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

Mol Metab. 2020 Dec;42:101091. doi: 10.1016/j.molmet.2020.101091. Epub 2020 Oct 1.

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 β-catenin is an emerging regulator of vesicle trafficking in other tissues. Here, we investigated the involvement of β-catenin in skeletal muscle insulin-stimulated glucose transport.

Methods: Glucose homeostasis and transport was investigated in inducible muscle specific β-catenin knockout (BCAT-mKO) mice. The effect of β-catenin deletion and mutation of β-catenin serine 552 on signal transduction, glucose uptake and protein-protein interactions were determined in L6-G4-myc cells, and β-catenin insulin-responsive binding partners were identified via immunoprecipitation coupled to label-free proteomics.

Results: Skeletal muscle specific deletion of β-catenin impaired whole-body insulin sensitivity and insulin-stimulated glucose uptake into muscle independent of canonical Wnt signalling. In response to insulin, β-catenin was phosphorylated at serine 552 in an Akt-dependent manner, and in L6-G4-myc cells, mutation of β-cateninS552 impaired insulin-induced actin-polymerisation, resulting in attenuated insulin-induced glucose transport and GLUT4 translocation. β-catenin was found to interact with M-cadherin in an insulin-dependent β-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 β-catenin is a novel mediator of glucose transport in skeletal muscle and may contribute to insulin-induced actin-cytoskeleton remodelling to support GLUT4 translocation.

Keywords: Actin-remodelling; Beta-catenin; GLUT4 trafficking; Glucose transport; M-cadherin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Actins / physiology
  • Animals
  • Biological Transport
  • Cadherins / metabolism
  • Cadherins / physiology
  • Glucose / metabolism
  • Glucose Transport Proteins, Facilitative / genetics
  • Glucose Transport Proteins, Facilitative / metabolism*
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Insulin / metabolism
  • Insulin Resistance / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Protein Binding
  • Protein Transport
  • Signal Transduction
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Actins
  • Cadherins
  • Glucose Transport Proteins, Facilitative
  • Glucose Transporter Type 4
  • Insulin
  • Slc2a4 protein, mouse
  • beta Catenin
  • Glucose