Katsuki Okada1, Atsuhiko T Naito2, Tomoaki Higo2, Akito Nakagawa2, Masato Shibamoto2, Taku Sakai2, Akihito Hashimoto2, Yuki Kuramoto2, Tomokazu Sumida2, Seitaro Nomura2, Masamichi Ito2, Toshihiro Yamaguchi2, Toru Oka2, Hiroshi Akazawa2, Jong-Kook Lee2, Sachio Morimoto2, Yasushi Sakata2, Ichiro Shiojima2, Issei Komuro1. 1. From the Departments of Cardiovascular Medicine (K.O., A.T.N., T.H., A.N., M.S., T.S., A.H., Y.K., T.O., Y.S.) and Cardiovascular Regenerative Medicine (J.-K.L.), Osaka University Graduate School of Medicine, Osaka, Japan; Japan Science and Technology Agency, CREST, Tokyo, Japan (A.T.N., T.S., S.N., T.O., H.A., J.-K.L., I.S., I.K.); Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (A.T.N., T.S., S.N., M.I., T.Y., H.A., I.K.); Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (S.M.); Department of Medicine II, Kansai Medical University, Osaka, Japan (I.S.); and Institute for Academic Initiatives, Osaka University, Osaka, Japan (I.K.). katsu-ki@umin.ac.jp komuro-tky@umin.ac.jp. 2. From the Departments of Cardiovascular Medicine (K.O., A.T.N., T.H., A.N., M.S., T.S., A.H., Y.K., T.O., Y.S.) and Cardiovascular Regenerative Medicine (J.-K.L.), Osaka University Graduate School of Medicine, Osaka, Japan; Japan Science and Technology Agency, CREST, Tokyo, Japan (A.T.N., T.S., S.N., T.O., H.A., J.-K.L., I.S., I.K.); Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (A.T.N., T.S., S.N., M.I., T.Y., H.A., I.K.); Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (S.M.); Department of Medicine II, Kansai Medical University, Osaka, Japan (I.S.); and Institute for Academic Initiatives, Osaka University, Osaka, Japan (I.K.).
Abstract
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS AND RESULTS: 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 cardiomyopathymice 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 cardiomyopathymice. CONCLUSIONS: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.
Authors: William A Murphy; Nan Lin; Amy Damask; Gregory G Schwartz; P Gabriel Steg; Michael Szarek; Poulabi Banerjee; Sergio Fazio; Garen Manvelian; Robert Pordy; Alan R Shuldiner; Charles Paulding Journal: Circ Genom Precis Med Date: 2022-05-11
Authors: Aurelija Abraityte; Ida G Lunde; Erik T Askevold; Annika E Michelsen; Geir Christensen; Pål Aukrust; Arne Yndestad; Arnt Fiane; Arne Andreassen; Svend Aakhus; Christen P Dahl; Lars Gullestad; Kaspar Broch; Thor Ueland Journal: Sci Rep Date: 2017-06-14 Impact factor: 4.379