Résumé :
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In humans, selenoprotein N (SelN) deficiency, due to mutations in the SEPN1 gene, causes a group of inherited neuromuscular disorders termed SEPN1-Related Myopathies. These congenital diseases are characterized by an early onset generalized muscle atrophy and weakness leading to spinal rigidity, severe scoliosis and respiratory insufficiency. Although the function of SelN remains unknown, recent data demonstrated that it is dispensable for mouse embryogenesis and suggested its involvement in the regulation of ryanodine receptors and/or cellular redox homeostasis. Here, we investigate the role of SelN in satellite cell function and muscle regeneration, using the knock-out Sepn1-/-mouse model. Following cardiotoxin-induced injury, SelN expression was strongly up-regulated in wild-type muscles and, for the first time, we detected its endogenous expression in a subset of mononucleated cells by immunohistochemistry. We show that SelN deficiency results in a reduced basal satellite cell pool in adult skeletal muscle and in an imperfect muscle restoration following a single injury. A dramatic depletion of the satellite cell pool was detected after the first round of degeneration /regeneration that totally prevented subsequent regeneration of Sepn1-/-muscles. We demonstrate that SelN deficiency affects satellite cell dynamics on isolated single fibres, and increases the proliferation of Sepn1-/- muscle precursors in vivo and in vitro. Most importantly, exhaustion of the satellite cell population was specifically identified in muscle biopsies from patients with SEPN1 mutations. In conclusion, we describe for the first time a major physiological function of SelN in skeletal muscle, as a key regulator of satellite cell maintenance. We propose that the satellite cell defect described herein is responsible for the characteristic muscle atrophy in SEPN1-Related Myopathy, by reducing the pool of muscle progenitors participating in muscle growth.
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