Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / metabolism
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Cell Differentiation
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Cell Proliferation
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Cells, Cultured
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Chromatin / genetics
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Chromatin / metabolism
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DNA Damage
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DNA Helicases / genetics*
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DNA Helicases / metabolism
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DNA Helicases / physiology
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DNA Replication
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DNA-Binding Proteins / metabolism
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Female
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Genomic Instability*
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Histones / metabolism
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Humans
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Male
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Mental Retardation, X-Linked / genetics
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Mental Retardation, X-Linked / physiopathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitosis
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Muscle Development*
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Muscle, Skeletal / pathology
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Muscle, Skeletal / physiopathology
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology
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Primary Cell Culture
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Protein Serine-Threonine Kinases / metabolism
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Rad51 Recombinase / metabolism
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Regeneration / genetics
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S Phase Cell Cycle Checkpoints
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Satellite Cells, Skeletal Muscle / pathology
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Satellite Cells, Skeletal Muscle / physiology
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Telomere / genetics
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Telomere / metabolism
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / metabolism
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X-linked Nuclear Protein
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alpha-Thalassemia / genetics
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alpha-Thalassemia / physiopathology
Substances
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Cell Cycle Proteins
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Chromatin
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DNA-Binding Proteins
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Histones
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Nuclear Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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gamma-H2AX protein, mouse
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Rad51 Recombinase
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Rad51 protein, mouse
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DNA Helicases
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Atrx protein, mouse
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X-linked Nuclear Protein