title: DUX4-induced constitutive DNA damage and oxidative stress contribute to aberrant differentiation of myoblasts from FSHD patients.
abstract: 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.
authors: UMR 8126, Univ. Paris-Sud, CNRS, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France; PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, F-34295 Montpellier cedex 5, France.
authors: Petr
authors: P
authors: Dmitriev
authors: UMR 8126, Univ. Paris-Sud, CNRS, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors: Yara
authors: Y
authors: Bou Saada
authors: UMR 8126, Univ. Paris-Sud, CNRS, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors: Carla
authors: C
authors: Dib
authors: Laboratory of Molecular Biology, University of Mons, 20 place du Parc, B700 Mons, Belgium.
authors: Eugénie
authors: E
authors: Ansseau
authors: UMR 8126, Univ. Paris-Sud, CNRS, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors: Ana
authors: A
authors: Barat
authors: ER030-EDST, Department of Life and Earth Sciences, Faculty of Sciences II, Lebanese University, Lebanon.
authors: Aline
authors: A
authors: Hamade
authors: Functional Genomics Unit, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors: Philippe
authors: P
authors: Dessen
authors: Functional Genomics Unit, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors: Thomas
authors: T
authors: Robert
authors: Functional Genomics Unit, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors: Vladimir
authors: V
authors: Lazar
authors: UMR 8200, Univ., Paris-Sud, CNRS, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors: Ruy A N
authors: RAN
authors: Louzada
authors: UMR 8200, Univ., Paris-Sud, CNRS, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors: Corinne
authors: C
authors: Dupuy
authors: Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, 119991 Moscow, Russia.
authors: Vlada
authors: V
authors: Zakharova
authors: PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, F-34295 Montpellier cedex 5, France.
authors: Gilles
authors: G
authors: Carnac
authors: UMR 8126, Univ. Paris-Sud, CNRS, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors: Marc
authors: M
authors: Lipinski
authors: UMR 8126, Univ. Paris-Sud, CNRS, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France; Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, 119991 Moscow, Russia. Electronic address: vassetzky@igr.fr.
authors: Yegor S
authors: YS
authors: Vassetzky
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D016022:Case-Control Studies; D002454:Cell Differentiation; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004249:DNA Damage; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D058977:Molecular Sequence Annotation; D005810:Multigene Family; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013113:Spin Labels; D014162:Transfection
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D013113:Spin Labels; C001803:tempol
keywords: Antioxidants; DNA damage; DUX4; Facioscapulohumeral dystrophy; Oxidative stress