title: Transcriptomic analysis reveals abnormal muscle repair and remodeling in survivors of critical illness with sustained weakness.
abstract: ICU acquired weakness (ICUAW) is a common complication of critical illness characterized by structural and functional impairment of skeletal muscle. The resulting physical impairment may persist for years after ICU discharge, with few patients regaining functional independence. Elucidating molecular mechanisms underscoring sustained ICUAW is crucial to understanding outcomes linked to different morbidity trajectories as well as for the development of novel therapies. Quadriceps muscle biopsies and functional measures of muscle strength and mass were obtained at 7 days and 6 months post-ICU discharge from a cohort of ICUAW patients. Unsupervised co-expression network analysis of transcriptomic profiles identified discrete modules of co-expressed genes associated with the degree of muscle weakness and atrophy in early and sustained ICUAW. Modules were enriched for genes involved in skeletal muscle regeneration and extracellular matrix deposition. Collagen deposition in persistent ICUAW was confirmed by histochemical stain. Modules were further validated in an independent cohort of critically ill patients with sepsis-induced multi-organ failure and a porcine model of ICUAW, demonstrating disease-associated conservation across species and peripheral muscle type. Our findings provide a pathomolecular basis for sustained ICUAW, implicating aberrant expression of distinct skeletal muscle structural and regenerative genes in early and persistent ICUAW.
authors.affiliation: Keenan and Li Ka Shing Knowledge Institute of Saint Michael's Hospital, Toronto, Ontario, Canada.|Institute of Medical Sciences and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Walsh
authors.affiliation: Keenan and Li Ka Shing Knowledge Institute of Saint Michael's Hospital, Toronto, Ontario, Canada.|Institute of Medical Sciences and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jane
authors.initials: J
authors.lastname: Batt
authors.affiliation: University Health Network, Interdepartmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Herridge
authors.affiliation: Department of Physical Therapy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sunita
authors.initials: S
authors.lastname: Mathur
authors.affiliation: The Donnelly Center, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.affiliation: Keenan and Li Ka Shing Knowledge Institute of Saint Michael's Hospital, Toronto, Ontario, Canada.|Interdepartmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Dos Santos
mesh_terms: D016638:Critical Illness; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D018908:Muscle Weakness / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology*; D012038:Regeneration / Q000235:genetics*; D017741:Survivors