title: Oxidative stress in SEPN1-related myopathy: from pathophysiology to treatment.
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 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.
  
  
  CONCLUSIONS
  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.
authors: INSERM-Institut National de la Sante et de la Recherche Médicale, U582, Institut de Myologie, Paris, France.
authors: Sandrine
authors: S
authors: Arbogast
authors: Maud
authors: M
authors: Beuvin
authors: Bodvaël
authors: B
authors: Fraysse
authors: Haïyan
authors: H
authors: Zhou
authors: Francesco
authors: F
authors: Muntoni
authors: Ana
authors: A
authors: Ferreiro
mesh_terms: D000293:Adolescent; D000975:Antioxidants / Q000627:therapeutic use*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D018390:Gene Targeting; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009135:Muscular Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D051140:Selenoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000975:Antioxidants; D009124:Muscle Proteins; C435489:SELENON protein, human; D051140:Selenoproteins