Abstract
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.
Highlights
Selenium is of fundamental importance to human and animal health
SEPN1-Related Myopathy describes a group of muscle diseases, clinically homogeneous with variable severity, all caused by mutations in the gene encoding selenoprotein N (SelN)
Development of animal models reproducing the biochemical defect of the human condition is an important step
Summary
Selenium is of fundamental importance to human and animal health. Dietary restriction of this trace element pointed to its implication in cancer prevention, viral infections protection, fertility and aging [1,2]. Since 2001, mutations in the human SEPN1 gene encoding selenoprotein N (SelN) have been associated with four early-onset, autosomal recessive neuromuscular disorders, recognised to represent a unique disease termed SEPN1-Related Myopathy (SEPN1-RM) [8,9,10,11]; reviewed in [12]. This muscular disease is clinically homogeneous, characterized by generalized muscle atrophy and predominant weakness of neck and trunk muscles from infancy, leading to severe scoliosis, spinal rigidity and life-threatening respiratory insufficiency in childhood or adolescence, but contrasting with relatively unaffected limb strength and ambulation. This observation, together with the large morphological spectrum of SEPN1-RM, suggests a complex underlying pathophysiological mechanism
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