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DOI: 10.1055/s-0035-1549519
The role of TBC1D1 and TBC1D4 in contraction-induced glucose uptake in mouse skeletal muscle
Background and aims: The RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4 (AS160) are key players in AKT- and AMPK-regulated glucose metabolism. The aim of this study is to analyze the contribution of these two homologous proteins to the contraction-mediated glucose uptake and metabolism in skeletal muscle.
Methods: TBC1D1/TBC1D4-double-deficient mice (D1/4KO) were generated. Ex vivo muscle contraction was conducted using isolated Extensor digitorum longus (EDL) and Soleus muscles and contraction force and time for half-capacity were measured in a myograph chamber. Subsequently, contraction- and insulin-induced 3H-2-deoxyglucose uptake and glycogen levels were determined.
Results: D1/4 knockout muscles showed substantially (50%) reduced GLUT4 protein abundance in EDL and Soleus muscle. Consistently, contraction-induced glucose uptake was similarly reduced in both, glycolytic EDL and oxidative Soleus muscle from D1/4KO mice. Combined stimulation of the muscles with ex vivo contraction and insulin further increased glucose uptake in wildtype controls. In skeletal muscle from D1/4KO mice this effect was blunted. Moreover, contraction force and time for half-capacity were unchanged between the genotypes. Glycogen levels were increased in skeletal muscle of D1/4KO mice.
Conclusions: Contraction-induced glucose uptake is severely reduced but not completely eliminated in EDL and Soleus muscle from D1/4KO mice, suggesting that a TBC1D-independent pathway also contributes to contraction-mediated GLUT4 translocation. Elevated glycogen levels may enable muscles of D1/4KO mice to develop the same contraction forces and times for half-capacity as wildtype controls.