イチハラ　アツヒロ   ICHIHARA Atsuhiro   市原　淳弘    所属   医学部 医学科（東京女子医科大学病院）    職種   教授・基幹分野長
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	(Pro)renin receptor accelerates development of sarcopenia via activation of Wnt/YAP signaling axis.
掲載誌名	正式名：Aging cell 略　 称：Aging Cell ISSNコード：(1474-9726)1474-9718(Linking)
掲載区分	国外
巻・号・頁	pp.e12991
著者・共著者	Yoshida Naohiro†, Endo Jin, Kinouchi Kenichiro, Kitakata Hiroki, Moriyama Hidenori, Kataoka Masaharu, Yamamoto Tsunehisa, Shirakawa Kohsuke, Morimoto Satoshi, Nishiyama Akira, Hashiguchi Akihiro, Higuchi Itsuro, Fukuda Keiichi, Ichihara Atsuhiro, Sano Motoaki
発行年月	2019/07
概要	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.
DOI	10.1111/acel.12991
PMID	31282603