Functional analysis reveals that Tinagl1 is required for normal muscle development in mice through the activation of ERK signaling
Functional analysis reveals that Tinagl1 is required for normal muscle development in mice through the activation of ERK signaling
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功能分析表明 Tinagl1 通过激活 ERK 信号是小鼠正常肌肉发育所必需的
DOI：
10.1016/j.bbamcr.2022.119294
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Sato Yusuke
中科院分区：
文献类型：
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作者：
Sato Yoriko;Kawashima Keisuke;Fukui Emiko;Matsumoto Hiromichi;Yoshizawa Fumiaki;Sato Yusuke
Tinagl1(小管间质性肾炎抗原样蛋白1)是一种基质细胞蛋白，与女性不孕症和乳腺癌的发生有关。在这项研究中，我们利用基因敲除小鼠和细胞实验分析了Tinagl1在骨骼肌中的功能。虽然从Tinagl1-Decifient(Tinagl1−/−)小鼠分离的原代成肌细胞分化为正常肌管，并且重组Tinagl1处理没有影响C2C12成肌细胞的增殖或分化，但Tinagl1−/−小鼠的体重和小腿肌肉重量与对照组(Tinagl1 Flox/Flox)相比有所减轻。此外，Tinagl1−/−小鼠的肌纤维显示出位于中央的细胞核，这是再生肌肉或肌病的形态标志。此外，Tinagl1−/−小鼠比目鱼肌的毛细血管密度与对照组相比呈下降趋势。重要的是，si-RNA介导的TINAGL1基因敲除导致人脐静脉内皮细胞(HUVECs)管形成减少，而Tinagl1处理促进了管形成。免疫印迹分析显示，Tinagl1激活了HUVECs和C2C12成肌细胞和肌管中的ERK信号，参与了肌源性分化、增殖、代谢和血管生成的调节。我们的结果表明，Tinagl1可能是正常肌肉和毛细血管发育所必需的，通过激活ERK信号。
Tinagl1 (tubulointerstitial nephritis antigen-like 1) is a matricellular protein involved in female infertility and breast cancer tumorigenesis. In this study, we analyzed the function of Tinagl1 in skeletal muscle using knockout mice and cell experiments. Although primary myoblasts isolated fromTinagl1-decifient (Tinagl1−/−) mice differentiated into normal myotubes, and treatment with recombinant Tinagl1 did not affect the proliferation or differentiation of C2C12 myoblasts,Tinagl1−/−mice exhibited reduced body mass and calf muscle weights compared to the control group (Tinagl1flox/flox). Furthermore,Tinagl1−/−mice showed myofibers with centrally located nuclei, which is a morphological marker of regenerating muscle or myopathy. In addition, the capillary density in the soleus muscle ofTinagl1−/−mice showed a decreasing trend compared to that of the control group. Importantly, si-RNA-mediated knockdown ofTINAGL1resulted in reduced tube formation in human umbilical vein endothelial cells (HUVECs), whereas treatment with Tinagl1 promoted tube formation. Immunoblot analysis revealed that Tinagl1 activates ERK signaling in both HUVECs and C2C12 myoblasts and myotubes, which are involved in the regulation of myogenic differentiation, proliferation, metabolism, and angiogenesis. Our results demonstrate that Tinagl1 may be required for normal muscle and capillary development through the activation of ERK signaling.