Ablating the protein TBC1D1 impairs contraction-induced sarcolemmal glucose transporter 4 redistribution but not insulin-mediated responses in rats
Autor: | Gregory R. Steinberg, Paula M. Miotto, Eric A.F. Herbst, Genevieve Simnett, Jamie Whitfield, Holly Robson, Brennan K. Smith, David J. Dyck, Sabina Paglialunga, Graham P. Holloway, Lawrence L. Spriet, Swati S. Jain, Eric M. Desjardins |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
medicine.medical_specialty skeletal muscle metabolism Glucose uptake medicine.medical_treatment GTPase-activating protein (GAP) Biology Carbohydrate metabolism Biochemistry Rats Sprague-Dawley 03 medical and health sciences Oxygen Consumption Sarcolemma Internal medicine medicine Animals Insulin carbohydrate metabolism glucose transporter type 4 (GLUT4) Muscle Skeletal Molecular Biology Protein kinase B Exercise Tolerance Glucose Transporter Type 4 Glucose transporter Proteins Skeletal muscle TBC1D1 Cell Biology Rats Protein Transport Metabolism 030104 developmental biology medicine.anatomical_structure Endocrinology fatty acid metabolism biology.protein Rats Transgenic Oxidation-Reduction GLUT4 Muscle Contraction |
Zdroj: | Journal of Biological Chemistry. 292:16653-16664 |
ISSN: | 0021-9258 |
Popis: | 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. |
Databáze: | OpenAIRE |
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