ß-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding.

ABSTRACT

OBJECTIVE: Skeletal muscle glucose disposal following a meal is mediated through insulin-stimulated movement of the GLUT4-containing vesicles to the cell surface. The highly conserved scaffold-protein ß-catenin is an emerging regulator of vesicle trafficking in other tissues. Here, we investigated the involvement of ß-catenin in skeletal muscle insulin-stimulated glucose transport. METHODS: Glucose homeostasis and transport was investigated in inducible muscle specific ß-catenin knockout (BCAT-mKO) mice. The effect of ß-catenin deletion and mutation of ß-catenin serine 552 on signal transduction, glucose uptake and protein-protein interactions were determined in L6-G4-myc cells, and ß-catenin insulin-responsive binding partners were identified via immunoprecipitation coupled to label-free proteomics. RESULTS: Skeletal muscle specific deletion of ß-catenin impaired whole-body insulin sensitivity and insulin-stimulated glucose uptake into muscle independent of canonical Wnt signalling. In response to insulin, ß-catenin was phosphorylated at serine 552 in an Akt-dependent manner, and in L6-G4-myc cells, mutation of ß-cateninS552 impaired insulin-induced actin-polymerisation, resulting in attenuated insulin-induced glucose transport and GLUT4 translocation. ß-catenin was found to interact with M-cadherin in an insulin-dependent ß-cateninS552-phosphorylation dependent manner, and loss of M-cadherin in L6-G4-myc cells attenuated insulin-induced actin-polymerisation and glucose transport. CONCLUSIONS: Our data suggest that ß-catenin is a novel mediator of glucose transport in skeletal muscle and may contribute to insulin-induced actin-cytoskeleton remodelling to support GLUT4 translocation.