Compromised genomic integrity impedes muscle growth after Atrx inactivation
Compromised genomic integrity impedes muscle growth after Atrx inactivation
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DOI：
10.1172/jci63765
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发表时间：
2012-12-01
影响因子：
15.9
通讯作者：
Picketts, David J.
中科院分区：
文献类型：
--
作者：
Huh, Michael S.;O'Dea, Tina Price;Picketts, David J.
ATR-X综合征是一种由ATRX基因突变引起的严重智能障碍。许多辅助的临床特征被归因于中枢神经系统的缺陷，但大多数患者都有肌肉低张延迟行走或后凸，这里指出潜在的骨骼肌缺陷，我们确定了在小鼠出生后肌肉生长和再生中对ATRX的细胞内在需求。骨骼肌特异性ATRX条件性基因敲除小鼠(ATRX CKO小鼠)是存活的，但在3周后出现肌肉不发达的特征，包括脊柱后凸，体重减少20%，肌肉纤维直径减少34%。ATRX CKO小鼠也表现出明显的再生缺陷，这不是由于常驻卫星细胞较少或它们无法终末分化所致。然而，从分离的肌肉纤维中激活ATRX缺失的卫星细胞导致成肌细胞扩张减少9倍，这是由于S相中后期进展延迟所致。而在S期，ATRX共定位于晚期复制的染色质，它的丢失导致了基因组不稳定的迹象。这些观察支持了ATRX在组织的快速发育过程中保持染色质完整性的模型。
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 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.