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Endoplasmic reticulum stress in myotonic dystrophy type 1 muscle

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Abstract

In myotonic dystrophy type 1 (DM1), alternative splicing of ryanodine receptor 1 (RyR1) and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) genes has been reported. These proteins are essential for maintaining intracellular Ca2+ in skeletal muscle. To clarify involvement of endoplasmic reticulum (ER) stress in DM1 muscles, we examined the activation of ER stress-related proteins by immunohistochemistry, western blot analysis and RT-PCR. In four of five DM1 muscle biopsies, except for a muscle biopsy from a patient with the shortest CTG expansion and no myotonia, increased expression of GRP78 and calnexin, and phosphorylation of PERK and eIF-2α were revealed in fibers with sarcoplasmic masses and in highly atrophic fibers with pyknotic nuclear clumps. Caspase-3 and -7 were also expressed in these fibers. Increased expression of GRP78 in these DM1 muscles was confirmed by western blot analysis. GRP78 mRNA and spliced isoform of XBP1 mRNA were also increased in DM1 muscle biopsies. Furthermore, we demonstrated increased expression of GRP78 in highly atrophic fibers with pyknotic nuclear clumps in all three muscle biopsies from neurogenic muscular atrophies. However, five muscle biopsies from central core disease presumably with disturbed intracellular Ca2+ homeostasis and a muscle biopsy from paramyotonia congenita with myotonia showed no activation of these proteins. Taken together, ER stress is involved in muscle wasting in DM1. However, it seems to be evoked not only by disrupted intracellular Ca2+ homeostasis.

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Acknowledgments

Parts of this work were supported by a Research Grant (17A-10) for nervous and mental disorders from the ministry of Health, Labor and Welfare, Japan, to J.K. and S.S., and by Grants-in Aid for Scientific Research from the Japan Society for the Promotion of Science to M.P.T. We are grateful to Miss S. Nagae for her excellent technical assistance.

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Authors and Affiliations

  1. Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Koji Ikezoe, Hajime Arahata & Jun-ichi Kira

  2. Department of Neurology, National Omuta Hospital, Omuta, Fukuoka, Japan

    Koji Ikezoe, Hirokazu Furuya & Naoki Fujii

  3. Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Masayuki Nakamori, Takashi Kimura, Masanori P. Takahashi & Saburo Sakoda

  4. Division of Molecular and Cellular Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    Soshi Kanemoto & Kazunori Imaizumi

  5. Structural Cellular Biology, Nara Institute of Science and Technology, Ikoma, Nara, Japan

    Soshi Kanemoto

  6. Division of Neurology, Department of Internal Medicine, Hyogo Medicine College, Nishinomiya, Hyogo, Japan

    Takashi Kimura

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  1. Koji Ikezoe
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  2. Masayuki Nakamori
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  8. Masanori P. Takahashi
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Correspondence to Koji Ikezoe.

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Ikezoe, K., Nakamori, M., Furuya, H. et al. Endoplasmic reticulum stress in myotonic dystrophy type 1 muscle. Acta Neuropathol 114, 527–535 (2007). https://doi.org/10.1007/s00401-007-0267-9

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  • DOI: https://doi.org/10.1007/s00401-007-0267-9

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