title: Mechanisms of Chronic Muscle Wasting and Dysfunction after an Intensive Care Unit Stay. A Pilot Study.
abstract: BACKGROUND
  Critical illness survivors often experience permanent functional disability due to intensive care unit (ICU)-acquired weakness. The mechanisms responsible for long-term weakness persistence versus resolution are unknown.
  
  
  OBJECTIVE
  To delineate cellular mechanisms underlying long-term weakness persistence in ICU survivors.
  
  
  METHODS
  We conducted a nested, prospective study of critically ill patients mechanically ventilated for 7 days or longer. The patients were recruited from the RECOVER program and serially assessed over 6 months after ICU discharge. Twenty-seven of 82 patients consented to participate; 15 and 11 patients were assessed at 7 days and 6 months after ICU discharge, respectively.
  
  
  RESULTS
  We assessed motor functional capacity, quadriceps size, strength, and voluntary contractile capacity and performed electromyography, nerve conduction studies, and vastus lateralis biopsies for histologic, cellular, and molecular analyses. Strength and quadriceps cross-sectional areas were decreased 7 days after ICU discharge. Weakness persisted to 6 months and correlated with decreased function. Quadriceps atrophy resolved in 27% patients at 6 months. Muscle mass reconstitution did not correlate with resolution of weakness, owing to persistent impaired voluntary contractile capacity. Compared with Day 7, increased ubiquitin-proteasome system-mediated muscle proteolysis, inflammation, and decreased mitochondrial content all normalized at 6 months. Autophagy markers were normal at 6 months. Patients with sustained atrophy had decreased muscle progenitor (satellite) cell content.
  
  
  CONCLUSIONS
  Long-term weakness in ICU survivors results from heterogeneous muscle pathophysiology with variable combinations of muscle atrophy and impaired contractile capacity. These findings are not explained by ongoing muscle proteolysis, inflammation, or diminished mitochondrial content. Sustained muscle atrophy is associated with decreased satellite cell content and compromised muscle regrowth, suggesting impaired regenerative capacity.
authors.affiliation: 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|2 Division of Critical Care Medicine, Department of Medicine.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dos Santos
authors.affiliation: 3 Department of Critical Care, McGill University Health Centre, and Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
authors.forename: Sabah N A
authors.initials: SN
authors.lastname: Hussain
authors.affiliation: 4 Department of Physiotherapy.
authors.forename: Sunita
authors.initials: S
authors.lastname: Mathur
authors.affiliation: 5 Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Martin
authors.initials: M
authors.lastname: Picard
authors.affiliation: 2 Division of Critical Care Medicine, Department of Medicine.|6 Division of Critical Care Medicine, University Health Network, Toronto, Ontario, Canada; and.
authors.forename: Margaret
authors.initials: M
authors.lastname: Herridge
authors.affiliation: 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Judy
authors.initials: J
authors.lastname: Correa
authors.affiliation: 7 Division of Respirology, Department of Medicine.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bain
authors.affiliation: 3 Department of Critical Care, McGill University Health Centre, and Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
authors.forename: Yeting
authors.initials: Y
authors.lastname: Guo
authors.affiliation: 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|8 Department of Medicine.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.affiliation: 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|8 Department of Medicine.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Advani
authors.affiliation: 8 Department of Medicine.
authors.forename: George
authors.initials: G
authors.lastname: Tomlinson
authors.affiliation: 9 Division of Neurology, Department of Medicine.
authors.forename: Hans
authors.initials: H
authors.lastname: Katzberg
authors.affiliation: 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|10 Department of Laboratory Medicine and Pathobiology, and.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Streutker
authors.affiliation: 11 Department of Occupational Science and Occupational Therapy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jill I
authors.initials: JI
authors.lastname: Cameron
authors.affiliation: 12 Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Annemie
authors.initials: A
authors.lastname: Schols
authors.affiliation: 12 Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Gosker
authors.affiliation: 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|7 Division of Respirology, Department of Medicine.
authors.forename: Jane
authors.initials: J
authors.lastname: Batt
keywords: autophagy; mitochondria; muscle atrophy; satellite cell; ubiquitin–proteasome system