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A chemical chaperone improves muscle function in mice with a RyR1 mutation

Author

Listed:
  • Chang Seok Lee

    (Baylor College of Medicine)

  • Amy D. Hanna

    (Baylor College of Medicine)

  • Hui Wang

    (Baylor College of Medicine)

  • Adan Dagnino-Acosta

    (Baylor College of Medicine)

  • Aditya D. Joshi

    (Baylor College of Medicine)

  • Mark Knoblauch

    (Baylor College of Medicine)

  • Yan Xia

    (Baylor College of Medicine)

  • Dimitra K. Georgiou

    (Baylor College of Medicine)

  • Jianjun Xu

    (Baylor College of Medicine)

  • Cheng Long

    (Baylor College of Medicine)

  • Hisayuki Amano

    (Baylor College of Medicine)

  • Corey Reynolds

    (Baylor College of Medicine)

  • Keke Dong

    (Baylor College of Medicine)

  • John C. Martin

    (Baylor College of Medicine)

  • William R. Lagor

    (Baylor College of Medicine)

  • George G. Rodney

    (Baylor College of Medicine)

  • Ergun Sahin

    (Baylor College of Medicine)

  • Caroline Sewry

    (Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital)

  • Susan L. Hamilton

    (Baylor College of Medicine)

Abstract

Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca2+ release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticulum (SR) Ca2+ transient, resting cytosolic Ca2+ levels, muscle triadin content and calsequestrin (CSQ) localization to the junctional SR, and increases endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and mitochondrial ROS production. Treatment of mice carrying the I4895T mutation with a chemical chaperone, sodium 4-phenylbutyrate (4PBA), reduces ER stress/UPR and improves muscle function, but does not restore SR Ca2+ transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca2+ release is not the major driver of the myopathy. These findings suggest that 4PBA, an FDA-approved drug, has potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress.

Suggested Citation

  • Chang Seok Lee & Amy D. Hanna & Hui Wang & Adan Dagnino-Acosta & Aditya D. Joshi & Mark Knoblauch & Yan Xia & Dimitra K. Georgiou & Jianjun Xu & Cheng Long & Hisayuki Amano & Corey Reynolds & Keke Don, 2017. "A chemical chaperone improves muscle function in mice with a RyR1 mutation," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14659
    DOI: 10.1038/ncomms14659
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