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Published online 9 September 2002. doi:10.1083/jcb.200204076
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© The Rockefeller University Press, 0021-9525/2002/9/1097 $5.00
The Journal of Cell Biology, Volume 158, Number 6, September 16, 2002 1097-1107

Article

{alpha}1-Syntrophin–deficient skeletal muscle exhibits hypertrophy and aberrant formation of neuromuscular junctions during regeneration



Yukio Hosaka1,2, Toshifumi Yokota1,3, Yuko Miyagoe-Suzuki1, Katsutoshi Yuasa1, Michihiro Imamura1, Ryoichi Matsuda4, Takaaki Ikemoto5, Shuhei Kameya6 and Shin'ichi Takeda1

1 Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira 187-8502, Tokyo, Japan
2 Department of Neurology, Nakadori General Hospital, Akita 010-8577, Japan
3 Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-8654, Japan
4 Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, Japan
5 Department of Pharmacology, Saitama Medical School, Moroyama-machi, Saitama 350-0495, Japan
6 Department of Ophthalmology, Akita University, Akita 010-8543, Japan

Address correspondence to Shin'ichi Takeda, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, 187-8502 Kodaira, Tokyo, Japan. Tel.: 81-42-346-1720. Fax: 81-42-346-1750. E-mail: takeda{at}ncnp.go.jp

{alpha}1-Syntrophin is a member of the family of dystrophin-associated proteins; it has been shown to recruit neuronal nitric oxide synthase and the water channel aquaporin-4 to the sarcolemma by its PSD-95/SAP-90, Discs-large, ZO-1 homologous domain. To examine the role of {alpha}1-syntrophin in muscle regeneration, we injected cardiotoxin into the tibialis anterior muscles of {alpha}1-syntrophin–null ({alpha}1syn-/-) mice. After the treatment, {alpha}1syn-/- muscles displayed remarkable hypertrophy and extensive fiber splitting compared with wild-type regenerating muscles, although the untreated muscles of the mutant mice showed no gross histological change. In the hypertrophied muscles of the mutant mice, the level of insulin-like growth factor-1 transcripts was highly elevated. Interestingly, in an early stage of the regeneration process, {alpha}1syn-/- mice showed remarkably deranged neuromuscular junctions (NMJs), accompanied by impaired ability to exercise. The contractile forces were reduced in {alpha}1syn-/- regenerating muscles. Our results suggest that the lack of {alpha}1-syntrophin might be responsible in part for the muscle hypertrophy, abnormal synapse formation at NMJs, and reduced force generation during regeneration of dystrophin-deficient muscle, all of which are typically observed in the early stages of Duchenne muscular dystrophy patients.

Key Words: {alpha}1-syntrophin; skeletal muscle; hypertrophy; regeneration; neuromuscular junction


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