Tubular aggregate myopathy (TAM) is a heritable myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates (TAs). Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca2+ entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.

中文翻译：

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Orai1 功能获得性肾小管聚集体肌病小鼠模型表型复制了人类疾病的关键特征。


肾小管聚集体肌病 （TAM） 是一种遗传性肌病，主要特征是进行性肌无力、肌酸激酶 （CK） 水平升高、低钙血症、运动不耐受和肾小管聚集体 （TA） 的存在。在这里，我们基于人类功能获得性突变生成了一个敲入小鼠模型，该模型通过在 ORAI1 孔中诱导甘氨酸到丝氨酸点突变（Orai1G100S/+ 或 GS 小鼠）导致严重的早发性 TAM。到 8 个月大时，GS 小鼠表现出明显的肌肉无力、运动不耐受、CK 水平升高、低钙血症和强烈的 TA 存在。出乎意料的是，突变小鼠的组成型 Ca2 + 进入仅在早期发育期间在肌肉中观察到，并且在成年骨骼肌中被消除，部分原因是 ORAI1 表达降低。与蛋白质组学结果一致，在 GS 小鼠骨骼肌中观察到显着的线粒体损伤和功能障碍。因此，GS 小鼠代表了研究关键 TAM 症状背后的病理生理机制的强大模型，以及限制不受控制的 ORAI1 介导的 Ca2 + 内流的破坏作用的那些代偿反应。