Original Article

Oxidative stress in SEPN1-related myopathy: From pathophysiology to treatment†

  1. Sandrine Arbogast PhD1,2,
  2. Maud Beuvin MS1,2,
  3. Bodvaël Fraysse PhD1,2,
  4. Haïyan Zhou PhD3,
  5. Francesco Muntoni MD, PhD3,
  6. Ana Ferreiro MD, PhD1,2,4,*

Article first published online: 19 MAR 2009

DOI: 10.1002/ana.21644

Issue

Annals of Neurology

Annals of Neurology

Volume 65, Issue 6, pages 677–686, June 2009

Additional Information

How to Cite

Arbogast, S., Beuvin, M., Fraysse, B., Zhou, H., Muntoni, F. and Ferreiro, A. (2009), Oxidative stress in SEPN1-related myopathy: From pathophysiology to treatment. Annals of Neurology, 65: 677–686. doi: 10.1002/ana.21644

Author Information

  1. 1

    INSERM (Institut National de la Sante et de la Recherche Médicale), U582, Institut de Myologie, France

  2. 2

    Université Pierre et Marie Curie Univ Paris 06, UMR_S582, Institut Fédératif de Recherche 14, Paris, France

  3. 3

    Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Children Hospital, London, United Kingdom

  4. 4

    Assistance Publique-Hospitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Consultation des Maladies Neuromusculaires, Paris, France

*INSERM U787, GH Pitié-Salpêtrière, 105 Boulevard de l'Hôpital, 75013 Paris, France

  1. †

    Potential conflict of interest: Nothing to report.

Publication History

  1. Issue published online: 25 JUN 2009
  2. Article first published online: 19 MAR 2009
  3. Accepted manuscript online: 19 MAR 2009 12:00AM EST
  4. Manuscript Accepted: 6 JAN 2009
  5. Manuscript Revised: 17 DEC 2008
  6. Manuscript Received: 25 JUN 2008

Funded by

  • Institut National de la Sante et de la Recherche Médicale (INSERM)
  • Association Française contre les Myopathies (AFM). Grant Numbers: AIM 12329, 12865
  • Agence National de la Recherche (ANR). Grant Numbers: ANR-06-MRAR-03901, ANR-06-MRAR-044-02

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Abstract

Objective

Mutations of the selenoprotein N gene (SEPN1) cause SEPN1-related myopathy (SEPN1-RM), a novel early-onset muscle disorder formerly divided into four different nosological categories. Selenoprotein N (SelN) is the only selenoprotein involved in a genetic disease; its function being unknown, no treatment is available for this potentially lethal disorder. Our objective was to clarify the role of SelN and the pathophysiology of SEPN1-RM to identify therapeutic targets.

Methods

We established and analyzed an ex vivo model of SelN deficiency using fibroblast and myoblast primary cultures from patients with null SEPN1 mutations. DCFH assay, OxyBlot, Western blot, Fura-2, and cell survival studies were performed to measure intracellular oxidant activity, oxidative stress markers, calcium handling, and response to exogenous treatments.

Results

SelN-depleted cells showed oxidative/nitrosative stress manifested by increased intracellular oxidant activity (reactive oxygen species and nitric oxide) and/or excessive oxidation of proteins, including the contractile proteins actin and myosin heavy chain II in myotubes. SelN-devoid myotubes showed also Ca2+ homeostasis abnormalities suggesting dysfunction of the redox-sensor Ca2+ channel ryanodine receptor type 1. Furthermore, absence of SelN was associated with abnormal susceptibility to H2O2-induced oxidative stress, demonstrated by increased cell death. This cell phenotype was restored by pretreatment with the antioxidant N-acetylcysteine.

Interpretation

SelN plays a key role in redox homeostasis and human cell protection against oxidative stress. Oxidative/nitrosative stress is a primary pathogenic mechanism in SEPN1-RM, which can be effectively targeted ex vivo by antioxidants. These findings pave the way to SEPN1-RM treatment, which would represent a first specific pharmacological treatment for a congenital myopathy. Ann Neurol 2009;65:677–686

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