1. BETs inhibition attenuates oxidative stress and preserves muscle integrity in Duchenne muscular dystrophy
- Author
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L. Nevi, Panagis Filippakopoulos, Raffaella Fittipaldi, Marco Segatto, Roberta Szokoll, Kamel Mamchaoui, Cinzia Bottino, Giuseppina Caretti, Università degli Studi di Milano [Milano] (UNIMI), University of Molise [Campobasso] (UNIMOL), University of Molise, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford], Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Università degli Studi di Milano = University of Milan (UNIMI), Università degli Studi del Molise = University of Molise (UNIMOL), University of Oxford, and Gestionnaire, Hal Sorbonne Université
- Subjects
0301 basic medicine ,mdx mouse ,Duchenne muscular dystrophy ,[SDV]Life Sciences [q-bio] ,General Physics and Astronomy ,Skeletal muscle ,medicine.disease_cause ,Inbred C57BL ,Mice ,0302 clinical medicine ,Myocyte ,Muscular Dystrophy ,Multidisciplinary ,NADPH oxidase ,biology ,Nuclear Proteins ,Azepines ,Skeletal ,Neuromuscular Diseases ,Neuromuscular disease ,3. Good health ,Cell biology ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Muscle ,Epigenetics ,medicine.symptom ,Animals ,Disease Models, Animal ,Inflammation ,Mice, Inbred C57BL ,Mice, Inbred mdx ,Muscle, Skeletal ,Muscular Dystrophy, Duchenne ,NADP ,NADPH Oxidases ,Oxidative Stress ,Reactive Oxygen Species ,Transcription Factors ,Triazoles ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Science ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,medicine ,business.industry ,Animal ,Inbred mdx ,General Chemistry ,medicine.disease ,Duchenne ,Bromodomain ,030104 developmental biology ,Disease Models ,biology.protein ,business ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Duchenne muscular dystrophy (DMD) affects 1 in 3500 live male births. To date, there is no effective cure for DMD, and the identification of novel molecular targets involved in disease progression is important to design more effective treatments and therapies to alleviate DMD symptoms. Here, we show that protein levels of the Bromodomain and extra-terminal domain (BET) protein BRD4 are significantly increased in the muscle of the mouse model of DMD, the mdx mouse, and that pharmacological inhibition of the BET proteins has a beneficial outcome, tempering oxidative stress and muscle damage. Alterations in reactive oxygen species (ROS) metabolism are an early event in DMD onset and they are tightly linked to inflammation, fibrosis, and necrosis in skeletal muscle. By restoring ROS metabolism, BET inhibition ameliorates these hallmarks of the dystrophic muscle, translating to a beneficial effect on muscle function. BRD4 direct association to chromatin regulatory regions of the NADPH oxidase subunits increases in the mdx muscle and JQ1 administration reduces BRD4 and BRD2 recruitment at these regions. JQ1 treatment reduces NADPH subunit transcript levels in mdx muscles, isolated myofibers and DMD immortalized myoblasts. Our data highlight novel functions of the BET proteins in dystrophic skeletal muscle and suggest that BET inhibitors may ameliorate the pathophysiology of DMD., Duchenne muscular dystrophy (DMD) is characterised by progressive muscle degeneration. Here, the authors show that the BET protein BRD4 is increased in the muscle of DMD mouse models, and that pharmacological inhibition of BRD4 leads to reduced muscle pathology in mice, by modulating NADPH oxidase expression.
- Published
- 2020