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The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy

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Item Type:Article
Title:The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy
Creators Name:Schmidt, F., Kny, M., Zhu, X., Wollersheim, T., Persicke, K., Langhans, C., Lodka, D., Kleber, C., Weber-Carstens, S. and Fielitz, J.
Abstract:Introduction: Intensive care unit (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 TRIM62, an E3-ubiquitin ligase and modifier of inflammation, is increased in skeletal muscle of ICUAW patients. We investigated regulation and function of muscular TRIM62 in critical illness. Methods: Twenty-six critically ill patients with Sequential Organ Failure Assessment scores more than or equal to 8 underwent two skeletal muscle biopsies from the vastus lateralis at median days 5 and 15 in ICU. Four patients undergoing elective orthopedic surgery served as controls. TRIM62 expression and protein content was analyzed in these biopsies. Kinetics of Trim62, Atrogin1 and MuRF1 expression were determined in the gastrocnemius/plantaris and tibialis anterior from mouse models of inflammation, denervation and starvation induced muscle atrophy to differentiate between these contributors of ICUAW. Cultured myocytes were used for mechanistic analyses. Results: TRIM62 expression and protein content was increased early and remained elevated in muscle 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 siRNA inhibited lipopolysaccharide induced interleukin-6 expression. Conclusions: TRIM62 is activated in muscle of critically ill patients. It could play a role in the pathogenesis of ICUAW by activating and maintaining inflammation in myocytes. Trial registration: Current Controlled Trials, ISRCTN77569430. Registered 13 February 2008.
Keywords:Animal Disease Models, Critical Illness, Inflammation, Intensive Care Units, Muscular Atrophy, Skeletal Muscle, Ubiquitin-Protein Ligases, Animals, Mice
Source:Critical Care
Publisher:BioMed Central
Page Range:545
Date:29 September 2014
Official Publication:https://doi.org/10.1186/s13054-014-0545-6
PubMed:View item in PubMed

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