Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
FASEB J. 2021 May;35(5):e21349. doi: 10.1096/fj.202001653RR.
Mice with a mutation (D244G, DG) in calsequestrin 1 (CASQ1), analogous to a human mutation in CASQ1 associated with a delayed onset human myopathy (vacuolar aggregate myopathy), display a progressive myopathy characterized by decreased activity, decreased ability of fast twitch muscles to generate force and low body weight after one year of age. The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER). Decreased junctional CASQ1 reduces SR Ca release. Muscles from older DG mice display ER stress, ER expansion, increased mTOR signaling, inadequate clearance of aggregated proteins by the proteasomes, and elevation of protein aggregates and lysosomes. This study suggests that the myopathy associated with the D244G mutation in CASQ1 is driven by CASQ1 mislocalization, reduced SR Ca release, CASQ1 misfolding/aggregation and ER stress. The subsequent maladaptive increase in protein synthesis and decreased protein aggregate clearance are likely to contribute to disease progression.
在肌联蛋白 1（CASQ1）中具有突变（D244G，DG）的小鼠，类似于与 CASQ1 相关的人类突变，与延迟发作的人类肌病（空泡聚集性肌病）有关，表现为进行性肌病，其特征是一年后活动能力下降，快速抽搐肌肉产生力量的能力下降和体重下降。DG 突变导致 CASQ1 部分从连接肌浆网（SR）解离并在内质网（ER）中积累。连接的 CASQ1 减少会降低 SR Ca 释放。来自老年 DG 小鼠的肌肉显示内质网应激、内质网扩张、mTOR 信号增加、蛋白酶体对聚集蛋白的清除不足以及蛋白聚集体和溶酶体升高。这项研究表明，与 CASQ1 中的 D244G 突变相关的肌病是由 CASQ1 定位错误、SR Ca 释放减少、CASQ1 错误折叠/聚集和内质网应激驱动的。随后蛋白质合成的适应性增加和蛋白聚集体清除减少可能导致疾病进展。
