TBC1D4-S711 Controls Skeletal Muscle Insulin Sensitization After Exercise and Contraction

Rasmus Kjøbsted*, Jonas M Kristensen, Nicolas O Eskesen, Kohei Kido, Klara Fjorder, Ditte F Damgaard, Jeppe K Larsen, Nicoline R Andersen, Jesper B Birk, Anders Gudiksen, Jonas T Treebak, Peter Schjerling, Henriette Pilegaard, Jørgen F P Wojtaszewski

*Corresponding author af dette arbejde


The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise, and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated a TBC1D4 knock-in mouse model with a serine-to-alanine point mutation at residue 711 that is phosphorylated in response to both insulin and AMPK activation. Female TBC1D4-S711A mice exhibited normal growth and eating behavior as well as intact whole-body glycemic control on chow and high-fat diets. Moreover, muscle contraction increased glucose uptake, glycogen utilization, and AMPK activity similarly in wild-type and TBC1D4-S711A mice. In contrast, improvements in whole-body and muscle insulin sensitivity after exercise and contractions were only evident in wild-type mice and occurred concomitantly with enhanced phosphorylation of TBC1D4-S711. These results provide genetic evidence to support that TBC1D4-S711 serves as a major point of convergence for AMPK- and insulin-induced signaling that mediates the insulin-sensitizing effect of exercise and contractions on skeletal muscle glucose uptake.

Udgave nummer7
Sider (fra-til)857-871
Antal sider15
StatusUdgivet - 1 jul. 2023


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