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

• Published in: FEBS letters Vol. 596; no. 24; pp. 3159 - 3175
• Main Authors: Liu, Sasa, Qi, Rui, Zhang, Juan, Zhang, Chang, Chen, Liming, Yao, Zhi, Niu, Wenyan
• Format: Journal Article
• Language: English
• Published: England 01-12-2022
• Subjects: Animals; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; calcium/calmodulin‐dependent protein kinase II; contraction; Glucose - metabolism; glucose uptake; Kalirin; Mice; Muscle Contraction - physiology; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - metabolism; Rac1; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; skeletal muscle; Kalirin; contraction; Rac1; calcium/calmodulin-dependent protein kinase II; glucose uptake; skeletal muscle
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.14428

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.
We demonstrate that CaMKII‐Kalirin‐Rac1 signaling mediates contraction‐stimulated glucose uptake in skeletal muscle cells. Muscle contraction triggers Ca2+ influx, activating CaMKII. Within an hour, CaMKII upregulates the expression of the Rac1‐GEF Kalirin and possibly alternative pathways (dotted line), leading to Rac1 activation. Previous work links Rac1 to pathways that induce GLUT4 glucose transporters to move to the plasma membrane and enhance glucose entry.