肌营养不良蛋白-糖蛋白复合物(DGC)在维持质膜和神经肌肉接头的结构完整性中起着至关重要的作用。在这项研究中,我们调查了α-dstrobrevin(αdbn)缺乏的影响,DGC的一个组成部分,细胞内细胞器的稳态,特别是线粒体和肌浆网(SR)。在αdbn缺乏的肌肉中,我们观察到膜结合ATP合酶复合物水平显着增加,与野生型相比,氧化肌纤维类型中线粒体的标记。此外,使用电子显微镜检查缺乏αdbn的肌纤维,发现线粒体组织和肌纤维某些肌原纤维内的SR发生了深刻的变化。这包括形成具有扩展连接的超支肌纤维间线粒体,跨越几个肌原纤维的广泛网络,肌膜下线粒体的数量/密度大幅增加。同时,在某些情况下,我们观察到线粒体的显著结构改变,例如cristae损失,碎片化,肿胀,以及线粒体基质cr内空泡和内含物的形成。缺乏αdbn的肌肉在SR的形态上也表现出明显的改变,伴随着称为螺纹的独特的异常同心SR结构的形成。这些螺纹在αdbn缺陷小鼠中普遍存在,但在野生型肌肉中却不存在。这些结果表明DGCαdbn在调节细胞内细胞器中的关键作用,特别是线粒体和SR,在肌肉细胞内。SR的重塑和螺纹的形成可能代表了肌肉细胞中展开蛋白反应(UPR)的新机制。
The dystrophin-glycoprotein complex (DGC) plays a crucial role in maintaining the structural integrity of the plasma membrane and the neuromuscular junction. In this study, we investigated the impact of the deficiency of α-dystrobrevin (αdbn), a component of the DGC, on the homeostasis of intracellular organelles, specifically mitochondria and the sarcoplasmic reticulum (SR). In αdbn deficient muscles, we observed a significant increase in the membrane-bound ATP synthase complex levels, a marker for mitochondria in oxidative muscle fiber types compared to wild-type. Furthermore, examination of muscle fibers deficient in αdbn using electron microscopy revealed profound alterations in the organization of mitochondria and the SR within certain myofibrils of muscle fibers. This included the formation of hyper-branched intermyofibrillar mitochondria with extended connections, an extensive network spanning several myofibrils, and a substantial increase in the number/density of subsarcolemmal mitochondria. Concurrently, in some cases, we observed significant structural alterations in mitochondria, such as cristae loss, fragmentation, swelling, and the formation of vacuoles and inclusions within the mitochondrial matrix cristae. Muscles deficient in αdbn also displayed notable alterations in the morphology of the SR, along with the formation of distinct anomalous concentric SR structures known as whorls. These whorls were prevalent in αdbn-deficient mice but were absent in wild-type muscles. These results suggest a crucial role of the DGC αdbn in regulating intracellular organelles, particularly mitochondria and the SR, within muscle cells. The remodeling of the SR and the formation of whorls may represent a novel mechanism of the unfolded protein response (UPR) in muscle cells.