1. Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1.
- Author
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de Wendt C, Espelage L, Eickelschulte S, Springer C, Toska L, Scheel A, Bedou AD, Benninghoff T, Cames S, Stermann T, Chadt A, and Al-Hasani H
- Subjects
- AMP-Activated Protein Kinases metabolism, Animals, Biological Transport genetics, GTPase-Activating Proteins genetics, GTPase-Activating Proteins metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuropeptides genetics, Neuropeptides metabolism, Physical Conditioning, Animal physiology, Signal Transduction genetics, rac1 GTP-Binding Protein genetics, rac1 GTP-Binding Protein metabolism, Glucose metabolism, Muscle Contraction physiology, Muscle, Skeletal metabolism
- 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 Tbc1d1 , Tbc1d4 , or both RabGAPs. AMPK deficiency in muscle reduced treadmill exercise performance. Additional deletion of Tbc1d1 but not Tbc1d4 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 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., (© 2021 by the American Diabetes Association.)
- Published
- 2021
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