Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1.

Abstract

The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4, both substrates for AMPK, play important roles in exercise metabolism and contraction-dependent translocation of GLUT4 in skeletal muscle. However, the specific contribution of each RabGAP in contraction signaling is mostly unknown. In this study, we investigated the cooperative AMPK-RabGAP signaling axis in the metabolic response to exercise/contraction using a novel mouse model deficient in active skeletal muscle AMPK combined with knockout of either <i>Tbc1d1</i>, <i>Tbc1d4</i>, or both RabGAPs. AMPK deficiency in muscle reduced treadmill exercise performance. Additional deletion of <i>Tbc1d1</i> but not <i>Tbc1d4</i> resulted in a further decrease in exercise capacity. In oxidative soleus muscle, AMPK deficiency reduced contraction-mediated glucose uptake, and deletion of each or both RabGAPs had no further effect. In contrast, in glycolytic extensor digitorum longus muscle, AMPK deficiency reduced contraction-stimulated glucose uptake, and deletion of <i>Tbc1d1</i>, but not <i>Tbc1d4</i>, led to a further decrease. Importantly, skeletal muscle deficient in AMPK and both RabGAPs still exhibited residual contraction-mediated glucose uptake, which was completely abolished by inhibition of the GTPase Rac1. Our results demonstrate a novel mechanistic link between glucose transport and the GTPase signaling framework in skeletal muscle in response to contraction.