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Research ArticleToxicology

Inhibition of Rab1 GTPase and Endoplasmic Reticulum-to-Golgi Trafficking Underlies Statin's Toxicity in Rat Skeletal Myofibers

Kazuho Sakamoto, Ikuo Wada and Junko Kimura
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 62-69; DOI: https://doi.org/10.1124/jpet.111.179762
Kazuho Sakamoto
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Ikuo Wada
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Junko Kimura
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Abstract

HMG-CoA reductase inhibitor statins are used for the treatment of hypercholesterolemia. However, statins have adverse effects on skeletal muscles with unknown mechanism. We have reported previously that fluvastatin induced vacuolation and cell death in rat skeletal myofibers by depleting geranylgeranylpyrophosphate (GGPP) and suppressing small GTPases, particularly Rab (FASEB J 21:4087–4094, 2007). Rab1 is one of the most susceptible Rab isoforms to GGPP depletion and is essential for endoplasmic reticulum (ER)-to-Golgi trafficking. Here, we explored whether Rab1 and ER-to-Golgi vesicle trafficking were affected by statins in cultured single myofibers isolated from flexor digitorum brevis muscles of adult rats. Western blot analysis revealed that Rab1A protein resided predominantly in membrane but not in cytosol in control myofibers, whereas it was opposite in fluvastatin-treated myofibers, indicating that fluvastatin inhibited Rab1A translocation from cytosol to membrane. GGPP supplementation prevented the effect of fluvastatin on Rab1A translocation. Brefeldin A, a specific suppressor of ER-to-Golgi trafficking, induced vacuolation and cell death in myofibers in a manner similar to that of fluvastatin. Although ER-to-Golgi traffic suppression induces unfolded protein response (UPR) and cell death in some cell types, neither fluvastatin nor brefeldin A up-regulated UPR in myofibers. Immunofluorescence study revealed that the distribution of an ER marker, calnexin, was restricted to the region around nucleus with fluvastatin, suggesting the inhibition of ER membrane traffic by fluvastatin. We conclude that suppression of Rab1 GTPase and the subsequent inhibition of ER-to-Golgi traffic are involved in statin-induced skeletal myotoxicity.

Footnotes

  • This study was supported by Grants-in-aid for Young Scientists (B) [Grants 20790210, 22790257] (to K.S.) and Grants-in-aid for Scientific Research (C) [Grant 21590288] (to J.K.) from the Japan Society for the Promotion of Science and in part by the Smoking Research Foundation [Grant KI18003] (to J.K.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.179762.

  • ABBREVIATIONS:

    GGPP
    geranylgeranylpyrophosphate
    Arf
    ADP ribosylation factor
    BFA
    brefeldin A
    CBB
    Coomassie Brilliant blue
    ER
    endoplasmic reticulum
    Flv
    fluvastatin
    FPP
    farnesylpyrophosphate
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    GRP
    glucose-regulated protein
    Oatp
    organic anion transporting polypeptide
    PBS
    phosphate-buffered saline
    Tum
    tunicamycin
    UPR
    unfolded protein response.

  • Received January 21, 2011.
  • Accepted April 5, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleToxicology

Inhibition of Rab1 GTPase and Endoplasmic Reticulum-to-Golgi Trafficking Underlies Statin's Toxicity in Rat Skeletal Myofibers

Kazuho Sakamoto, Ikuo Wada and Junko Kimura
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 62-69; DOI: https://doi.org/10.1124/jpet.111.179762

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Research ArticleToxicology

Inhibition of Rab1 GTPase and Endoplasmic Reticulum-to-Golgi Trafficking Underlies Statin's Toxicity in Rat Skeletal Myofibers

Kazuho Sakamoto, Ikuo Wada and Junko Kimura
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 62-69; DOI: https://doi.org/10.1124/jpet.111.179762
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