Genetic compensation for sarcoglycan loss by integrin α7β1 in muscle
Genetic compensation for sarcoglycan loss by integrin α7β1 in muscle
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DOI：
10.1242/jcs.01234
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发表时间：
2004-08-01
影响因子：
4
通讯作者：
McNally, EM
中科院分区：
文献类型：
--
作者：
Allikian, MJ;Hack, AA;McNally, EM
肌聚糖复合物的破坏会导致人类和小鼠的肌膜不稳定和肌营养不良。通过肌营养不良蛋白糖蛋白复合物，肌聚糖参与将内部细胞骨架与膜和细胞外基质连接。整合素 α7β1 也是骨骼肌和心肌的跨膜蛋白，同样将细胞骨架与细胞外基质连接起来。缺乏整合素α7的小鼠会出现轻度肌肉变性，而肌聚糖突变小鼠则表现出明显的肌肉变性和肌营养不良。在肌聚糖缺乏的肌肉中，质膜上的整合素α7蛋白上调。为了确定整合素α7上调是否可以补偿肌聚糖缺陷肌肉中跨膜肌聚糖连接的损失，我们培育了同时缺乏整合素α7和γ-肌聚糖（gxi）的小鼠。这些双突变 gxi 小鼠表现出严重、快速的肌肉退化，导致一个月龄前死亡，这与细胞与细胞外基质的附着减弱一致。 gxi 肌肉的再生能力完整，胚胎肌球蛋白重链表达增加，肌纤维中央成核和体内成肌细胞分化正常。因此，整合素α7β1的上调作为肌聚糖的跨膜肌细胞附着进行补偿，这与肌聚糖和整合素在介导细胞骨架-膜-细胞外基质相互作用中的重叠作用一致。
Disruption of the sarcoglycan complex leads to muscle membrane instability and muscular dystrophy in humans and mice. Through the dystrophin glycoprotein complex, sarcoglycan participates in connecting the internal cytoskeleton to the membrane and the extracellular matrix. Integrin alpha7beta1 is also a transmembrane protein of skeletal and cardiac muscle that similarly links the cytoskeleton to the extracellular matrix. Mice lacking integrin alpha7 develop mild muscle degeneration, while sarcoglycan mutant mice display overt muscle degeneration and muscular dystrophy. In sarcoglycan-deficient muscle, integrin alpha7 protein was upregulated at the plasma membrane. To ascertain whether integrin alpha7 upregulation compensates for the loss of the transmembrane sarcoglycan linkage in sarcoglycan-deficient muscle, we generated mice lacking both integrin alpha7 and gamma-sarcoglycan (gxi). These double-mutant gxi mice exhibit profound, rapid muscle degeneration leading to death before one month of age consistent with a weakened cellular attachment to the extracellular matrix. The regenerative capacity of gxi muscle was intact with increased embryonic myosin heavy chain expression, myofiber central nucleation and normal in vivo myoblast differentiation. Therefore, upregulation of integrin alpha7beta1 compensates as a transmembrane muscle cell attachment for sarcoglycan consistent with overlapping roles for sarcoglycan and integrins in mediating cytoskeletal-membrane-extracellular matrix interaction.