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Human Molecular Genetics, 2001, Vol. 10, No. 3 173-178
© 2001 Oxford University Press

Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity

Yoshihide Sunada1,+, Hiroko Ohi2, Asako Hase2, Hiroaki Ohi3, Tomohiko Hosono4, Satoru Arata4, Shigesada Higuchi3, Kiichiro Matsumura2 and Teruo Shimizu2

1Division of Neurology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki-City, Okayama 701-0192, Japan, 2Department of Neurology and Neuroscience, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan and 3School of Pharmaceutical Sciences and 4Center for Biotechnology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

Caveolin-3 is the muscle-specific isoform of the caveolin protein family, which is a major component of caveolae, small membrane invaginations found in most cell types. Caveolins play important roles in the formation of caveola membranes, acting as scaffolding proteins to organize and concentrate lipid-modified signaling molecules, and modulate a signaling pathway. For instance, caveolin-3 interacts with neuronal nitric oxide synthase (nNOS) and inhibits its catalytic activity. Recently, specific mutations in the caveolin-3 gene, including the Pro104Leu missense mutation, have been shown to cause an autosomal dominant limb-girdle muscular dystrophy (LGMD1C), which is characterized by the deficiency of caveolin-3 in the sarcolemma. However, the molecular mechanism by which these mutations cause the deficiency of caveolin-3 and muscle cell degeneration remains elusive. Here we generated transgenic mice expressing the Pro104Leu mutant caveolin-3. They showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, indicating a dominant negative effect of mutant caveolin-3. Interestingly, we also found a great increase of nNOS activity in their skeletal muscle, which, we propose, may play a role in muscle fiber degeneration in caveolin-3 deficiency.

+ To whom correspondence should be addressed. Tel: +81 86 462 1111; Fax: +81 86 462 1199; Email: ysunada@med.kawasaki-m.ac.jp


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