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. 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.

Wnt5a is associated with right ventricular dysfunction and adverse outcome in dilated cardiomyopathy

“…Wnt signaling has recently been implicated in maladaptive cardiac remodeling and cardiomyopathy through activation of both canonical and non-canonical pathways 8, 26–28 . Herein we extend and lend clinical support to previous findings, showing that Wnt5a was associated with RV dysfunction and adverse outcome in patients with DCM.…”

FoxO1: a novel insight into its molecular mechanisms in the regulation of skeletal muscle differentiation and fiber type specification

“…FoxO1 inhibited the generation of insulin-positive cells [37] and insulin treatment significantly restored the inhibiting myogenic differentiation caused by FoxO1 [35]. Moreover, treatment with LiCl, a strong stimulator of myogenesis and an activator of Wnt signaling that cooperates with insulin to promote myogenesis [38, 39], parallelly significantly restored FoxO1 inhibiting function on myogenic differentiation [40]. Simultaneous application of insulin and LiCl can distinctly overcome the inhibiting effect caused by active FoxO1 and promote myoblast differentiation synergistically [35, 40].…”

Heart Failure as an Aging-Related Phenotype

“…17) Recently, C1q-induced activation of Wnt/β-catenin signaling in skeletal muscle during chronic heart failure was shown to contribute to skeletal myopathy via the functional interaction between β-catenin and transcription factor Forkhead box O1 (FoxO1). 18) In cultured C2C12 mouse myoblasts, serum of DCM model mice (knock-in mice with deletion mutation K210 in cardiac troponin T gene) activated both Wnt and FoxO signaling and induced a fiber type shift of myosin heavy chain towards fatigable fiber IIb (encoded by Myh4) (Figure 4) as were observed in the skeletal muscle of DCM model mice. The Wnt inhibitor DKK1 and a C1 inhibitor attenuated FoxO signaling and fiber type shift both in C2C12 cells and skeletal muscle of DCM model mice, suggesting that systemicallyincreased Wnt ligands (e,g,.…”