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Amyloid-β accumulation caused by chloroquine injections precedes ER stress and autophagosome formation in rat skeletal muscle

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Abstract

Chloroquine, an anti-malaria drug, is known to cause myopathy with rimmed vacuole formation. Although it disrupts the lysosomal degradation of proteins, the precise mechanism underlying muscle fiber degeneration has remained unclear. We investigated the temporal profiles of muscle fiber degeneration in chloroquine-treated rats, paying special attention to endoplasmic reticulum (ER) stress and autophagy. Male Wistar rats were intraperitoneally injected with chloroquine diphosphate at a dosage of 50 mg/kg body weight every day. We examined the localization and levels of proteins related to ER stress and autophagy in soleus muscle by means of immunohistochemistry and Western blotting at 3, 5, and 7 weeks after the beginning of the treatment. At 3 weeks, the levels of LC3-II and amyloid-β (Aβ) were increased. At 5 weeks, an unfolded protein response took place. At 7 weeks, rimmed vacuole formation became obvious. Interestingly, SERCA2, a Ca2+ -pump ATPase located in the endoplasmic/sarcoplasmic reticulum membrane was up-regulated at 5 weeks after treatment, but declined to the control level by 7 weeks. Taken together, these findings suggest that Aβ accumulation (at 3 weeks) caused by the disruption of lysosomal enzymes precedes an unfolded protein response (at 5 weeks). Next, activation of autophagy occurs (at 7 weeks), probably using sarcoplasmic reticulum membrane, the amount of which was increased. Chloroquine-treated rats could be useful for investigating the pathogenesis of diseases related to Aβ accumulation.

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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, Takahisa Tateishi & Jun-ichi Kira

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

    Koji Ikezoe, Hirokazu Furuya, Hajime Arahata & Naoki Fujii

  3. Department of Plastic Surgery, Shizuoka Cancer Center, Nagaizumi, Shizuoka, Japan

    Masahiro Nakagawa

Authors
  1. Koji Ikezoe
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  2. Hirokazu Furuya
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  3. Hajime Arahata
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  4. Masahiro Nakagawa
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  5. Takahisa Tateishi
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  6. Naoki Fujii
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  7. Jun-ichi Kira
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Correspondence to Koji Ikezoe.

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Ikezoe, K., Furuya, H., Arahata, H. et al. Amyloid-β accumulation caused by chloroquine injections precedes ER stress and autophagosome formation in rat skeletal muscle. Acta Neuropathol 117, 575–582 (2009). https://doi.org/10.1007/s00401-009-0488-1

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  • DOI: https://doi.org/10.1007/s00401-009-0488-1

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