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

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posted on 24.09.2021, 16:35 by Christian de Wendt, Lena Espelage, Samaneh Eickelschulte, Christian Springer, Laura Toska, Anna Scheel, Awovi Didi Bedou, Tim Benninghoff, Sandra Cames, Torben Stermann, Alexandra Chadt, Hadi Al-Hasani
The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4, both substrates for the AMP-activated protein kinase AMPK, play important roles in exercise metabolism and contraction-dependent translocation of the glucose transporter 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 Tbc1d1, Tbc1d4 or both RabGAPs. AMPK-deficiency in muscle reduced treadmill exercise performance. Additional deletion of Tbc1d1 but not Tbc1d4 resulted in 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 EDL muscle, AMPK deficiency reduced contraction-stimulated glucose uptake and deletion of Tbc1d1 but not Tbc1d4 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.

Funding

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (DFG-RTG 2576 vivid; CH1659 to AC), Deutsche Diabetes Gesellschaft (DDG), EFSD/Novo Nordisk Programme for Diabetes Research, and the Ministry of Science and Research of the State North Rhine-Westphalia (MIWF NRW) State of North Rhine-Westphalia (MIWF NRW) and the German Federal Ministry of Health (BMG).

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