Han Renzhi, Kanagawa Motoi, Yoshida-Moriguchi Takako, Rader Erik P, Ng Rainer A, Michele Daniel E, Muirhead David E, Kunz Stefan, Moore Steven A, Iannaccone Susan T, Miyake Katsuya, McNeil Paul L, Mayer Ulrike, Oldstone Michael B A, Faulkner John A, Campbell Kevin P
Howard Hughes Medical Institute, Department of Molecular Physiology, The University of Iowa, Iowa City, IA 52242, USA.
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12573-9. doi: 10.1073/pnas.0906545106. Epub 2009 Jul 24.
Skeletal muscle basal lamina is linked to the sarcolemma through transmembrane receptors, including integrins and dystroglycan. The function of dystroglycan relies critically on posttranslational glycosylation, a common target shared by a genetically heterogeneous group of muscular dystrophies characterized by alpha-dystroglycan hypoglycosylation. Here we show that both dystroglycan and integrin alpha7 contribute to force-production of muscles, but that only disruption of dystroglycan causes detachment of the basal lamina from the sarcolemma and renders muscle prone to contraction-induced injury. These phenotypes of dystroglycan-null muscles are recapitulated by Large(myd) muscles, which have an intact dystrophin-glycoprotein complex and lack only the laminin globular domain-binding motif on alpha-dystroglycan. Compromised sarcolemmal integrity is directly shown in Large(myd) muscles and similarly in normal muscles when arenaviruses compete with matrix proteins for binding alpha-dystroglycan. These data provide direct mechanistic insight into how the dystroglycan-linked basal lamina contributes to the maintenance of sarcolemmal integrity and protects muscles from damage.
骨骼肌基底膜通过跨膜受体与肌膜相连，这些受体包括整合素和肌营养不良聚糖。肌营养不良聚糖的功能严重依赖于翻译后糖基化，这是一组具有遗传异质性的肌营养不良症的共同靶点，其特征是α-肌营养不良聚糖低糖基化。在这里，我们表明肌营养不良聚糖和整合素α7都有助于肌肉产生力量，但只有肌营养不良聚糖的破坏会导致基底膜与肌膜分离，并使肌肉易于受到收缩诱导的损伤。肌营养不良聚糖缺失的肌肉的这些表型在Large(myd)肌肉中重现，Large(myd)肌肉具有完整的肌营养不良蛋白-糖蛋白复合物，仅在α-肌营养不良聚糖上缺乏层粘连蛋白球状结构域结合基序。当沙粒病毒与基质蛋白竞争结合α-肌营养不良聚糖时，Large(myd)肌肉中直接显示出肌膜完整性受损，正常肌肉中也同样如此。这些数据为肌营养不良聚糖连接的基底膜如何有助于维持肌膜完整性和保护肌肉免受损伤提供了直接的机制见解。
