Mutations in MYH3, the gene encoding the developmental myosin heavy chain-embryonic (MyHC-embryonic) skeletal muscle-specific contractile protein, cause several congenital contracture syndromes. Among these, recessive loss-of-function MYH3 mutations lead to spondylocarpotarsal synostosis (SCTS), characterized by vertebral fusions and scoliosis. We find that Myh3 germline knockout adult mice display SCTS phenotypes such as scoliosis and vertebral fusion, in addition to reduced body weight, muscle weight, myofiber size, and grip strength. Myh3 knockout mice also exhibit changes in muscle fiber type, altered satellite cell numbers and increased muscle fibrosis. A mass spectrometric analysis of embryonic skeletal muscle from Myh3 knockouts identified integrin signaling and cytoskeletal regulation as the most affected pathways. These pathways are closely connected to the mechanosensing Yes-associated protein (YAP) transcriptional regulator, which we found to be significantly activated in the skeletal muscle of Myh3 knockout mice. To test whether increased YAP signaling might underlie the musculoskeletal defects in Myh3 knockout mice, we treated these mice with CA3, a small molecule inhibitor of YAP signaling. This led to increased muscle fiber size, rescue of most muscle fiber type alterations, normalization of the satellite cell marker Pax7 levels, increased grip strength, reduced fibrosis, and decline in scoliosis in Myh3 knockout mice. Thus, increased YAP activation underlies the musculoskeletal defects seen in Myh3 knockout mice, indicating its significance as a key pathway to target in SCTS and other MYH3-related congenital syndromes.

中文翻译：

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与肌球蛋白重链胚胎功能丧失相关的肌肉骨骼缺陷是由 YAP 信号通路介导的

MYH3 （编码发育肌球蛋白重链胚胎（MyHC-胚胎）骨骼肌特异性收缩蛋白的基因）的突变会导致多种先天性挛缩综合征。其中，隐性功能丧失的MYH3突变会导致脊椎骨跗骨连接 (SCTS)，其特征是椎体融合和脊柱侧凸。我们发现Myh3种系敲除成年小鼠表现出 SCTS 表型，例如脊柱侧弯和椎体融合，此外体重、肌肉重量、肌纤维尺寸和握力也有所减轻。Myh3基因敲除小鼠还表现出肌纤维类型的变化、卫星细胞数量的改变和肌肉纤维化的增加。对Myh3敲除的胚胎骨骼肌的质谱分析发现，整合素信号传导和细胞骨架调节是受影响最大的途径。这些通路与机械传感 Yes 相关蛋白 (YAP) 转录调节因子密切相关，我们发现该调节因子在Myh3敲除小鼠的骨骼肌中显着激活。为了测试 YAP 信号传导的增加是否可能是Myh3敲除小鼠肌肉骨骼缺陷的原因，我们用 YAP 信号传导的小分子抑制剂 CA3 治疗这些小鼠。这导致 Myh3 敲除小鼠的肌纤维尺寸增加、大多数肌纤维类型改变得以挽救、卫星细胞标记 Pax7 水平正常化、握力增加、纤维化减少以及脊柱侧凸下降。因此，YAP 激活增加是Myh3敲除小鼠中观察到的肌肉骨骼缺陷的基础，表明其作为 SCTS 和其他MYH3相关先天性综合征的关键靶标途径的重要性。