Wnt/β-catenin signaling via Axin2 is required for myogenesis and, together with YAP/Taz and Tead1, active in IIa/IIx muscle fibers

Abstract

Canonical Wnt/β-catenin signaling plays an important role in myogenic differentiation, but its physiological role in muscle fibers remains elusive. Here, we studied activation of Wnt/β-catenin signaling in adult muscle fibers and muscle stem cells in an Axin2 reporter mouse. Axin2 is a negative regulator and a target of Wnt/β-catenin signaling. In adult muscle fibers, Wnt/β-catenin signaling is only detectable in a subset of fast fibers that have a significantly smaller diameter than other fast fibers. In the same fibers, immunofluorescence staining for YAP/Taz and Tead1 was detected. Wnt/β-catenin signaling was absent in quiescent and activated satellite cells. Upon injury, Wnt/β-catenin signaling was detected in muscle fibers with centrally located nuclei. During differentiation of myoblasts expression of Axin2, but not of Axin1, increased together with Tead1 target gene expression. Furthermore, absence of Axin1 and Axin2 interfered with myoblast proliferation and myotube formation, respectively. Treatment with the canonical Wnt3a ligand also inhibited myotube formation. Wnt3a activated TOPflash and Tead1 reporter activity, whereas neither reporter was activated in the presence of Dkk1, an inhibitor of canonical Wnt signaling. We propose that Axin2-dependent Wnt/β-catenin signaling is involved in myotube formation and, together with YAP/Taz/Tead1, associated with reduced muscle fiber diameter of a subset of fast fibers.

The roles of Wnt/β‐catenin pathway in tissue development and regenerative medicine

“…As considering the Wnt as a profibrotic factor, Majidinia and Yousefi () reported that a continued increase in activity of the canonical Wnt signaling pathway in myogenic progenitors is related to enhance in the differentiation of myogenic satellite cells to fibrogenic lineages in aging mice. Huraskin et al () also reported the same resulted and showed that upon injury, Wnt/β‐catenin signaling was detected in muscle fibers with centrally located nuclei. Another tissue with successful regulation after injuries induced by drug or alcohol toxicity and persistent viral infection is liver.…”

Wnt1‐inducible signaling protein 1 regulates laryngeal squamous cell carcinoma glycolysis and chemoresistance via the YAP1/TEAD1/GLUT1 pathway

“…Canonical Wnt signaling activates TEAD1 and Hippo transducer YAP1 in myoblast proliferation and differentiation (Huraskin et al, 2016). As WISP1 is a downstream target of Wnt signaling, we studied whether WISP1 regulates YAP1/TEAD1 activation.…”

Wnt target genes and where to find them

“…However, cooperation between the pathways consistent with the Piccolo model has been described during chronic inflammation-induced metaplasia in corneal epithelium 53 . In addition, Wnt3a activates both TCF and TEAD reporters in skeletal muscle cells 54 . Adding to the mechanistic insight linking YAP and β-cat, SET domain-containing lysine methyltransferase 7 (SETD7) is present in the destruction complex and methylates YAP, which is required for its ability to promote the nuclear accumulation of β-cat 55 .…”