title: Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms.
abstract: The muscle wasting and impaired muscle function in critically ill intensive care unit (ICU) patients delay recovery from the primary disease, and have debilitating consequences that can persist for years after hospital discharge. It is likely that, in addition to pernicious effects of the primary disease, the basic life support procedures of long-term ICU treatment contribute directly to the progressive impairment of muscle function. This study aims at improving our understanding of the mechanisms underlying muscle wasting in ICU patients by using a unique experimental rat ICU model where animals are mechanically ventilated, sedated and pharmacologically paralysed for duration varying between 6 h and 14 days. Results show that the ICU intervention induces a phenotype resembling the severe muscle wasting and paralysis associated with the acute quadriplegic myopathy (AQM) observed in ICU patients, i.e. a preferential loss of myosin, transcriptional down-regulation of myosin synthesis, muscle atrophy and a dramatic decrease in muscle fibre force generation capacity. Detailed analyses of protein degradation pathways show that the ubiquitin proteasome pathway is highly involved in this process. A sequential change in localisation of muscle-specific RING finger proteins 1/2 (MuRF1/2) observed during the experimental period is suggested to play an instrumental role in both transcriptional regulation and protein degradation. We propose that, for those critically ill patients who develop AQM, complete mechanical silencing, due to pharmacological paralysis or sedation, is a critical factor underlying the preferential loss of the molecular motor protein myosin that leads to impaired muscle function or persisting paralysis.
authors.affiliation: Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala, Sweden.
authors.forename: Julien
authors.initials: J
authors.lastname: Ochala
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Gustafson
authors.forename: Monica Llano
authors.initials: ML
authors.lastname: Diez
authors.forename: Guillaume
authors.initials: G
authors.lastname: Renaud
authors.forename: Meishan
authors.initials: M
authors.lastname: Li
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Aare
authors.forename: Rizwan
authors.initials: R
authors.lastname: Qaisar
authors.forename: Varuna C
authors.initials: VC
authors.lastname: Banduseela
authors.forename: Yvette
authors.initials: Y
authors.lastname: Hedström
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Tang
authors.forename: Barry
authors.initials: B
authors.lastname: Dworkin
authors.forename: G Charles
authors.initials: GC
authors.lastname: Ford
authors.forename: K Sreekumaran
authors.initials: KS
authors.lastname: Nair
authors.forename: Sue
authors.initials: S
authors.lastname: Perera
authors.forename: Mathias
authors.initials: M
authors.lastname: Gautel
authors.forename: Lars
authors.initials: L
authors.lastname: Larsson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003422:Critical Care; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D007103:Immobilization / Q000009:adverse effects*; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000378:metabolism; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009466:Neuromuscular Blocking Agents / Q000008:administration & dosage; D010243:Paralysis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial; D024744:Skeletal Muscle Myosins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D016474:Weight-Bearing
chemical_list: D009124:Muscle Proteins; D009466:Neuromuscular Blocking Agents; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D024744:Skeletal Muscle Myosins