The dystrophin–glycoprotein complex (DGC) is a membrane adhesion complex that provides structural stability at the sarcolemma by linking the myocyte’s internal cytoskeleton and external extracellular matrix. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to the loss of the DGC at the sarcolemma, resulting in sarcolemmal instability and progressive muscle damage. Utrophin (UTRN), an autosomal homolog of dystrophin, is upregulated in dystrophic muscle and partially compensates for the loss of dystrophin in muscle from patients with DMD. Here, we examine the interaction between Utr and sarcospan (SSPN), a small transmembrane protein that is a core component of both UTRN–glycoprotein complex (UGC) and DGC. We show that additional loss of SSPN causes an earlier onset of disease in dystrophin-deficient mdx mice by reducing the expression of the UGC at the sarcolemma. In order to further evaluate the role of SSPN in maintaining therapeutic levels of Utr at the sarcolemma, we tested the effect of Utr transgenic overexpression in mdx mice lacking SSPN (mdx:SSPN −/−:Utr-Tg). We found that overexpression of Utr restored SSPN to the sarcolemma in mdx muscle but that the ablation of SSPN in mdx muscle reduced Utr at the membrane. Nevertheless, Utr overexpression reduced central nucleation and improved grip strength in both lines. These findings demonstrate that high levels of Utr transgenic overexpression ameliorate the mdx phenotype independently of SSPN expression but that loss of SSPN may impair Utr-based mechanisms that rely on lower levels of Utr protein.

中文翻译：

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肌跨度的缺失加剧了 mdx 小鼠的病理，但不影响 utrophin 对疾病的改善

抗肌萎缩蛋白-糖蛋白复合物 (DGC) 是一种膜粘附复合物，通过连接肌细胞的内部细胞骨架和外部细胞外基质，在肌膜上提供结构稳定性。在杜氏肌营养不良症 (DMD) 中，抗肌萎缩蛋白的缺失导致肌膜处 DGC 的丢失，从而导致肌膜不稳定和进行性肌肉损伤。Utrophin (UTRN) 是肌营养不良蛋白的常染色体同系物，在营养不良的肌肉中上调，部分补偿 DMD 患者肌肉中肌营养不良蛋白的损失。在这里，我们检查了 Utr 和 sarcospan (SSPN) 之间的相互作用，SSPN 是一种小的跨膜蛋白，是 UTRN-糖蛋白复合物 (UGC) 和 DGC 的核心成分。我们表明，SSPN 的额外损失通过减少肌膜上 UGC 的表达导致肌营养不良蛋白缺陷型 mdx 小鼠疾病的早期发作。为了进一步评估 SSPN 在维持肌膜 Utr 治疗水平方面的作用，我们测试了 Utr 转基因过表达对缺乏 SSPN 的 mdx 小鼠的影响（mdx：SSPN -/-：Utr-Tg）。我们发现 Utr 的过表达使 SSPN 恢复到 mdx 肌肉中的肌膜，但 mdx 肌肉中 SSPN 的消融减少了膜上的 Utr。尽管如此，Utr 的过表达减少了两条线的中央成核并提高了抓地力。