posted on 2021-09-24, 16:35authored byChristian 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).