(Pro)renin receptor accelerates development of sarcopenia via activation of Wnt/YAP signaling axis
(Pro)renin receptor accelerates development of sarcopenia via activation of Wnt/YAP signaling axis
复制标题
DOI：
10.1111/acel.12991
复制
发表时间：
2019-07
期刊：
影响因子：
7.8
通讯作者：
N. Yoshida;J. Endo;Kenichiro Kinouchi;Hiroki Kitakata;Hidenori Moriyama;M. Kataoka;Tsunehisa Yamamoto;K. Shirakawa;S. Morimoto;A. Nishiyama;A. Hashiguchi;I. Higuchi;K. Fukuda;A. Ichihara;M. Sano
中科院分区：
文献类型：
--
作者：
N. Yoshida;J. Endo;Kenichiro Kinouchi;Hiroki Kitakata;Hidenori Moriyama;M. Kataoka;Tsunehisa Yamamoto;K. Shirakawa;S. Morimoto;A. Nishiyama;A. Hashiguchi;I. Higuchi;K. Fukuda;A. Ichihara;M. Sano
为了延长预期寿命和确保健康衰老，预防和减少年龄引起的骨骼肌萎缩至关重要，这种萎缩也称为骨质疏松症。然而，该病的分子机制仍不清楚。最近发现，与年龄相关的WnT/β-连环蛋白信号通路被(PRO)肾素受体((P)RR)激活。我们在此报告了(P)RR在衰老小鼠和人类萎缩的骨骼肌中的表达增加。因此，我们在CAG启动子的控制下，通过转基因表达(P)RR建立了老年性骨质疏松症的功能获得性模型。与我们的假设一致，(P)RR-TG小鼠死亡早，并表现出肌肉萎缩，组织学特征为骨质疏松症。此外，在(P)RR-TG小鼠中，由于细胞融合失败，Wnt/β-catenin信号通路被激活，肌祖细胞在心脏毒素损伤后的再生能力受损。(P)RR蛋白在C2C12成肌细胞中的强制表达通过激活Wnt/β-catenin信号通路抑制肌管的形成。给予WNT/β-连环蛋白信号的抑制剂Dickkopf相关蛋白1和抑制(P)RR与Wnt受体结合的抗(P)RR中和抗体，显著改善(P)RR-TG小鼠的骨骼肌减少。此外，抗(P)RR中和抗体的使用显著提高了老年小鼠骨骼肌的再生能力。最后，我们发现由Wnt/β-catenin协调调节的YAP信号参与了(P)RR诱导的骨骼肌减少症的发生。本研究证实了(P)RR-Tg小鼠作为一种新的骨质疏松症模型的应用，并表明(P)RR-Wnt-Yap信号在本病的发病机制中起着关键作用。
To extend life expectancy and ensure healthy aging, it is crucial to prevent and minimize age‐induced skeletal muscle atrophy, also known as sarcopenia. However, the disease's molecular mechanism remains unclear. The age‐related Wnt/β‐catenin signaling pathway has been recently shown to be activated by the (pro)renin receptor ((P)RR). We report here that (P)RR expression was increased in the atrophied skeletal muscles of aged mice and humans. Therefore, we developed a gain‐of‐function model of age‐related sarcopenia via transgenic expression of (P)RR under control of the CAG promoter. Consistent with our hypothesis, (P)RR‐Tg mice died early and exhibited muscle atrophy with histological features of sarcopenia. Moreover, Wnt/β‐catenin signaling was activated and the regenerative capacity of muscle progenitor cells after cardiotoxin injury was impaired due to cell fusion failure in (P)RR‐Tg mice. In vitro forced expression of (P)RR protein in C2C12 myoblast cells suppressed myotube formation by activating Wnt/β‐catenin signaling. Administration of Dickkopf‐related protein 1, an inhibitor of Wnt/β‐catenin signaling, and anti‐(P)RR neutralizing antibody, which inhibits binding of (P)RR to the Wnt receptor, significantly improved sarcopenia in (P)RR‐Tg mice. Furthermore, the use of anti‐(P)RR neutralizing antibodies significantly improved the regenerative ability of skeletal muscle in aged mice. Finally, we show that Yes‐associated protein (YAP) signaling, which is coordinately regulated by Wnt/β‐catenin, contributed to the development of (P)RR‐induced sarcopenia. The present study demonstrates the use of (P)RR‐Tg mice as a novel sarcopenia model, and shows that (P)RR‐Wnt‐YAP signaling plays a pivotal role in the pathogenesis of this disease.