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Critical illness myopathy and GLUT4 - significance of insulin and muscle contraction

Authors

  • S. Weber-Carstens
  • J. Schneider
  • T. Wollersheim
  • A. Assmann
  • J. Bierbrauer
  • A. Marg
  • H. Al Hasani
  • A. Chadt
  • K. Wenzel
  • S. Koch
  • J. Fielitz
  • C. Kleber
  • K. Faust
  • K. Mai
  • C.D. Spies
  • F.C. Luft
  • M. Boschmann
  • J. Spranger
  • S. Spuler

Journal

  • American Journal of Respiratory and Critical Care Medicine

Citation

  • Am J Respir Crit Care Med 187 (4): 387-396

Abstract

  • Rationale: Critical illness myopathy (CIM) has no known cause and no treatment. Immobilization and impaired glucose metabolism are implicated. Objectives: We assessed signal transduction in skeletal muscle of patients at risk for CIM. We also investigated the effects of evoked muscle contraction (ISRCTN77569430). Methods: Prospective observational and interventional pilot study. We screened 874 mechanically ventilated patients with sepsis-related organ-failure assessment score >= 8 for three consecutive days in the first five days of ICU. 30 patients at risk for CIM underwent euglycemic-hyperinsulinemic clamp, muscle microdialysis studies, and muscle biopsies. Controls were healthy. In five additional patients at risk for CIM, we performed corresponding analyses after 12-day, daily, unilateral electrical muscle stimulation (EMS) with the contralateral leg as control. Measurements: We performed successive muscle biopsies, assessed systemic insulin sensitivity and signal transduction pathways of glucose utilization at mRNA and protein level and glucose transporter-4 (GLUT4) localization in skeletal muscle tissue. Main results: Skeletal muscle GLUT4 was trapped at perinuclear spaces, most pronounced in CIM patients, but resided at the sarcolemma in controls. Glucose metabolism was not stimulated during euglycemic-hyperinsulinergic clamp. Insulin signal transduction was competent up to p-Akt activation; however, p-AMPK was not detectable in CIM muscle. EMS 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 CIM patients. Failed AMPK activation is involved. Evoked muscle contraction may prevent muscle-specific AMPK failure, restore GLUT4 disposition, and diminish protein breakdown.


DOI

doi:10.1164/rccm.201209-1649OC