Dystrophin is required for the normal function of the cardio-protective K(ATP) channel in cardiomyocytes.
Dystrophin is required for the normal function of the cardio-protective K(ATP) channel in cardiomyocytes.
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DOI：
10.1371/journal.pone.0027034
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Fulgenzi G
中科院分区：
文献类型：
--
作者：
Graciotti L;Becker J;Granata AL;Procopio AD;Tessarollo L;Fulgenzi G
杜氏肌营养不良症和贝克尔肌营养不良症患者经常出现心肌病，其发病机制仍不清楚。我们采用杜氏肌营养不良症 (mdx) 小鼠动物模型来研究这种病理学的分子基础，该病会发展为一种包含人类疾病某些特征的心肌病。在这里，我们发现 mdx 小鼠心脏存在与调节能量稳态的化合物改变一致的缺陷，包括磷酸肌酸 (PC) 的显着减少。此外，mdx 心脏比对照心脏更容易缺氧。由于心脏保护性 ATP 敏感钾通道 (KATP) 复合物和 PC 已被证明存在相互作用，因此我们研究了 PC 水平的缺陷是否与其他分子事件相关，包括 KATP 离子通道复合物的存在、其功能以及与肌营养不良蛋白的相互作用。我们发现这种通道复合物存在于营养不良的心肌细胞膜中，但其感知细胞内 ATP 浓度下降并因此打开的能力因缺乏肌营养不良蛋白而受到损害。我们进一步证明肌酸激酶肌肉亚型（CKm）从 mdx 心肌细胞的质膜上被取代。考虑到 CKm 是 KATP 通道复合体功能的决定因素，我们假设肌营养不良蛋白充当组织 KATP 通道复合体及其正确功能所需的酶的支架蛋白。因此，mdx 心肌细胞中心脏保护性 KATP 系统缺乏正常功能可能是导致营养不良患者发生心脏病的部分机制。
Duchenne and Becker muscular dystrophy patients often develop a cardiomyopathy for which the pathogenesis is still unknown. We have employed the murine animal model of Duchenne muscular dystrophy (mdx), which develops a cardiomyopathy that includes some characteristics of the human disease, to study the molecular basis of this pathology. Here we show that the mdx mouse heart has defects consistent with alteration in compounds that regulate energy homeostasis including a marked decrease in creatine-phosphate (PC). In addition, the mdx heart is more susceptible to anoxia than controls. Since the cardio-protective ATP sensitive potassium channel (KATP) complex and PC have been shown to interact we investigated whether deficits in PC levels correlate with other molecular events including KATP ion channel complex presence, its functionality and interaction with dystrophin. We found that this channel complex is present in the dystrophic cardiac cell membrane but its ability to sense a drop in the intracellular ATP concentration and consequently open is compromised by the absence of dystrophin. We further demonstrate that the creatine kinase muscle isoform (CKm) is displaced from the plasma membrane of the mdx cardiac cells. Considering that CKm is a determinant of KATP channel complex function we hypothesize that dystrophin acts as a scaffolding protein organizing the KATP channel complex and the enzymes necessary for its correct functioning. Therefore, the lack of proper functioning of the cardio-protective KATP system in the mdx cardiomyocytes may be part of the mechanism contributing to development of cardiac disease in dystrophic patients.
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影响因子：
4.8
作者：
Abraham, MR;Selivanov, VA;Terzic, A
通讯作者：
Terzic, A
影响因子：
4.8
作者：
Crawford, RM;Ranki, HJ;Jovanovic, A
通讯作者：
Jovanovic, A
影响因子：
--
作者：
Morrissey, Alison;Rosner, Erika;Coetzee, William A
通讯作者：
Coetzee, William A
影响因子：
20.1
作者：
Hu X;Xu X;Huang Y;Fassett J;Flagg TP;Zhang Y;Nichols CG;Bache RJ;Chen Y
通讯作者：
Chen Y
影响因子：
3.4
作者：
DUPONTVERSTEEGDEN, EE;MCCARTER, RJ
通讯作者：
MCCARTER, RJ