Oxidative stress in SEPN1-related myopathy: from pathophysiology to treatment

Ann Neurol. 2009 Jun;65(6):677-86. doi: 10.1002/ana.21644.


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 Ca(2+) homeostasis abnormalities suggesting dysfunction of the redox-sensor Ca(2+) channel ryanodine receptor type 1. Furthermore, absence of SelN was associated with abnormal susceptibility to H(2)O(2)-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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antioxidants / therapeutic use*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Gene Targeting
  • Homeostasis / genetics
  • Humans
  • Male
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics
  • Muscle Proteins / physiology*
  • Muscular Diseases / metabolism
  • Muscular Diseases / pathology
  • Muscular Diseases / physiopathology*
  • Muscular Diseases / therapy*
  • Mutation / genetics
  • Oxidation-Reduction
  • Oxidative Stress* / genetics
  • Selenoproteins / deficiency
  • Selenoproteins / genetics
  • Selenoproteins / physiology*


  • Antioxidants
  • Muscle Proteins
  • SEPN1 protein, human
  • Selenoproteins