RAGE-NF-κB pathway activation in response to oxidative stress in facioscapulohumeral muscular dystrophy

Objectives - An increased expression of adenine nucleotide translocator (ANT1), found in facioscapulohumeral muscular dystrophy (FSHD), is known to lead to a decrease in nuclear factor-kappa B (NF-kappa B) DNA binding and to sensitize muscle cells to oxidative stress and apoptosis. Receptor for advanced glycation end products (RAGE) mediated by NF-kappa B activation is involved in proinflammatory pathomechanism and in muscle fiber regeneration in inflammatory myopathies and in limb girdle muscular dystrophy. Oxidative stress can stimulate RAGE- NF-kappa B pathway. Our purpose was to verify if oxidative stress may induce RAGE- NF-kappa B pathway activation in FSHD, contributing to the pathogenesis of such a disease. Materials and methods - On muscle samples of eight patients with FSHD, eight patients with Duchenne muscular dystrophy and eight normal controls the following studies were carried out: immunocytochemistry for activated NF-kappa B; electrophoretic mobility shift assay of NF-kappa B DNA binding activity; Western blot studies of RAGE and ANT1; hydrogen peroxide (HP), peroxidase and glutathione peroxidase (GPx) assays. Results - An increased RAGE and ANT1 expression in FSHD with moderate increase of NF-kappa B DNA binding activity was found together with an increased production of HP and a reduced activity of peroxidase and GPx. Conclusions - Our data confirm that response to oxidative stress and ANT1 increased activity are early events in FSHD muscle. The study also reveals that the RAGE- NF-kappa B pathway, induced by oxidative stress, is activated independently of the presence of a clear histochemical evidence of muscle damage in FSHD.