title: The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy.
abstract: BACKGROUND
  ICU-acquired weakness (ICUAW) complicates the disease course of critically ill patients. Inflammation and acute-phase response occur directly within myocytes and contribute to ICUAW. We observed that tripartite motif-containing 62 (TRIM62), an E3 ubiquitin ligase and modifier of inflammation, is increased in the skeletal muscle of ICUAW patients. We investigated the regulation and function of muscular TRIM62 in critical illness.
  
  
  METHODS
  Twenty-six critically ill patients with Sequential Organ Failure Assessment scores ≥8 underwent two skeletal muscle biopsies from the vastus lateralis at median days 5 and 15 in the ICU. Four patients undergoing elective orthopedic surgery served as controls. TRIM62 expression and protein content were analyzed in these biopsies. The kinetics of Trim62, Atrogin1 and MuRF1 expression were determined in the gastrocnemius/plantaris and tibialis anterior muscles from mouse models of inflammation-, denervation- and starvation-induced muscle atrophy to differentiate between these contributors to ICUAW. Cultured myocytes were used for mechanistic analyses.
  
  
  RESULTS
  TRIM62 expression and protein content were increased early and remained elevated in muscles from critically ill patients. In all three animal models, muscular Trim62 expression was early and continuously increased. Trim62 was expressed in myocytes, and its overexpression activated the atrophy-inducing activator protein 1 signal transduction pathway. Knockdown of Trim62 by small interfering RNA inhibited lipopolysaccharide-induced interleukin 6 expression.
  
  
  CONCLUSIONS
  TRIM62 is activated in the muscles of critically ill patients. It could play a role in the pathogenesis of ICUAW by activating and maintaining inflammation in myocytes.
  
  
  BACKGROUND
  Current Controlled Trials ID: ISRCTN77569430 (registered 13 February 2008).
authors.forename: Franziska
authors.initials: F
authors.lastname: Schmidt
authors.forename: Melanie
authors.initials: M
authors.lastname: Kny
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhu
authors.forename: Tobias
authors.initials: T
authors.lastname: Wollersheim
authors.forename: Kathleen
authors.initials: K
authors.lastname: Persicke
authors.forename: Claudia
authors.initials: C
authors.lastname: Langhans
authors.forename: Doerte
authors.initials: D
authors.lastname: Lodka
authors.forename: Christian
authors.initials: C
authors.lastname: Kleber
authors.forename: Steffen
authors.initials: S
authors.lastname: Weber-Carstens
authors.forename: Jens
authors.initials: J
authors.lastname: Fielitz
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016638:Critical Illness / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation; D007362:Intensive Care Units; D008297:Male; D051379:Mice; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000070584:Tripartite Motif Proteins; C583162:TRIM62 protein, human; D044767:Ubiquitin-Protein Ligases