title: The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle.
abstract: Insulin and exercise stimulate glucose uptake into skeletal muscle via different pathways. Both stimuli converge on the translocation of the glucose transporter GLUT4 from intracellular vesicles to the cell surface. Two Rab guanosine triphosphatases-activating proteins (GAPs) have been implicated in this process: AS160 for insulin stimulation and its homolog, TBC1D1, are suggested to regulate exercise-mediated glucose uptake into muscle. TBC1D1 has also been implicated in obesity in humans and mice. We investigated the role of TBC1D1 in glucose metabolism by generating TBC1D1(-/-) mice and analyzing body weight, insulin action, and exercise. TBC1D1(-/-) mice showed normal glucose and insulin tolerance, with no difference in body weight compared with wild-type littermates. GLUT4 protein levels were reduced by ∼40% in white TBC1D1(-/-) muscle, and TBC1D1(-/-) mice showed impaired exercise endurance together with impaired exercise-mediated 2-deoxyglucose uptake into white but not red muscles. These findings indicate that the RabGAP TBC1D1 plays a key role in regulating GLUT4 protein levels and in exercise-mediated glucose uptake in nonoxidative muscle fibers.
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia Garvan Institute of Medical Research, Sydney, New South Wales, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Stöckli
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Meoli
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Nolan J
authors.initials: NJ
authors.lastname: Hoffman
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Fazakerley
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Himani
authors.initials: H
authors.lastname: Pant
authors.affiliation: The Royal Veterinary College, University of London, London, U.K.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cleasby
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Xiuquan
authors.initials: X
authors.lastname: Ma
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales, Australia Molecular Physiology Group, Department of Nutrition, Exercise and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kleinert
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Brandon
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Lopez
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia Garvan Institute of Medical Research, Sydney, New South Wales, Australia School of Medicine, University of Sydney, Sydney, New South Wales, Australia david.james@sydney.edu.au.
authors.forename: David E
authors.initials: DE
authors.lastname: James
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D018274:Electroporation; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D009687:Nuclear Proteins; C095906:Tbc1d1 protein, mouse; D006003:Glycogen