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

91 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 - 2009
Externally publishedYes

Fingerprint

Muscular Dystrophies
Inbred mdx Mouse
Animal Models
Muscles
Dystrophin
Cricetinae
Transgenic Mice
Sarcoglycans
Transient Receptor Potential Channels
Muscle Weakness
Creatine Kinase
Adenoviridae
Glycoproteins
Skeletal Muscle
Fibrosis
Apoptosis
Pathology
Membranes
Serum
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models. / Iwata, Yuko; Katanosaka, Yuki; Arai, Yuji; Shigekawa, Munekazu; Wakabayashi, Shigeo.

In: Human Molecular Genetics, Vol. 18, No. 5, 2009, p. 824-834.

Research output: Contribution to journalArticle

Iwata, Yuko ; Katanosaka, Yuki ; Arai, Yuji ; Shigekawa, Munekazu ; Wakabayashi, Shigeo. / Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 5. pp. 824-834.
@article{ace44fb794964b0abfa2e2175988b0ae,
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 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.",
author = "Yuko Iwata and Yuki Katanosaka and Yuji Arai and Munekazu Shigekawa and Shigeo Wakabayashi",
year = "2009",
doi = "10.1093/hmg/ddn408",
language = "English",
volume = "18",
pages = "824--834",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models

AU - Iwata, Yuko

AU - Katanosaka, Yuki

AU - Arai, Yuji

AU - Shigekawa, Munekazu

AU - Wakabayashi, Shigeo

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=60549111210&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=60549111210&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddn408

DO - 10.1093/hmg/ddn408

M3 - Article

C2 - 19050039

AN - SCOPUS:60549111210

VL - 18

SP - 824

EP - 834

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 5

ER -