Claudia Dos Santos1,2, Sabah N A Hussain3, Sunita Mathur4, Martin Picard5, Margaret Herridge2,6, Judy Correa1, Alexandra Bain7, Yeting Guo3, Andrew Advani1,8, Suzanne L Advani1,8, George Tomlinson8, Hans Katzberg9, Catherine J Streutker1,10, Jill I Cameron11, Annemie Schols12, Harry R Gosker12, Jane Batt1,7. 1. 1 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada. 2. 2 Division of Critical Care Medicine, Department of Medicine. 3. 3 Department of Critical Care, McGill University Health Centre, and Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada. 4. 4 Department of Physiotherapy. 5. 5 Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania. 6. 6 Division of Critical Care Medicine, University Health Network, Toronto, Ontario, Canada; and. 7. 7 Division of Respirology, Department of Medicine. 8. 8 Department of Medicine. 9. 9 Division of Neurology, Department of Medicine. 10. 10 Department of Laboratory Medicine and Pathobiology, and. 11. 11 Department of Occupational Science and Occupational Therapy, University of Toronto, Toronto, Ontario, Canada. 12. 12 Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
Abstract
RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
RATIONALE: 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. OBJECTIVES: To delineate cellular mechanisms underlying long-term weakness persistence in ICU survivors. METHODS: We conducted a nested, prospective study of critically illpatients 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. MEASUREMENTS AND MAIN 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.
Entities:
Keywords:
autophagy; mitochondria; muscle atrophy; satellite cell; ubiquitin–proteasome system
Authors: Kathryn A Radigan; Trevor T Nicholson; Lynn C Welch; Monica Chi; Luciano Amarelle; Martín Angulo; Masahiko Shigemura; Atsuko Shigemura; Constance E Runyan; Luisa Morales-Nebreda; Harris Perlman; Ermelinda Ceco; Emilia Lecuona; Laura A Dada; Alexander V Misharin; Gokhan M Mutlu; Jacob I Sznajder; G R Scott Budinger Journal: J Immunol Date: 2018-12-07 Impact factor: 5.422
Authors: Ariel Jaitovich; Malik M H S Khan; Ria Itty; Hau C Chieng; Camille L Dumas; Pallavi Nadendla; John P Fantauzzi; Recai M Yucel; Paul J Feustel; Marc A Judson Journal: Chest Date: 2018-10-28 Impact factor: 9.410
Authors: Brian J Rosenberg; Michio Hirano; Catarina M Quinzii; Elizabeth Colantuoni; Dale M Needham; David J Lederer; Matthew R Baldwin Journal: Thorax Date: 2019-09-18 Impact factor: 9.139