title: Wnt/β-Catenin Signaling Contributes to Skeletal Myopathy in Heart Failure via Direct Interaction With Forkhead Box O.
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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Katsuki
authors.initials: K
authors.lastname: Okada
authors.affiliation: 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.).
authors.forename: Atsuhiko T
authors.initials: AT
authors.lastname: Naito
authors.affiliation: 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.).
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Higo
authors.affiliation: 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.).
authors.forename: Akito
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: 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.).
authors.forename: Masato
authors.initials: M
authors.lastname: Shibamoto
authors.affiliation: 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.).
authors.forename: Taku
authors.initials: T
authors.lastname: Sakai
authors.affiliation: 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.).
authors.forename: Akihito
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: 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.).
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuramoto
authors.affiliation: 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.).
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Sumida
authors.affiliation: 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.).
authors.forename: Seitaro
authors.initials: S
authors.lastname: Nomura
authors.affiliation: 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.).
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ito
authors.affiliation: 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.).
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: 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.).
authors.forename: Toru
authors.initials: T
authors.lastname: Oka
authors.affiliation: 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.).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.affiliation: 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.).
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.affiliation: 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.).
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: 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.).
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: 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.).
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.affiliation: 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.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D015922:Complement C1q / Q000378:metabolism; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D018763:Muscle Fatigue; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009135:Muscular Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D034622:RNA Interference; D014162:Transfection; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; D015922:Complement C1q
keywords: Wnt beta-catenin signaling pathway; complement C1q; dilated cardiomyopathy; forkhead box transcription factors; heart failure; serum; skeletal muscle fibers