title: Rac1 governs exercise-stimulated glucose uptake in skeletal muscle through regulation of GLUT4 translocation in mice.
abstract: Exercise increases skeletal muscle energy turnover and one of the important substrates for the working muscle is glucose taken up from the blood. The GTPase Rac1 can be activated by muscle contraction and has been found to be necessary for insulin-stimulated glucose uptake, although its role in exercise-stimulated glucose uptake is unknown. We show that Rac1 regulates the translocation of the glucose transporter GLUT4 to the plasma membrane in skeletal muscle during exercise. We find that Rac1 knockout mice display significantly reduced glucose uptake in skeletal muscle during exercise.
  
  
  
  Exercise increases skeletal muscle energy turnover and one of the important substrates for the working muscle is glucose taken up from the blood. Despite extensive efforts, the signalling mechanisms vital for glucose uptake during exercise are not yet fully understood, although the GTPase Rac1 is a candidate molecule. The present study investigated the role of Rac1 in muscle glucose uptake and substrate utilization during treadmill exercise in mice in vivo. Exercise-induced uptake of radiolabelled 2-deoxyglucose at 65% of maximum running capacity was blocked in soleus muscle and decreased by 80% and 60% in gastrocnemius and tibialis anterior muscles, respectively, in muscle-specific inducible Rac1 knockout (mKO) mice compared to wild-type littermates. By developing an assay to quantify endogenous GLUT4 translocation, we observed that GLUT4 content at the sarcolemma in response to exercise was reduced in Rac1 mKO muscle. Our findings implicate Rac1 as a regulatory element critical for controlling glucose uptake during exercise via regulation of GLUT4 translocation.
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Lykke
authors.initials: L
authors.lastname: Sylow
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Ida L
authors.initials: IL
authors.lastname: Nielsen
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kleinert
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Lisbeth L V
authors.initials: LL
authors.lastname: Møller
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Thorkil
authors.initials: T
authors.lastname: Ploug
authors.affiliation: Institute of Sports Medicine, Department of Orthopedic Surgery, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Schjerling
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bilan
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Jensen
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Erik A
authors.identifier: 0000-0002-6850-3056
authors.initials: EA
authors.lastname: Richter
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051275:Glucose Transporter Type 4; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C495693:Slc2a4 protein, mouse; D055372:AMP-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; D005947:Glucose