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BETs inhibition attenuates oxidative stress and preserves muscle integrity in Duchenne muscular dystrophy
Nature Communications ( IF 14.7 ) Pub Date : 2020-11-30 , DOI: 10.1038/s41467-020-19839-x
Marco Segatto , Roberta Szokoll , Raffaella Fittipaldi , Cinzia Bottino , Lorenzo Nevi , Kamel Mamchaoui , Panagis Filippakopoulos , Giuseppina Caretti

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.



中文翻译:

BETs抑制可减轻氧化应激并保持Duchenne肌营养不良症的肌肉完整性

杜兴氏肌营养不良症(DMD)影响3500例活产男性中的1例。迄今为止,尚无有效的DMD疗法,识别与疾病进展有关的新型分子靶标对于设计更有效的疗法和疗法以减轻DMD症状很重要。在这里,我们表明,DMD小鼠模型(mdx小鼠)的肌肉中Bromodomain和末端外域(BET)蛋白BRD4的蛋白水平显着增加,并且BET蛋白的药理抑制作用是有益的,缓解氧化应激和肌肉损伤。活性氧(ROS)代谢的改变是DMD发作的早期事件,并且与骨骼肌的炎症,纤维化和坏死紧密相关。通过恢复ROS代谢,BET抑制可改善营养不良性肌肉的这些特征,从而对肌肉功能产生有益作用。BRD4直接关联到NADPH氧化酶亚基的染色质调节区,mdx肌肉增加,JQ1给药减少了这些区域的BRD4和BRD2募集。JQ1处理可降低mdx肌肉,离体的肌纤维和DMD永生化成肌细胞中NADPH亚基的转录水平。我们的数据突出了营养不良性骨骼肌中BET蛋白的新功能,并暗示BET抑制剂可能改善DMD的病理生理。JQ1处理可降低mdx肌肉,离体的肌纤维和DMD永生化成肌细胞中NADPH亚基的转录水平。我们的数据突出了营养不良性骨骼肌中BET蛋白的新功能,并暗示BET抑制剂可能改善DMD的病理生理。JQ1处理可降低mdx肌肉,离体的肌纤维和DMD永生化成肌细胞中NADPH亚基的转录水平。我们的数据突出了营养不良性骨骼肌中BET蛋白的新功能,并暗示BET抑制剂可能改善DMD的病理生理。

更新日期:2020-12-01
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