Institut NeuroMyoGène, CNRS UMR5310, INSERM U1217, Université Lyon 1, F-69622 Villeurbanne, France.
Int J Mol Sci. 2018 Jan 7;19(1):178. doi: 10.3390/ijms19010178.
The maintenance of proteome integrity is of primary importance in post-mitotic tissues such as muscle cells; thus, protein quality control mechanisms must be carefully regulated to ensure their optimal efficiency, a failure of these processes being associated with various muscular disorders. Duchenne muscular dystrophy (DMD) is one of the most common and severe forms of muscular dystrophies and is caused by mutations in the dystrophin gene. Protein quality control modulations have been diversely observed in degenerating muscles of patients suffering from DMD or in animal models of the disease. In this study, we investigated whether modulations of protein quality control mechanisms already pre-exist in undifferentiated myoblasts originating from DMD patients. We report for the first time that the absence of dystrophin in human myoblasts is associated with protein aggregation stress characterized by an increase of protein aggregates. This stress is combined with BAG1 to BAG3 switch, NFκB activation and up-regulation of BAG3/HSPB8 complexes that ensure preferential routing of misfolded/aggregated proteins to autophagy rather than to deficient 26S proteasome. In this context, restoration of pre-existing alterations of protein quality control processes might represent an alternative strategy for DMD therapies.
蛋白质组完整性的维持对于像肌肉细胞这样的有丝分裂后组织至关重要；因此，蛋白质质量控制机制必须得到精心调节，以确保其最佳效率，如果这些过程出现故障，就会导致各种肌肉疾病。杜氏肌营养不良症（DMD）是最常见和最严重的肌肉营养不良症之一，是由肌营养不良蛋白基因突变引起的。在患有 DMD 的患者的退化肌肉或疾病的动物模型中，已经观察到蛋白质质量控制的调节多样化。在这项研究中，我们研究了源自 DMD 患者的未分化成肌细胞中是否已经存在蛋白质质量控制机制的调节。我们首次报道，人成肌细胞中肌营养不良蛋白的缺失与蛋白质聚集应激有关，其特征是蛋白质聚集体增加。这种应激与 BAG1 到 BAG3 开关、NFκB 激活以及 BAG3/HSPB8 复合物的上调相结合，该复合物确保错误折叠/聚集的蛋白质优先被自噬而不是缺陷的 26S 蛋白酶体所处理。在这种情况下，恢复蛋白质质量控制过程中预先存在的改变可能代表 DMD 治疗的一种替代策略。
