Increased Muscle Stress-Sensitivity Induced by Selenoprotein N Inactivation in Mouse: A Mammalian Model for SEPN1-Related Myopathy

Selenium is an essential trace element and selenoprotein N (SelN) was the first selenium-containing protein shown to be directly involved in human inherited diseases. Mutations in the SEPN1 gene, encoding SelN, cause a group of muscular disorders characterized by predominant affection of axial muscles. SelN has been shown to participate in calcium and redox homeostasis, but its pathophysiological role in skeletal muscle remains largely unknown. To address SelN function in vivo, we generated a Sepn1-null mouse model by gene targeting. The Sepn1−/− mice had normal growth and lifespan, and were macroscopically indistinguishable from wild-type littermates. Only minor defects were observed in muscle morphology and contractile properties in SelN-deficient mice in basal conditions. However, when subjected to challenging physical exercise and stress conditions (forced swimming test), Sepn1−/− mice developed an obvious phenotype, characterized by limited motility and body rigidity during the swimming session, as well as a progressive curvature of the spine and predominant alteration of paravertebral muscles. This induced phenotype recapitulates the distribution of muscle involvement in patients with SEPN1-Related Myopathy, hence positioning this new animal model as a valuable tool to dissect the role of SelN in muscle function and to characterize the pathophysiological process.硒（Selenium）是一种必需的微量元素，硒蛋白N（selenoprotein N，SelN）是首个被证实直接参与人类遗传性疾病的含硒蛋白。编码SelN的SEPN1基因发生突变，可引发一组以轴肌受累为主要特征的肌肉疾病。现有研究表明，SelN参与钙稳态与氧化还原稳态的调控，但其在骨骼肌中的病理生理作用仍未完全明确。为阐明SelN在体内的生物学功能，我们通过基因靶向技术构建了Sepn1基因敲除（Sepn1-null）小鼠模型。Sepn1−/−小鼠的生长发育与寿命均正常，宏观外观与野生型同窝仔鼠无显著差异。在基础状态下，SelN缺陷小鼠仅在肌肉形态与收缩特性上存在轻微异常。然而，当施加挑战性体力运动与应激条件（强迫游泳实验，forced swimming test）时，Sepn1−/−小鼠出现了显著表型：游泳过程中运动能力受限、躯体僵硬，同时伴随进行性脊柱弯曲与椎旁肌的显著病变。该诱导表型重现了SEPN1相关肌病（SEPN1-Related Myopathy）患者的肌肉受累分布特征，因此这一新的动物模型可作为有效工具，用于解析SelN在肌肉功能中的具体作用，并阐明其相关病理生理过程。