Abstract
TBC1 domain family member 1 (TBC1D1), a Rab GTPase-activating protein and paralogue of Akt substrate of 160 kDa (AS160), has been implicated in both insulin- and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase-mediated glucose transporter type 4 (GLUT4) translocation. However, the role of TBC1D1 in contracting muscle remains ambiguous. We therefore explored the metabolic consequence of ablating TBC1D1 in both resting and contracting skeletal muscles, utilizing a rat TBC1D1 KO model. Although insulin administration rapidly increased (p < 0.05) plasma membrane GLUT4 content in both red and white gastrocnemius muscles, the TBC1D1 ablation did not alter this response nor did it affect whole-body insulin tolerance, suggesting that TBC1D1 is not required for insulin-induced GLUT4 trafficking events. Consistent with findings in other models of altered TBC1D1 protein levels, whole-animal and ex vivo skeletal muscle fat oxidation was increased in the TBC1D1 KO rats. Although there was no change in mitochondrial content in the KO rats, maximal ADP-stimulated respiration was higher in permeabilized muscle fibers, which may contribute to the increased reliance on fatty acids in resting KO animals. Despite this increase in mitochondrial oxidative capacity, run time to exhaustion at various intensities was impaired in the KO rats. Moreover, contraction-induced increases in sarcolemmal GLUT4 content and glucose uptake were lower in the white gastrocnemius of the KO animals. Altogether, our results highlight a critical role for TBC1D1 in exercise tolerance and contraction-mediated translocation of GLUT4 to the plasma membrane in skeletal muscle.
Highlights
Results in animals lacking TBC1 domain family member 1 (TBC1D1) show no difference in whole-body glucose or insulin tolerance, whereas in vivo maximal insulin-stimulated skeletal muscle glucose uptake is impaired [12, 13], which is contradictory to the proposed mechanism of action for this protein in glucose handling and glucose transporter 4 (GLUT4) trafficking
We first characterized TBC1D1 KO animals to determine whether they displayed phenotypic differences compared with wild-type (WT) animals (Table 1)
We provide evidence that contraction-mediated glucose uptake and GLUT4 translocation in KO animals are impaired in TBC1D1 KO animals, and this is associated with compromised exercise capacity
Summary
Upstream intracellular signaling events (e.g. insulin stimulation or contraction) result in the phosphorylation of AS160 and TBC1D1 and binding of these proteins to the molecular adaptor protein 14-3-3 These events enable GAPs to return to an active GTPbound state and initiate vesicle exocytosis and trafficking of GLUT4 transporters [8]. Results in animals lacking TBC1D1 show no difference in whole-body glucose or insulin tolerance, whereas in vivo maximal insulin-stimulated skeletal muscle glucose uptake is impaired [12, 13], which is contradictory to the proposed mechanism of action for this protein in glucose handling and GLUT4 trafficking. The decreased GLUT4 content suggests that TBC1D1 influences glucose homeostasis and may represent a compensatory attempt by the cell to maintain glucose homeostasis and limit glucose flux into the muscle
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