{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:35:25Z","timestamp":1791232525183,"version":"4.1.0"},"reference-count":227,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T00:00:00Z","timestamp":1603324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intensive care unit-acquired weakness (ICUAW) occurs in critically ill patients stemming from the critical illness itself, and results in sustained disability long after the ICU stay. Weakness can be attributed to muscle wasting, impaired contractility, neuropathy, and major pathways associated with muscle protein degradation such as the ubiquitin proteasome system and dysregulated autophagy. Furthermore, it is characterized by the preferential loss of myosin, a distinct feature of the condition. While many risk factors for ICUAW have been identified, effective interventions to offset these changes remain elusive. In addition, our understanding of the mechanisms underlying the long-term, sustained weakness observed in a subset of patients after discharge is minimal. Herein, we discuss the various proposed pathways involved in the pathophysiology of ICUAW, with a focus on the mechanisms underpinning skeletal muscle wasting and impaired contractility, and the animal models used to study them. Furthermore, we will explore the contributions of inflammation, steroid use, and paralysis to the development of ICUAW and how it pertains to those with the corona virus disease of 2019 (COVID-19). We then elaborate on interventions tested as a means to offset these decrements in muscle function that occur as a result of critical illness, and we propose new strategies to explore the molecular mechanisms of ICUAW, including serum-related biomarkers and 3D human skeletal muscle culture models.<\/jats:p>","DOI":"10.3390\/ijms21217840","type":"journal-article","created":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T10:27:58Z","timestamp":1603362478000},"page":"7840","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["Intensive Care Unit-Acquired Weakness: Not Just Another Muscle Atrophying Condition"],"prefix":"10.3390","volume":"21","author":[{"given":"Heta","family":"Lad","sequence":"first","affiliation":[{"name":"Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada"},{"name":"Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3475-0665","authenticated-orcid":false,"given":"Tyler M.","family":"Saumur","sequence":"additional","affiliation":[{"name":"Rehabilitation Sciences Institute, University of Toronto, Toronto, ON M5G 2A2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret S.","family":"Herridge","sequence":"additional","affiliation":[{"name":"Division of Critical Care Medicine, University Health Network, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia C.","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Keenan Research Center for Biomedical Science, St. Michael\u2019s Unity Health Toronto, Toronto, ON M5B 1T8, Canada"},{"name":"Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5564-9796","authenticated-orcid":false,"given":"Sunita","family":"Mathur","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, University of Toronto, Toronto, ON M5G 1V7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Batt","sequence":"additional","affiliation":[{"name":"Keenan Research Center for Biomedical Science, St. Michael\u2019s Unity Health Toronto, Toronto, ON M5B 1T8, Canada"},{"name":"Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5509-9616","authenticated-orcid":false,"given":"Penney M.","family":"Gilbert","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada"},{"name":"Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada"},{"name":"Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S299","DOI":"10.1097\/CCM.0b013e3181b6ef67","article-title":"A framework for diagnosing and classifying intensive care unit-acquired weakness","volume":"37","author":"Stevens","year":"2009","journal-title":"Crit. 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