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. 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. MEASUREMENTS AND MAIN 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).
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. 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. MEASUREMENTS AND MAIN 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: Liyang Zhao; Florencia Pascual; Lawrence Bacudio; Amanda L Suchanek; Pamela A Young; Lei O Li; Sarah A Martin; Joao-Paulo Camporez; Rachel J Perry; Gerald I Shulman; Eric L Klett; Rosalind A Coleman Journal: J Biol Chem Date: 2019-04-11 Impact factor: 5.157
Authors: Nicola Latronico; Margaret Herridge; Ramona O Hopkins; Derek Angus; Nicholas Hart; Greet Hermans; Theodore Iwashyna; Yaseen Arabi; Giuseppe Citerio; E. Wesley Ely; Jesse Hall; Sangeeta Mehta; Kathleen Puntillo; Johannes Van den Hoeven; Hannah Wunsch; Deborah Cook; Claudia Dos Santos; Gordon Rubenfeld; Jean-Louis Vincent; Greet Van den Berghe; Elie Azoulay; Dale M Needham Journal: Intensive Care Med Date: 2017-03-13 Impact factor: 17.440
Authors: O Friedrich; M B Reid; G Van den Berghe; I Vanhorebeek; G Hermans; M M Rich; L Larsson Journal: Physiol Rev Date: 2015-07 Impact factor: 37.312
Authors: Nicholas A Mignemi; P Mason McClatchey; Kameron V Kilchrist; Ian M Williams; Bryan A Millis; Kristen E Syring; Craig L Duvall; David H Wasserman; Owen P McGuinness Journal: Am J Physiol Endocrinol Metab Date: 2019-03-12 Impact factor: 4.310
Authors: Greet Hermans; Helena Van Mechelen; Frans Bruyninckx; Tine Vanhullebusch; Beatrix Clerckx; Philippe Meersseman; Yves Debaveye; Michael P Casaer; Alexander Wilmer; Pieter J Wouters; Ilse Vanhorebeek; Rik Gosselink; Greet Van den Berghe Journal: Intensive Care Med Date: 2015-08-13 Impact factor: 17.440
Authors: Stefan J Schaller; Michio Nagashima; Martin Schönfelder; Tomoki Sasakawa; Fabian Schulz; Mohammed A S Khan; William R Kem; Gerhard Schneider; Jürgen Schlegel; Heidrun Lewald; Manfred Blobner; J A Jeevendra Martyn Journal: Pflugers Arch Date: 2018-07-13 Impact factor: 3.657
Authors: William E Balch; Jacob I Sznajder; Scott Budinger; Daniel Finley; Aaron D Laposky; Ana Maria Cuervo; Ivor J Benjamin; Esther Barreiro; Richard I Morimoto; Lisa Postow; Allan M Weissman; Dorothy Gail; Susan Banks-Schlegel; Thomas Croxton; Weiniu Gan Journal: Am J Respir Crit Care Med Date: 2014-01-01 Impact factor: 21.405