title: Rac1 and AMPK Account for the Majority of Muscle Glucose Uptake Stimulated by Ex Vivo Contraction but Not In Vivo Exercise.
abstract: Exercise bypasses insulin resistance to increase glucose uptake in skeletal muscle and therefore represents an important alternative to stimulate glucose uptake in insulin-resistant muscle. Both Rac1 and AMPK have been shown to partly regulate contraction-stimulated muscle glucose uptake, but whether those two signaling pathways jointly account for the entire signal to glucose transport is unknown. We therefore studied the ability of contraction and exercise to stimulate glucose transport in isolated muscles with AMPK loss of function combined with either pharmacological inhibition or genetic deletion of Rac1.Muscle-specific knockout (mKO) of Rac1, a kinase-dead α2 AMPK (α2KD), and double knockout (KO) of β1 and β2 AMPK subunits (β1β2 KO) each partially decreased contraction-stimulated glucose transport in mouse soleus and extensor digitorum longus (EDL) muscle. Interestingly, when pharmacological Rac1 inhibition was combined with either AMPK β1β2 KO or α2KD, contraction-stimulated glucose transport was almost completely inhibited. Importantly, α2KD+Rac1 mKO double-transgenic mice also displayed severely impaired contraction-stimulated glucose transport, whereas exercise-stimulated glucose uptake in vivo was only partially reduced by Rac1 mKO with no additive effect of α2KD. It is concluded that Rac1 and AMPK together account for almost the entire ex vivo contraction response in muscle glucose transport, whereas only Rac1, but not α2 AMPK, regulates muscle glucose uptake during submaximal exercise in vivo.
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark lshansen@nexs.ku.dk.
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, Copenhagen, Denmark.
authors.forename: Lisbeth L V
authors.initials: LLV
authors.lastname: Møller
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maximilian
authors.identifier: 0000-0002-8069-9055
authors.initials: M
authors.lastname: Kleinert
authors.affiliation: Department of Kinesiology, Exercise Physiology Research Group, Faculty of Kinesiology and Rehabilitation Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Gommaar
authors.initials: G
authors.lastname: D'Hulst
authors.affiliation: Université Catholique de Louvain, Leuven, Belgium.
authors.forename: Estelle
authors.initials: E
authors.lastname: De Groote
authors.affiliation: Institute of Sports Medicine, Department of Orthopedic Surgery, Bispebjerg Hospital, Copenhagen, Denmark.|Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Schjerling
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 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, Copenhagen, Denmark.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001823:Body Composition; D003847:Deoxyglucose / Q000378:metabolism; D004558:Electric Stimulation; D017079:Exercise Tolerance; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D015151:Immunoblotting; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D010805:Physical Conditioning, Animal; D014316:Tritium; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D014316:Tritium; D019298:Glucose-6-Phosphate; D006003:Glycogen; D003847:Deoxyglucose; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; D005947:Glucose