disease Models, Animal; D015536:Down-Regulation; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D050916:TRPV Cation Channels; C485717:Trpv2 protein, mouse; D002118:Calcium