title: Critical illness myopathy and GLUT4: significance of insulin and muscle contraction.
abstract: BACKGROUND
  Critical illness myopathy (CIM) has no known cause and no treatment. Immobilization and impaired glucose metabolism are implicated.
  
  
  OBJECTIVE
  We assessed signal transduction in skeletal muscle of patients at risk for CIM. We also investigated the effects of evoked muscle contraction.
  
  
  METHODS
  In a prospective observational and interventional pilot study, we screened 874 mechanically ventilated patients with a sepsis-related organ-failure assessment score greater than or equal to 8 for 3 consecutive days in the first 5 days of intensive care unit stay. Thirty patients at risk for CIM underwent euglycemic-hyperinsulinemic clamp, muscle microdialysis studies, and muscle biopsies. Control subjects were healthy. In five additional patients at risk for CIM, we performed corresponding analyses after 12-day, daily, unilateral electrical muscle stimulation with the contralateral leg as control.
  
  
  RESULTS
  We performed successive muscle biopsies and assessed systemic insulin sensitivity and signal transduction pathways of glucose utilization at the mRNA and protein level and glucose transporter-4 (GLUT4) localization in skeletal muscle tissue. Skeletal muscle GLUT4 was trapped at perinuclear spaces, most pronounced in patients with CIM, but resided at the sarcolemma in control subjects. Glucose metabolism was not stimulated during euglycemic-hyperinsulinergic clamp. Insulin signal transduction was competent up to p-Akt activation; however, p-adenosine monophosphate-activated protein kinase (p-AMPK) was not detectable in CIM muscle. Electrical muscle stimulation increased p-AMPK, repositioned GLUT4, locally improved glucose metabolism, and prevented type-2 fiber atrophy.
  
  
  CONCLUSIONS
  Insufficient GLUT4 translocation results in decreased glucose supply in patients with CIM. Failed AMPK activation is involved. Evoked muscle contraction may prevent muscle-specific AMPK failure, restore GLUT4 disposition, and diminish protein breakdown. Clinical trial registered with http://www.controlled-trials.com (registration number ISRCTN77569430).
authors.affiliation: Department of Anesthesiology and Operative Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. steffen.weber-carstens@charite.de
authors.forename: Steffen
authors.initials: S
authors.lastname: Weber-Carstens
authors.forename: Joanna
authors.initials: J
authors.lastname: Schneider
authors.forename: Tobias
authors.initials: T
authors.lastname: Wollersheim
authors.forename: Anke
authors.initials: A
authors.lastname: Assmann
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bierbrauer
authors.forename: Andreas
authors.initials: A
authors.lastname: Marg
authors.forename: Hadi
authors.initials: H
authors.lastname: Al Hasani
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chadt
authors.forename: Katrin
authors.initials: K
authors.lastname: Wenzel
authors.forename: Susanne
authors.initials: S
authors.lastname: Koch
authors.forename: Jens
authors.initials: J
authors.lastname: Fielitz
authors.forename: Christian
authors.initials: C
authors.lastname: Kleber
authors.forename: Katharina
authors.initials: K
authors.lastname: Faust
authors.forename: Knut
authors.initials: K
authors.lastname: Mai
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Spies
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Michael
authors.initials: M
authors.lastname: Boschmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Spranger
authors.forename: Simone
authors.initials: S
authors.lastname: Spuler
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001706:Biopsy / Q000379:methods; D016638:Critical Illness; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D015309:Glucose Clamp Technique / Q000379:methods; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D008875:Middle Aged; D009119:Muscle Contraction; D009135:Muscular Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D063305:Organ Dysfunction Scores; D010865:Pilot Projects; D011446:Prospective Studies; D012121:Respiration, Artificial; D018805:Sepsis / Q000150:complications; D015398:Signal Transduction
chemical_list: D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin