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N‐acetylcysteine is an effective ex vivo treatment of oxidative stress in SEPN1 – related myopathy
Author(s) -
Arbogast Sandrine,
Ferreiro Ana
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb134
Subject(s) - oxidative stress , fisetin , myopathy , chemistry , ex vivo , acetylcysteine , myocyte , oxidative phosphorylation , microbiology and biotechnology , pharmacology , biochemistry , medicine , antioxidant , biology , in vitro , flavonoid
Selenoprotein N (SelN) defects are responsible for a congenital muscle disorder (SEPN1‐related myopathy) for which no treatment is available. We have recently established that human cells devoid of SelN show abnormal susceptibility to oxidative stress, increased intracellular oxidant activity and excessive protein oxidation. Therefore, SelN plays a role in cell protection against oxidative stress. We hypothesized that oxidative stress in SelN deficiency can be effectively targeted by antioxidants, and developed an ex vivo model to test potential‐therapeutic drugs using muscle cells and fibroblasts from patients carrying SEPN1 null mutations. We analyzed the susceptibility of SelN‐devoid fibroblasts to H2O2 before and after pre‐treatment with the antioxidants astaxanthin, fisetin and N‐acetyl cysteine (NAC). Astaxanthin and fisetin had a partial protective effect. In contrast, NAC protected SelN‐devoid fibroblasts and muscle cells from cell death in OxS conditions and normalized the levels of oxidized proteins in SEPN1‐mutant myotubes. NAC efficiency on mutant cells suggests that this thiol‐donor targets more directly the pathway altered by SelN deficiency. This study establishes for the first time that antioxidants can effectively target the primary defect in this genetic disorder, thus representing the first specific pharmacological treatment for a congenital myopathy. Supported by AFM.