ATR-X syndrome is a severe intellectual disability disorder caused by mutations in the ATRX gene. Many ancillary clinical features are attributed to CNS deficiencies, yet most patients have muscle hypotonia, delayed ambulation, or kyphosis, pointing to an underlying skeletal muscle defect. Here, we identified a cell-intrinsic requirement for Atrx in postnatal muscle growth and regeneration in mice. Mice with skeletal muscle-specific Atrx conditional knockout (Atrx cKO mice) were viable, but by 3 weeks of age presented hallmarks of underdeveloped musculature, including kyphosis, 20% reduction in body mass, and 34% reduction in muscle fiber caliber. Atrx cKO mice also demonstrated a marked regeneration deficit that was not due to fewer resident satellite cells or their inability to terminally differentiate. However, activation of Atrx-null satellite cells from isolated muscle fibers resulted in a 9-fold reduction in myoblast expansion, caused by delayed progression through mid to late S phase. While in S phase, Atrx colocalized specifically to late-replicating chromatin, and its loss resulted in rampant signs of genomic instability. These observations support a model in which Atrx maintains chromatin integrity during the rapid developmental growth of a tissue.
Author contributions M.G., I.A. and L.B. conceptualized and designed the study. M.G., I.A. and L.B. prepared the manuscript. M.G. performed, analyzed and interpreted the majority of the experiments describing the mouse modeling. D.O. and L.B. designed, performed and interpreted the majority of the proteomics experiments. I.D., Y.G., L.Z.-R. and A.T. performed all of the computational analysis. N.K. generated mouse strains. Y.D., K.C. and M.M. provided technical assistance with animal models. A.S., L.F. and M.P.W. performed the mass spectrometry. S.T.Y. and K.M.K. performed and interpreted the tissue immunofluorescence and the influenza experiment. C.P. analyzed the mouse pathology. C.B. provided the Spop antibody and shared experimental protocols. A.N.T., K.M.K., C.P. and C.B. provided intellectual input.
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