Negamycin Restores Dystrophin Expression in Skeletal and Cardiac Muscles of mdx Mice

Masayuki Arakawa; Masataka Shiozuka; Yuki Nakayama; Takahiko Hara; Masa Hamada; Shin'ichi Kondo; Daishiro Ikeda; Yoshikazu Takahashi; Ryuichi Sawa; Yoshiaki Nonomura; Kianoush Sheykholeslami; Kenji Kondo; Kimitaka Kaga; Toshio Kitamura; Yuko Suzuki-Miyagoe; Shin'ichi Takeda; Ryoichi Matsuda

doi:10.1093/jb/mvg203

Negamycin Restores Dystrophin Expression in Skeletal and Cardiac Muscles of mdx Mice

Masayuki Arakawa, Masataka Shiozuka, Yuki Nakayama, Takahiko Hara, Masa Hamada, Shin'ichi Kondo, Daishiro Ikeda, Yoshikazu Takahashi, Ryuichi Sawa, Yoshiaki Nonomura, Kianoush Sheykholeslami, Kenji Kondo, Kimitaka Kaga, Toshio Kitamura, Yuko Suzuki-Miyagoe, Shin'ichi Takeda, Ryoichi Matsuda

Author information

Masayuki Arakawa
Department of Life Sciences, The University of Tokyo
Masataka Shiozuka
Department of Life Sciences, The University of Tokyo
Yuki Nakayama
Department of Tumor Biochemistry, Tokyo Metropolitan Institute of Medical Sciences
Takahiko Hara
Department of Tumor Biochemistry, Tokyo Metropolitan Institute of Medical Sciences
Masa Hamada
The Institute Tokyo
Shin'ichi Kondo
The Institute Tokyo
Daishiro Ikeda
The Institute Tokyo
Yoshikazu Takahashi
The Institute Tokyo
Ryuichi Sawa
The Institute Tokyo
Yoshiaki Nonomura
The Institute Tokyo
Kianoush Sheykholeslami
Department of Otolaryngology, The University of Tokyo
Kenji Kondo
Department of Otolaryngology, The University of Tokyo
Kimitaka Kaga
Department of Otolaryngology, The University of Tokyo
Toshio Kitamura
Division of Cellular TheraDv. The Institute of Medical Science. The University of Tokyo
Yuko Suzuki-Miyagoe
Department of Molecular Therapy, National Institute of Neuroscience
Shin'ichi Takeda
Department of Molecular Therapy, National Institute of Neuroscience
Ryoichi Matsuda
Department of Life Sciences, The University of Tokyo

Keywords: dystrophin, mdx mouse, muscular dystrophy, negamycin, nonsense mutation

JOURNAL FREE ACCESS

2003 Volume 134 Issue 5 Pages 751-758

DOI https://doi.org/10.1093/jb/mvg203

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Abstract

The ability of aminoglycoside antibiotics to promote read-through of nonsense muta diseases. However, the toxicity of aminoglycoside antibiotics may result in severe side effects during long-term treatment. In this paper, we report that negamycin, a dipeptide antibiotic, also restores dystrophin expression in skeletal and cardiac muscles of the mdx mouse, an animal model of Duchenne muscular dystrophy (DMD) with a nonsense mutation in the dystrophin gene, and in cultured mdx myotubes. Dystrophin expression was confirmed by immunohistochemistry and immunoblotting. We also compared the toxicity of negamycin and gentamicin, and found negamycin to be less toxic. Furthermore, we demonstrate that negamycin binds to a partial sequence of the eukaryotic rRNA-decoding A-site. We conclude that negamycin is a promising new therapeutic candidate for DMD and other genetic diseases caused by nonsense mutations.

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