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

SUBMITTER: Masson SWC 

PROVIDER: S-EPMC7568189 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature