Résumé :
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Boys born with the ATR-X syndrome have severe skeletal muscle weakness and hypotonia at birth. The resulting muscle weakness delays developmental milestones such as sitting, standing, and walking and many never become ambulatory during their life. To investigate the role of ATRX in muscle development a Cre-loxP approach was used to inactivate the ATRX gene specifically in skeletal muscle. ATRXf/y:Myf5Cre+/- mice were born with a reduced muscle mass, smaller fibres, and a normal number of satellite cells. Primary myoblasts from ATRXf/y:Myf5Cre+/- muscle failed to proliferate in culture suggesting a defect in satellite cell activation or proliferation. To further characterize ATRX function, we infected adult derived ATRXf/y primary myoblasts with Cre recombinase expressing adenovirus (ATRXf/y:Ad-Cre). ATRXf/y:Ad-Cre myoblasts display a lower proliferative capacity than ATRXf/y:Lac-Z controls in high mitogen growth media. Despite their inability to expand in culture, ATRX deficient primary myoblasts were capable of sequentially expressing the early and terminal markers myogenin and Myosin Heavy Chain. The activation and proliferative potential of ATRX deficient myoblasts were tested in vivo by cardiotoxin (CTX) muscle injury experiments. CTX treated ATRXf/y:Myf5Cre+/- mice demonstrated a poor ability to regenerate, highlighted by fewer numbers of centrally located nuclei and the presence of improperly regenerated fibrotic tissue. Taken together, ATRX is required for the expansion of satellite cells that is necessary for the growth and regeneration of skeletal muscle.
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