Requirement for PINCH in skeletal myoblast differentiation.
Requirement for PINCH in skeletal myoblast differentiation.
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DOI：
10.1007/s00441-022-03701-1
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发表时间：
2023-01
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Pinch是焦点黏附复合体的适配子，在多种细胞过程和器官发生中发挥重要作用。在这里，我们使用MyoD-Cre去除了骨骼肌祖细胞中的PINCH1或PINCH1和PINCH2。重复消融PINCH1和PINCH2可导致早期死亡，骨骼肌体积缩小，横隔肌脱离体壁。Pinch突变的肌纤维不能进行多核，并显示出肌节结构的破坏。突变的成肌细胞能够附着在新形成的肌管上，但阻碍了细胞融合和随后的肌节发生和细胞骨架组织。与此相一致的是，在PINCH突变体中，整合素β-1和一些细胞骨架蛋白的表达以及ERK和AKT的磷酸化显著降低。然而，在突变型PINCH细胞中，N-钙粘附素在细胞黏附部位正确表达，提示PINCH可能在成肌细胞融合中发挥直接作用。MRF4是肌肉发生后期最高表达的生肌因子，在PINCH突变体中表达被取消，这可能有助于观察到的表型。此外，在成肌前体细胞中去除PINCH1的小鼠仅表现出轻微的中心核肌病改变，表明PINCH2在成肌分化中起代偿作用。我们的结果揭示了PINCH蛋白在肌源性分化中的关键作用。
PINCH, an adaptor of focal adhesion complex, plays essential roles in multiple cellular processes and organogenesis. Here, we ablated PINCH1 or both of PINCH1 and PINCH2 in skeletal muscle progenitors using MyoD-Cre. Double ablation of PINCH1 and PINCH2 resulted in early postnatal lethality with reduced size of skeletal muscles and detachment of diaphragm muscles from the body wall. PINCH mutant myofibers failed to undergo multinucleation and exhibited disrupted sarcomere structures. The mutant myoblasts in culture were able to adhere to newly formed myotubes but impeded in cell fusion and subsequent sarcomere genesis and cytoskeleton organization. Consistent with this, expression of integrin β1 and some cytoskeleton proteins and phosphorylation of ERK and AKT were significantly reduced in PINCH mutants. However, N-cadherin was correctly expressed at cell adhesion sites in PINCH mutant cells, suggesting that PINCH may play a direct role in myoblast fusion. Expression of MRF4, the most highly expressed myogenic factor at late stages of myogenesis, was abolished in PINCH mutants that could contribute to observed phenotypes. In addition, mice with PINCH1 being ablated in myogenic progenitors exhibited only mild centronuclear myopathic changes, suggesting a compensatory role of PINCH2 in myogenic differentiation. Our results revealed a critical role of PINCH proteins in myogenic differentiation.
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