Diabetologie und Stoffwechsel 2015; 10 - FV13
DOI: 10.1055/s-0035-1549519

The role of TBC1D1 and TBC1D4 in contraction-induced glucose uptake in mouse skeletal muscle

C de Wendt 1, 2, A Chadt 1, 2, J Loffing 3, D Loffing-Cueni 3, HG Joost 2, 4, H Al-Hasani 1, 2
  • 1German Diabetes Center (DDZ), Leibniz-Center for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Institute for Clinical Biochemistry and Pathobiochemistry, Düsseldorf, Germany
  • 2German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
  • 3Institute of Anatomy, University of Zürich, Zürich, Switzerland
  • 4German Institute of Human Nutrition Potsdam Rehbruecke (DIfE), Potsdam, Germany

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.