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Targeting the Type I TGF-β Receptor for Treating Caveolin-3-Deficient Autosomal Dominant Limb-Girdle Muscular Dystrophy Type 1C and Muscle Wasting Disorders

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Translational Research in Muscular Dystrophy

Abstract

Caveolin-3, the principal scaffold protein in sarcolemmal caveolae, regulates signal transduction and vesicular trafficking. Dominant-negative mutations in the caveolin-3 gene (CAV3) cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C) and autosomal dominant rippling muscle disease (AD-RMD). Myostatin, a member of the muscle-specific transforming growth factor (TGF)-β family, negatively regulates muscle growth and volume. We recently showed that wild-type caveolin-3 binds to and inhibits TGF-β type I receptor (TβRI), thereby suppressing intracellular TGF-β signaling. In contrast, LGMD1C-causing mutant caveolin-3 activates TβRI, resulting in muscle atrophy. Recently, small-molecule compounds suppressing activation of TβRI, also known as activin receptor-like kinase 5 (ALK5), have been developed as anticancer agents. Oral administration of a TβRI inhibitor, Ki26894, ameliorates muscle atrophy and weakness in a caveolin-3-deficient LGMD1C mouse model. The therapeutic effect of Ki26894 is associated with a reduction in TGF-β signaling and an increase in the number of muscle precursor satellite cells. This suggests that the caveolin-3/TβRI signaling pathway plays an important role in the pathogenesis of LGMD1C and that it regulates skeletal muscle size by controlling the number of muscle precursor cells. Consequently, drugs that target the TGF-β pathway may have therapeutic potential for diseases characterized by muscle atrophy.

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Acknowledgment

We are grateful to all collaborators involved in developing anti-myostatin therapeutics and to T. Kenmotsu, N. Naoe, M Harada, M. Kimura, F Uemura, E Sugita, and K. Tanda (Department of Neurology, Kawasaki Medical School) for providing technical assistance. This work was supported by a research grant for Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry (23–5, 26–8) and Welfare of Japan and from the Japan Society for the Promotion of Science (JST, AS24212769) and by research project grants from Kawasaki Medical School (23-T1, 26-T1).

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Authors and Affiliations

  1. Department of Neurology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan

    Yutaka Ohsawa & Yoshihide Sunada

  2. Molecular and Developmental Biology, Kawasaki Medical School, Okayama, Japan

    Shin-ichiro Nishimatsu

  3. Department of Health and Sports Science, Faculty of Health Science and Technology, Kawasaki University of Medical Welfare, Okayama, Japan

    Masahiro Fujino

Authors
  1. Yutaka Ohsawa
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  2. Shin-ichiro Nishimatsu
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  3. Masahiro Fujino
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  4. Yoshihide Sunada
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Corresponding author

Correspondence to Yutaka Ohsawa .

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Editors and Affiliations

  1. National Institute of Neuroscience, Kodaira, Tokyo, Tokyo, Japan

    Shin'ichi Takeda

  2. National Institute of Neuroscience, Kodaira, Tokyo, Tokyo, Japan

    Yuko Miyagoe-Suzuki

  3. National Institute of Neuroscience, Kodaira, Tokyo, Tokyo, Japan

    Madoka Mori-Yoshimura

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Ohsawa, Y., Nishimatsu, Si., Fujino, M., Sunada, Y. (2016). Targeting the Type I TGF-β Receptor for Treating Caveolin-3-Deficient Autosomal Dominant Limb-Girdle Muscular Dystrophy Type 1C and Muscle Wasting Disorders. In: Takeda, S., Miyagoe-Suzuki, Y., Mori-Yoshimura, M. (eds) Translational Research in Muscular Dystrophy. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55678-7_5

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  • DOI: https://doi.org/10.1007/978-4-431-55678-7_5

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  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-55677-0

  • Online ISBN: 978-4-431-55678-7

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