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Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice

Masashi Nakatani^*,, Yuka Takehara, Hiromu Sugino^,1, Mitsuru Matsumoto, Osamu Hashimoto, Yoshihisa Hasegawa, Tatsuya Murakami^*, Akiyoshi Uezumi^*, Shin’ichi Takeda, Sumihare Noji^||, Yoshihide Sunada and Kunihiro Tsuchida^*,2

^* Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Sciences, Fujita Health University, Toyoake, Aichi, Japan;

The Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan;

Laboratories of Experimental Animal Science, Kitasato University School of Veterinary Medicine and Animal Sciences, Towada, Aomori, Japan;

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan;

^|| Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, Tokushima, Japan; and

Division of Neurology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan

²Correspondence: Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Sciences (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan. E-mail: tsuchida{at}fujita-hu.ac.jp

Myostatin is a potent negative regulator of skeletal muscle growth. Therefore, myostatin inhibition offers a novel therapeutic strategy for muscular dystrophy by restoring skeletal muscle mass and suppressing the progression of muscle degeneration. The known myostatin inhibitors include myostatin propeptide, follistatin, follistatin-related proteins, and myostatin antibodies. Although follistatin shows potent myostatin-inhibiting activities, it also acts as an efficient inhibitor of activins. Because activins are involved in multiple functions in various organs, their blockade by follistatin would affect multiple tissues other than skeletal muscles. In the present study, we report the characterization of a myostatin inhibitor derived from follistatin, which does not affect activin signaling. The dissociation constants (K_d) of follistatin to activin and myostatin are 1.72 nM and 12.3 nM, respectively. By contrast, the dissociation constants (K_d) of a follistatin-derived myostatin inhibitor, designated FS I-I, to activin and myostatin are 64.3 µM and 46.8 nM, respectively. Transgenic mice expressing FS I-I, under the control of a skeletal muscle-specific promoter showed increased skeletal muscle mass and strength. Hyperplasia and hypertrophy were both observed. We crossed FS I-I transgenic mice with mdx mice, a model for Duchenne muscular dystrophy. Notably, the skeletal muscles in the mdx/FS I-I mice showed enlargement and reduced cell infiltration. Muscle strength is also recovered in the mdx/FS I-I mice. These results indicate that myostatin blockade by FS I-I has a therapeutic potential for muscular dystrophy.—Nakatani, M., Takehara, Y., Sugino, H., Matsumoto, M., Hashimoto, O., Hasegawa, Y., Murakami, T., Uezumi, A., Takeda, S., Noji, S., Sunada, Y., Tsuchida, K. Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice.

Key Words: Duchenne muscular dystrophy • activin • therapy • myostatin blockade

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