Dystrobrevin increases dystrophin's binding to the dystrophin-glycoprotein complex and provides protection during cardiac stress.
Dystrobrevin increases dystrophin's binding to the dystrophin-glycoprotein complex and provides protection during cardiac stress.
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Dystrobrevin 增加肌营养不良蛋白与肌营养不良蛋白-糖蛋白复合物的结合，并在心脏应激期间提供保护。
DOI：
10.1016/j.yjmcc.2014.08.013
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发表时间：
2014
影响因子：
5
通讯作者：
Townsend,DeWayne
中科院分区：
文献类型：
--
作者：
Strakova,Jana;Dean,JonD;Sharpe,KatharineM;Meyers,TatyanaA;Odom,GuyL;Townsend,DeWayne
杜氏肌营养不良症是一种致命的进行性疾病的心脏和骨骼肌造成的突变基因和蛋白质dystrophin的损失。α-短肌营养不良蛋白（α-DB）与肌营养不良蛋白密切相关，但这种相互作用在心肌细胞内的意义知之甚少。在目前的研究中，α-DB在心肌细胞中的功能作用及其对肌营养不良蛋白功能的影响进行了研究。心脏负荷试验证明α-DB null（adbn−/−）小鼠存在显著的心脏病，其死亡率和病变大小与抗肌萎缩蛋白缺陷mdx小鼠相当。尽管抗肌萎缩蛋白在adbn−/−心脏中正常表达和亚细胞定位，但抗肌萎缩蛋白与膜结合的抗肌萎缩蛋白相关糖蛋白复合物（DGC）的相互作用强度显著降低。在缺乏肌聚糖复合物的小鼠中观察到肌养蛋白-膜界面的类似减弱。adbn−/−小鼠的心肌细胞较小，对肾上腺素能受体诱导的肥大反应较小。大小的基础减少不能归因于异常Akt激活。此外，微管网络的组织在adbn−/−心肌细胞中发生了显着改变，而微管蛋白的总表达在adbn−/−心脏中没有变化。这些研究表明，α-DB是一种多功能蛋白，可增加抗肌萎缩蛋白与抗肌萎缩蛋白-糖蛋白复合物的结合，并且对抗肌萎缩蛋白的全部功能至关重要。
Duchenne muscular dystrophy is a fatal progressive disease of both cardiac and skeletal muscle resulting from the mutations in the DMD gene and loss of the protein dystrophin. Alpha-dystrobrevin (α-DB) tightly associates with dystrophin but the significance of this interaction within cardiac myocytes is poorly understood. In the current study, the functional role of α-DB in cardiomyocytes and its implications for dystrophin function are examined. Cardiac stress testing demonstrated significant heart disease in α-DB null (adbn−/−) mice, which displayed mortality and lesion sizes that were equivalent to those seen in dystrophin-deficient mdx mice. Despite normal expression and subcellular localization of dystrophin in the adbn−/−heart, there is a significant decrease in the strength of dystrophin's interaction with the membrane-bound dystrophin-associated glycoprotein complex (DGC). A similar weakening of the dystrophin-membrane interface was observed in mice lacking the sarcoglycan complex. Cardiomyocytes from adbn−/−mice were smaller and responded less to adrenergic receptor induced hypertrophy. The basal decrease in size could not be attributed to aberrant Akt activation. In addition, the organization of the microtubule network was significantly altered in adbn−/−cardiac myocytes, while the total expression of tubulin was unchanged in adbn−/−hearts. These studies demonstrate that α-DB is a multifunctional protein that increases dystrophin's binding to the dystrophin–glycoprotein complex, and is critical for the full functionality of dystrophin.