Kalirin mediates Rac1 activation downstream of calcium/calmodulin-dependent protein kinase II to stimulate glucose uptake during muscle contraction

Abstract

In this study, we investigated the role of calcium/calmodulin-dependent protein kinase II (CaMKII) in contraction-stimulated glucose uptake in skeletal muscle. C2C12 myotubes were contracted by electrical pulse stimulation (EPS), and treadmill running was used to exercise mice. The activities of CaMKII, the small G protein Rac1, and the Rac1 effector kinase PAK1 were elevated in muscle by running exercise or EPS, while they were lowered by the CaMKII inhibitor KN-93 and/or small interfering RNA (siRNA)-mediated knockdown. EPS induced the mRNA and protein expression of the Rac1-GEF Kalirin in a CaMKII-dependent manner. EPS-induced Rac1 activation was lowered by the Kalirin inhibitor ITX3 or siRNA-mediated Kalirin knockdown. KN-93, ITX3, and siRNA-mediated Kalirin knockdown reduced EPS-induced glucose uptake. These findings define a CaMKII-Kalirin-Rac1 signaling pathway that contributes to contraction-stimulated glucose uptake in skeletal muscle myotubes and tissue.

Keywords: Kalirin; Rac1; calcium/calmodulin-dependent protein kinase II; contraction; glucose uptake; skeletal muscle.