title: Regulation of glucose transporter 4 traffic by energy deprivation from mitochondrial compromise.
abstract: Skeletal muscle is the major store and consumer of fatty acids and glucose. Glucose enters muscle through glucose transporter 4 (GLUT4). Upon insufficient oxygen availability or energy compromise, aerobic metabolism of glucose and fatty aids cannot proceed, and muscle cells rely on anaerobic metabolism of glucose to restore cellular energy status. An increase in glucose uptake into muscle is a key response to stimuli requiring rapid energy supply. This chapter analyses the mechanisms of the adaptive regulation of glucose transport that rescue muscle cells from mitochondrial uncoupling. Under these conditions, the initial drop in ATP recovers rapidly, through a compensatory increase in glucose uptake. This adaptive response involves AMPK activation by the initial ATP drop, which elevates cell surface GLUT4 and glucose uptake. The gain in surface GLUT4 involves different signals and routes of intracellular traffic compared with those engaged by insulin. The hormone increases GLUT4 exocytosis through phosphatidylinositol 3-kinase and Akt, whereas energy stress retards GLUT4 endocytosis through AMPK and calcium inputs. Given that energy stress is a component of muscle contraction, and that contraction activates AMPK and raises cytosolic calcium, we hypothesize that the increase in glucose uptake during contraction may also involve a reduction in GLUT4 endocytosis.
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada. amira@sickkids.ca
authors.forename: A
authors.initials: A
authors.lastname: Klip
authors.forename: J D
authors.initials: JD
authors.lastname: Schertzer
authors.forename: P J
authors.initials: PJ
authors.lastname: Bilan
authors.forename: F
authors.initials: F
authors.lastname: Thong
authors.forename: C
authors.initials: C
authors.lastname: Antonescu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004140:Dinitrophenols / Q000378:metabolism; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014475:Uncoupling Agents / Q000378:metabolism
chemical_list: D004140:Dinitrophenols; D051275:Glucose Transporter Type 4; D007328:Insulin; D014475:Uncoupling Agents; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D002118:Calcium