Wnt/β-Catenin Signaling Contributes to Skeletal Myopathy in Heart Failure via Direct Interaction With Forkhead Box O. (July 2015)

• Record Type: Journal Article
• Authors: Okada, Katsuki; Naito, Atsuhiko T.; Higo, Tomoaki; Nakagawa, Akito; Shibamoto, Masato; Sakai, Taku; Hashimoto, Akihito; Kuramoto, Yuki; Sumida, Tomokazu; Nomura, Seitaro; Ito, Masamichi; Yamaguchi, Toshihiro; Oka, Toru; Akazawa, Hiroshi; Lee, Jong-Kook; Morimoto, Sachio; Sakata, Yasushi; Shiojima, Ichiro; Komuro, Issei
• Is Part Of: Circulation. Volume 8:Number 4(2015)
• Publication Date: 2015-07
• Subjects: Heart failure -- Periodicals; 616.129005
• DOI: 10.1161/CIRCHEARTFAILURE.114.001958
• Languages: English
• ISSNs: 1941-3289

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>There are changes in the skeletal muscle of patients with chronic heart failure (CHF), such as volume reduction and fiber type shift toward fatigable type IIb fiber. Forkhead box O (FoxO) signaling plays a critical role in the development of skeletal myopathy in CHF, and functional interaction between FoxO and the Wnt signal mediator β-catenin was previously demonstrated. We have recently reported that serum of CHF model mice activates Wnt signaling more potently than serum of control mice and that complement C1q mediates this activation. We, therefore, hypothesized that C1q-induced activation of Wnt signaling plays a critical role in skeletal myopathy via the interaction with FoxO.</p> </sec> <sec> <title>Methods and Results—</title> <p>Fiber type shift toward fatigable fiber was observed in the skeletal muscle of dilated cardiomyopathy model mice, which was associated with activation of both Wnt and FoxO signaling. Wnt3a protein activated FoxO signaling and induced fiber type shift toward fatigable fiber in C2C12 cells. Wnt3a-induced fiber type shift was inhibited by suppression of FoxO1 activity, whereas Wnt3a-independent fiber type shift was observed by overexpression of constitutively active FoxO1. Serum of dilated cardiomyopathy mice activated both Wnt and FoxO signaling and induced fiber type shift toward fatigable fiber in C2C12 cells. Wnt inhibitor and C1-inhibitor attenuated FoxO activation and fiber type shift both in C2C12 cells and in the skeletal muscle of dilated cardiomyopathy mice.</p> </sec> <sec> <title>Conclusions—</title> <p>C1q-induced activation of Wnt signaling contributes to fiber type shift toward fatigable fiber in CHF. Wnt signaling may be a novel therapeutic target to prevent skeletal myopathy in CHF.</p> </sec> </abstract>