Progressive myopathy and defects in the maintenance of myotendinous junctions in mice that lack talin 1 in skeletal muscle
Progressive myopathy and defects in the maintenance of myotendinous junctions in mice that lack talin 1 in skeletal muscle
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DOI：
10.1242/dev.015818
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发表时间：
2008-06-01
期刊：
影响因子：
4.6
通讯作者：
Mueller, Ulrich
中科院分区：
文献类型：
--
作者：
Conti, Francesco J.;Felder, Amanda;Mueller, Ulrich
骨骼肌的发育和功能依赖于连接肌纤维细胞骨架和细胞外基质的分子。β 1整联蛋白是骨骼肌中的ECM受体，影响α 7 β 1整联蛋白的突变导致人类肌病。在小鼠中，β 1整联蛋白控制成肌细胞融合、肌纤维细胞骨架的组装和肌腱连接（MTJ）的维持。在肌肉中介导β 1整合素功能的效应分子尚不清楚。先前的研究表明，talin 1控制整合素粘附复合物的力依赖性组装，并调节整合素对配体的亲和力。在这里，我们表明，塔林1是必不可少的骨骼肌的整合素附着位点在MTJ的维护。具有骨骼肌特异性talin 1基因消融的小鼠患有进行性肌病。令人惊讶的是，成肌细胞融合和装配的整合素含有粘附复合物在costameres和MTJs的进展正常的突变体。然而，随着年龄的增长，肌纤维细胞骨架从MTJ上脱落。对离体肌肉的力学测量显示talin 1缺陷肌肉产生力的能力存在缺陷。总的来说，我们的研究结果表明，talin 1是必不可少的提供机械稳定性的整合素依赖性粘附复合物在MTJ，这是至关重要的最佳力产生骨骼肌。
The development and function of skeletal muscle depend on molecules that connect the muscle fiber cytoskeleton to the extracellular matrix (ECM). beta 1 integrins are ECM receptors in skeletal muscle, and mutations that affect the alpha 7 beta 1 integrin cause myopathy in humans. In mice, beta 1 integrins control myoblast fusion, the assembly of the muscle fiber cytoskeleton, and the maintenance of myotendinous junctions (MTJs). The effector molecules that mediate beta 1 integrin functions in muscle are not known. Previous studies have shown that talin 1 controls the force-dependent assembly of integrin adhesion complexes and regulates the affinity of integrins for ligands. Here we show that talin 1 is essential in skeletal muscle for the maintenance of integrin attachment sites at MTJs. Mice with a skeletal muscle-specific ablation of the talin 1 gene suffer from a progressive myopathy. Surprisingly, myoblast fusion and the assembly of integrin-containing adhesion complexes at costameres and MTJs advance normally in the mutants. However, with progressive ageing, the muscle fiber cytoskeleton detaches from MTJs. Mechanical measurements on isolated muscles show defects in the ability of talin 1-deficient muscle to generate force. Collectively, our findings show that talin 1 is essential for providing mechanical stability to integrin-dependent adhesion complexes at MTJs, which is crucial for optimal force generation by skeletal muscle.