β‐Catenin is required for optimal exercise‐ and contraction‐stimulated skeletal muscle glucose uptake

Key points Loss of β‐catenin impairs in vivo and isolated muscle exercise/contraction‐stimulated glucose uptake. β‐Catenin is required for exercise‐induced skeletal muscle actin cytoskeleton remodelling. β‐Catenin 675 phosphorylation during exercise may be intensity dependent.Abstract The conserved structural protein β‐catenin is an emerging regulator of vesicle trafficking in multiple tissues and supports insulin‐stimulated glucose transporter 4 (GLUT4) translocation in skeletal muscle by facilitating cortical actin remodelling. Actin remodelling may be a convergence point between insulin and exercise/contraction‐stimulated glucose uptake. Here we investigated whether β‐catenin is involved in regulating exercise/contraction‐stimulated glucose uptake. We report that the muscle‐specific deletion of β‐catenin induced in adult mice (BCAT‐mKO) impairs both exercise‐ and contraction (isolated muscle)‐induced glucose uptake without affecting running performance or canonical exercise signalling pathways. Furthermore, high intensity exercise in mice and contraction of myotubes and isolated muscles led to the phosphorylation of β‐catenin S675 , and this was impaired by Rac1 inhibition. Moderate intensity exercise in control and Rac1 muscle‐specific knockout mice did not induce muscle β‐catenin S675 phosphorylation, suggesting exercise intensity‐dependent regulation of β‐catenin S675 . Introduction of a non‐phosphorylatable S675A mutant of β‐catenin into myoblasts impaired GLUT4 translocation and actin remodelling stimulated by carbachol, a Rac1 and RhoA activator. Exercise‐induced increases in cross‐sectional phalloidin staining (F‐actin marker) of gastrocnemius muscle was impaired in muscle from BCAT‐mKO mice. Collectively our findings suggest that β‐catenin is required for optimal glucose transport in muscle during exercise/contraction, potentially via facilitating actin cytoskeleton remodelling.