BETs inhibition attenuates oxidative stress and preserves muscle integrity in Duchenne muscular dystrophy

Marco Segatto, Roberta Szokoll, Raffaella Fittipaldi, Cinzia Bottino, Lorenzo Nevi, Kamel Mamchaoui, Panagis Filippakopoulos and Giuseppina Caretti ()
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Marco Segatto: Università degli Studi di Milano
Roberta Szokoll: Università degli Studi di Milano
Raffaella Fittipaldi: Università degli Studi di Milano
Cinzia Bottino: Università degli Studi di Milano
Lorenzo Nevi: Università degli Studi di Milano
Kamel Mamchaoui: Sorbonne Université, Inserm, Institut de Myologie, U974, Center for Research in Myology
Panagis Filippakopoulos: Structural Genomics Consortium, Old Road Campus Research Building, Nuffield Department of Medicine
Giuseppina Caretti: Università degli Studi di Milano

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19839-x

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