Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
J Muscle Res Cell Motil. 2013 Dec;34(5-6):395-405. doi: 10.1007/s10974-013-9362-9. Epub 2013 Oct 6.
Heart disease is a leading cause of death in patients with Duchenne muscular dystrophy (DMD). Patients with DMD lack the protein dystrophin, which is widely expressed in striated muscle. In skeletal muscle, the loss of dystrophin results in dramatically decreased expression of the dystrophin associated glycoprotein complex (DGC). Interestingly, in the heart the DGC is normally expressed without dystrophin; this has been attributed to presence of the dystrophin homologue utrophin. We demonstrate here that neither utrophin nor dystrophin are required for the expression of the cardiac DGC. However, alpha-dystroglycan (α-DG), a major component of the DGC, is differentially glycosylated in dystrophin-(mdx) and dystrophin-/utrophin-(dko) deficient mouse hearts. In both models the altered α-DG retains laminin binding activity, but has an altered localization at the sarcolemma. In hearts lacking both dystrophin and utrophin, the alterations in α-DG glycosylation are even more dramatic with changes in gel migration equivalent to 24 ± 3 kDa. These data show that the absence of dystrophin and utrophin alters the processing of α-DG; however it is not clear if these alterations are a consequence of the loss of a direct interaction with dystrophin/utrophin or results from an indirect response to the presence of severe pathology. Recently there have been great advances in our understanding of the glycosylation of α-DG regarding its role as a laminin receptor. Here we present data that alterations in glycosylation occur in the hearts of animal models of DMD, but these changes do not affect laminin binding. The physiological consequences of these alterations remain unknown, but may have significant implications for the development of therapies for DMD.
心脏病是杜氏肌营养不良症（DMD）患者的主要死因。DMD 患者缺乏广泛存在于横纹肌中的肌营养不良蛋白。在骨骼肌中，肌营养不良蛋白的缺失导致肌营养不良蛋白相关糖复合物（DGC）的表达显著降低。有趣的是，在心脏中，DGC 通常在没有肌营养不良蛋白的情况下表达；这归因于肌联蛋白的存在。我们在这里证明，心脏 DGC 的表达既不需要肌联蛋白也不需要肌营养不良蛋白。然而，DGC 的主要成分α-肌营养不良糖蛋白（α-DG）在肌营养不良蛋白（mdx）和肌营养不良蛋白/肌联蛋白（dko）缺失的小鼠心脏中存在差异糖基化。在这两种模型中，改变的α-DG 保留了层粘连蛋白结合活性，但在肌膜上的定位发生改变。在缺乏肌营养不良蛋白和肌联蛋白的心脏中，α-DG 糖基化的改变更为明显，迁移率的变化相当于 24 ± 3 kDa。这些数据表明，肌营养不良蛋白和肌联蛋白的缺失改变了α-DG 的加工；然而，尚不清楚这些改变是由于与肌营养不良蛋白/肌联蛋白的直接相互作用丧失所致，还是由于严重病理存在的间接反应所致。最近，我们对α-DG 糖基化在作为层粘连蛋白受体方面的作用有了更深入的了解。在这里，我们提供的数据表明，DMD 动物模型的心脏中存在糖基化改变，但这些变化不影响层粘连蛋白的结合。这些改变的生理后果尚不清楚，但可能对 DMD 治疗方法的发展具有重要意义。
