Dudhal Swati
PhD scholar at Université Paris Diderot, France
Title: Selenoprotein N, mutated in SEPN1-related myopathy, restrains muscle stem cell differentiation’
Biography
Biography: Dudhal Swati
Abstract
Mutations of selenoprotein N (SEPN1) cause a congenital myopathy, SEPN1-related myopathy (SEPN1-RM), characterized by severe weakness and wasting of neck and trunk muscles, scoliosis and lethal respiratory failure. SEPN1-RM has been associated with oxidative stress, reduced satellite cell population and defective muscle regeneration. To investigate the underlying mechanisms, particularly a potential role of SEPN1 in regulating the balance between self-renewal and differentiation of the satellite cell pool, we used Sepn1 KO mouse primary satellite cells and C2C12 cells knocked down for Sepn1, at different stages of differentiation (quiescent cells, myoblasts and myotubes).
Using a suspension system to generate synchronized quiescence on C2C12, we found that SEPN1 absence does not prevent cell cycle exiting and re-entering but prevents normal downregulation of myogenic factors in G0 cells and leads to higher cyclin D1 levels in quiescence conditions. Microarray, qRT-PCR and protein studies showed that SEPN1 depletion leads to significant increase of MYOG and MYOD1 expression in proliferative C2C12. Moreover, primary muscle cells from the Sepn1 KO mice showed increased myoblast fusion at early myogenic differentiation.
We are currently exploring the mechanistic pathways leading to this cell phenotype. While we found no abnormalities of the AMPK-mediated pathway, our data suggest that HDAC5 could be involved in the accelerated differentiation phenotype. Other mechanistic studies are in progress.
In conclusion, lack of SEPN1 leads to incomplete quiescence and accelerated myogenic differentiation. Thus, we identify SEPN1 as a novel regulator of the muscle progenitor’s cell fate decision process, and SEPN1 depletion favors differentiation over self-renewal. These results potentially explain the depletion of the satellite cell population and the regeneration defect in SEPN1-RM models, and identify novel biomarkers useful to assess potential therapeutic interventions.