Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice

Kaori Ito, Shigemi Kimura, Shiro Ozasa, Makoto Matsukura, Makoto Ikezawa, Kowashi Yoshioka, Hiroe Ueno, Misao Suzuki, Kimi Araki, Ken Ichi Yamamura, Takeshi Miwa, George Dickson, Gail D. Thomas, Teruhisa Miike

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disease caused by mutations of the gene encoding the cytoskeletal protein dystrophin. Therapeutic options for DMD are limited because the pathogenetic mechanism by which dystrophin deficiency produces the clinical phenotype remains obscure. Recent reports of abnormal α-adrenergic vasoregulation in the exercising muscles of DMD patients and in the mdx mouse, an animal model of DMD, prompted us to hypothesize that the dystrophin-deficient smooth muscle contributes to the vascular and dystrophic phenotypes of DMD. To test this, we generated transgenic mdx mice that express dystrophin only in smooth muscle (SMTg/mdx). We found that α-adrenergic vasoconstriction was markedly attenuated in the contracting hindlimbs of C57BL/10 wild-type mice, an effect that was mediated by nitric oxide (NO) and was severely impaired in the mdx mice. SMTg/mdx mice showed an intermediate phenotype, with partial restoration of the NO-dependent modulation of α-adrenergic vasoconstriction in active muscle. In addition, the elevated serum creatine kinase levels observed in mdx mice were significantly reduced in SMTg/mdx mice. This is the first report of a functional role of dystrophin in vascular smooth muscle.

Original languageEnglish (US)
Pages (from-to)2266-2275
Number of pages10
JournalHuman Molecular Genetics
Volume15
Issue number14
DOIs
StatePublished - Jul 15 2006

Fingerprint

Inbred mdx Mouse
Dystrophin
Duchenne Muscular Dystrophy
Smooth Muscle
Adrenergic Agents
Vasoconstriction
Phenotype
Muscles
Nitric Oxide
Wasting Syndrome
Cytoskeletal Proteins
Hindlimb
Creatine Kinase
Vascular Smooth Muscle
Transgenic Mice
Blood Vessels
Animal Models
Mutation
Serum
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Ito, K., Kimura, S., Ozasa, S., Matsukura, M., Ikezawa, M., Yoshioka, K., ... Miike, T. (2006). Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice. Human Molecular Genetics, 15(14), 2266-2275. https://doi.org/10.1093/hmg/ddl151
Ito, Kaori ; Kimura, Shigemi ; Ozasa, Shiro ; Matsukura, Makoto ; Ikezawa, Makoto ; Yoshioka, Kowashi ; Ueno, Hiroe ; Suzuki, Misao ; Araki, Kimi ; Yamamura, Ken Ichi ; Miwa, Takeshi ; Dickson, George ; Thomas, Gail D. ; Miike, Teruhisa. / Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice. In: Human Molecular Genetics. 2006 ; Vol. 15, No. 14. pp. 2266-2275.
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abstract = "Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disease caused by mutations of the gene encoding the cytoskeletal protein dystrophin. Therapeutic options for DMD are limited because the pathogenetic mechanism by which dystrophin deficiency produces the clinical phenotype remains obscure. Recent reports of abnormal α-adrenergic vasoregulation in the exercising muscles of DMD patients and in the mdx mouse, an animal model of DMD, prompted us to hypothesize that the dystrophin-deficient smooth muscle contributes to the vascular and dystrophic phenotypes of DMD. To test this, we generated transgenic mdx mice that express dystrophin only in smooth muscle (SMTg/mdx). We found that α-adrenergic vasoconstriction was markedly attenuated in the contracting hindlimbs of C57BL/10 wild-type mice, an effect that was mediated by nitric oxide (NO) and was severely impaired in the mdx mice. SMTg/mdx mice showed an intermediate phenotype, with partial restoration of the NO-dependent modulation of α-adrenergic vasoconstriction in active muscle. In addition, the elevated serum creatine kinase levels observed in mdx mice were significantly reduced in SMTg/mdx mice. This is the first report of a functional role of dystrophin in vascular smooth muscle.",
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Ito, K, Kimura, S, Ozasa, S, Matsukura, M, Ikezawa, M, Yoshioka, K, Ueno, H, Suzuki, M, Araki, K, Yamamura, KI, Miwa, T, Dickson, G, Thomas, GD & Miike, T 2006, 'Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice', Human Molecular Genetics, vol. 15, no. 14, pp. 2266-2275. https://doi.org/10.1093/hmg/ddl151

Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice. / Ito, Kaori; Kimura, Shigemi; Ozasa, Shiro; Matsukura, Makoto; Ikezawa, Makoto; Yoshioka, Kowashi; Ueno, Hiroe; Suzuki, Misao; Araki, Kimi; Yamamura, Ken Ichi; Miwa, Takeshi; Dickson, George; Thomas, Gail D.; Miike, Teruhisa.

In: Human Molecular Genetics, Vol. 15, No. 14, 15.07.2006, p. 2266-2275.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice

AU - Ito, Kaori

AU - Kimura, Shigemi

AU - Ozasa, Shiro

AU - Matsukura, Makoto

AU - Ikezawa, Makoto

AU - Yoshioka, Kowashi

AU - Ueno, Hiroe

AU - Suzuki, Misao

AU - Araki, Kimi

AU - Yamamura, Ken Ichi

AU - Miwa, Takeshi

AU - Dickson, George

AU - Thomas, Gail D.

AU - Miike, Teruhisa

PY - 2006/7/15

Y1 - 2006/7/15

N2 - Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disease caused by mutations of the gene encoding the cytoskeletal protein dystrophin. Therapeutic options for DMD are limited because the pathogenetic mechanism by which dystrophin deficiency produces the clinical phenotype remains obscure. Recent reports of abnormal α-adrenergic vasoregulation in the exercising muscles of DMD patients and in the mdx mouse, an animal model of DMD, prompted us to hypothesize that the dystrophin-deficient smooth muscle contributes to the vascular and dystrophic phenotypes of DMD. To test this, we generated transgenic mdx mice that express dystrophin only in smooth muscle (SMTg/mdx). We found that α-adrenergic vasoconstriction was markedly attenuated in the contracting hindlimbs of C57BL/10 wild-type mice, an effect that was mediated by nitric oxide (NO) and was severely impaired in the mdx mice. SMTg/mdx mice showed an intermediate phenotype, with partial restoration of the NO-dependent modulation of α-adrenergic vasoconstriction in active muscle. In addition, the elevated serum creatine kinase levels observed in mdx mice were significantly reduced in SMTg/mdx mice. This is the first report of a functional role of dystrophin in vascular smooth muscle.

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Ito K, Kimura S, Ozasa S, Matsukura M, Ikezawa M, Yoshioka K et al. Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice. Human Molecular Genetics. 2006 Jul 15;15(14):2266-2275. https://doi.org/10.1093/hmg/ddl151