title: Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle.
abstract: Critical illness myopathy (CIM) is characterized by a preferential loss of the motor protein myosin, muscle wasting, and impaired muscle function in critically ill intensive care unit (ICU) patients. CIM is associated with severe morbidity and mortality and has a significant negative socioeconomic effect. Neuromuscular blocking agents, corticosteroids, sepsis, mechanical ventilation, and immobilization have been implicated as important risk factors, but the causal relationship between CIM and the risk factors has not been established. A porcine ICU model has been used to determine the immediate molecular and cellular cascades that may contribute to the pathogenesis prior to myosin loss and extensive muscle wasting. Expression profiles have been compared between pigs exposed to the ICU interventions, i.e., mechanically ventilated, sedated, and immobilized for 5 days, with pigs exposed to critical illness interventions, i.e., neuromuscular blocking agents, corticosteroids, and induced sepsis in addition to the ICU interventions for 5 days. Impaired autophagy as well as impaired chaperone expression and protein synthesis were observed in the skeletal muscle in response to critical illness interventions. A novel finding in this study is impaired core autophagy machinery in response to critical illness interventions, which when in concert with downregulated chaperone expression and protein synthesis may collectively affect the proteostasis in skeletal muscle and may exacerbate the disease progression in CIM.
authors.affiliation: Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala, Sweden. varuna.banduseela@neuro.uu.se
authors.forename: Varuna C
authors.initials: VC
authors.lastname: Banduseela
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Hanna Göransson
authors.initials: HG
authors.lastname: Kultima
authors.forename: Holly S
authors.initials: HS
authors.lastname: Norman
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Aare
authors.forename: Peter
authors.initials: P
authors.lastname: Radell
authors.forename: Lars I
authors.initials: LI
authors.lastname: Eriksson
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Lars
authors.initials: L
authors.lastname: Larsson
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D016638:Critical Illness; D003599:Cytoskeleton / Q000235:genetics; D003720:Densitometry; D015536:Down-Regulation / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009135:Muscular Diseases / Q000235:genetics / Q000473:pathology*; D018384:Oxidative Stress / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger
keywords: autophagy; chaperones; critical illness myopathy and skeletal muscle proteostasis; intensive care unit; porcine ICU model; protein synthesis; skeletal muscle