1. DUX4-induced constitutive DNA damage and oxidative stress contribute to aberrant differentiation of myoblasts from FSHD patients
- Author
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Yegor S. Vassetzky, Vlada V. Zakharova, Philippe Dessen, Ruy A. N. Louzada, Carla Dib, Petr Dmitriev, Yara Bou Saada, Aline Hamade, Marc Lipinski, Eugénie Ansseau, Vladimir Lazar, Gilles Carnac, Corinne Dupuy, Thomas Robert, Ana Barat, Interactions moléculaires et cancer (IMC (UMR 8126)), Signalisation, noyaux et innovations en cancérologie (UMR8126), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université de Mons (UMons), Department of Biology, Faculty of Sciences II, Lebanese University [Beirut] (LU), Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Traitement et Communication de l'Information (LTCI), Télécom ParisTech-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Faculty of Bioengineering and Bioinformatics, Moscow, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), and Lomonosov Moscow State University (MSU)
- Subjects
0301 basic medicine ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA damage ,DUX4 ,[SDV]Life Sciences [q-bio] ,Muscle Fibers, Skeletal ,Primary Cell Culture ,Biology ,medicine.disease_cause ,Facioscapulohumeral dystrophy ,Transfection ,Biochemistry ,Antioxidants ,Cyclic N-Oxides ,Myoblasts ,03 medical and health sciences ,chemistry.chemical_compound ,Physiology (medical) ,medicine ,Myocyte ,Humans ,RNA, Small Interfering ,Muscle, Skeletal ,Homeodomain Proteins ,Myogenesis ,Gene Expression Profiling ,Dystrophy ,Cell Differentiation ,Molecular Sequence Annotation ,musculoskeletal system ,Molecular biology ,Muscular Dystrophy, Facioscapulohumeral ,Oxidative Stress ,030104 developmental biology ,Gene Ontology ,chemistry ,Gene Expression Regulation ,Case-Control Studies ,Multigene Family ,Homeobox ,Spin Labels ,Oxidative stress ,DNA ,DNA Damage - Abstract
International audience; Facioscapulohumeral dystrophy (FSHD) is one of the three most common muscular dystrophies in the Western world, however, its etiology remains only partially understood. Here, we provide evidence of constitutive DNA damage in in vitro cultured myoblasts isolated from FSHD patients and demonstrate oxidative DNA damage implication in the differentiation of these cells into phenotypically-aberrant myotubes. Double homeobox 4 (DUX4), the major actor in FSHD pathology induced DNA damage accumulation when overexpressed in normal human myoblasts, and RNAi-mediated DUX4 inhibition reduced the level of DNA damage in FSHD myoblasts. Addition of tempol, a powerful antioxidant, to the culture medium of proliferating DUX4-transfected myoblasts and FSHD myoblasts reduced the level of DNA damage, suggesting that DNA alterations are mainly due to oxidative stress. Antioxidant treatment during the myogenic differentiation of FSHD myoblasts significantly reduced morphological defects in myotube formation. We propose that the induction of DNA damage is a novel function of the DUX4 protein affecting myogenic differentiation of FSHD myoblasts.
- Published
- 2016