Satellite cell loss and impaired muscle regeneration in selenoprotein N deficiency

UPMC Univ Paris 06, IFR14, Paris F-75013, France.
Human Molecular Genetics (Impact Factor: 6.39). 02/2011; 20(4):694-704. DOI: 10.1093/hmg/ddq515
Source: PubMed


Selenoprotein N (SelN) deficiency causes a group of inherited neuromuscular disorders termed SEPN1-related myopathies (SEPN1-RM). 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 (SC) function and muscle regeneration, using the 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 SC pool in adult skeletal muscles and in an imperfect muscle restoration following a single injury. A dramatic depletion of the SC pool was detected after the first round of degeneration and regeneration that totally prevented subsequent regeneration of Sepn1(-/-) muscles. We demonstrate that SelN deficiency affects SC dynamics on isolated single fibres and increases the proliferation of Sepn1(-/-) muscle precursors in vivo and in vitro. Most importantly, exhaustion of the SC population was specifically identified in muscle biopsies from patients with mutations in the SEPN1 gene. In conclusion, we describe for the first time a major physiological function of SelN in skeletal muscles, as a key regulator of SC function, which likely plays a central role in the pathophysiological mechanism leading to SEPN1-RM.

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Available from: Pascale Guicheney
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    • "Glutathione peroxidases are a subfamily of selenoproteins involved in H 2 O 2 -dependent signaling, detoxification of hydroperoxides, and maintenance of cellular redox homeostasis [34]. Selenoprotein N is an important protein involved in muscle regeneration [35]. In vitro experiments have shown that treatment with statins decreases the expression of selenoproteins in myoblasts and also causes a reduction in antioxidant capacity, resulting in a decreased cell viability [36]. "
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    • "Such impairment could potentially explain the dystrophic features observed in patient biopsy tissue at ages 8 and 9. Notably, a recent study found that Sepn1−/− null mice showed a decrease in the baseline number of satellite cells in adult skeletal muscle, as well as imperfect muscle regeneration in response to a first injury and an inability to regenerate muscle following a second injury. MmD patients with SEPN1 deficiency also had a reduction in their satellite cell population [48]. These data suggest that both MmD and the myopathy described here, which share some clinical and histological characteristics, may arise through a common pathogenic mechanism of satellite cell dysfunction. "
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    • "This is the case for SEPN1-related myopathies caused by selenoprotein N deficiency and characterised by early-onset muscle atrophy. Similarly to humans with this condition, Sepn1 –/– mice are also defective in satellite cells and undergo a marked muscle atrophy with the presence of fat following repeated regenerative injury (Castets et al., 2010) in a manner that is reminiscent of DTdepleted Pax7 DTR/+ mice. The notion that a critical threshold for satellite cell numbers can be linked directly to the loss of muscle tissue may help to disentangle the metabolic and cellular intricacies involved in complex conditions, such as ageing or sarcopenic obesity. "
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