Satellite cell loss and impaired muscle regeneration in selenoprotein N deficiency.
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.
UPMC Univ Paris 06, IFR14, Paris F-75013, France.
Perrine
P
Castets
Anne T
AT
Bertrand
Maud
M
Beuvin
Arnaud
A
Ferry
Fabien
F
Le Grand
Marie
M
Castets
Guillaume
G
Chazot
Mathieu
M
Rederstorff
Alain
A
Krol
Alain
A
Lescure
Norma B
NB
Romero
Pascale
P
Guicheney
Valérie
V
Allamand
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004179:Cobra Cardiotoxin Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D009135:Muscular Diseases / Q000473:pathology; D009154:Mutation; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology*; D051140:Selenoproteins / Q000172:deficiency* / Q000235:genetics*
D004179:Cobra Cardiotoxin Proteins; D051140:Selenoproteins