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

Abstract

IntroductionICU-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.MethodsTwenty-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.ResultsTRIM62 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.ConclusionsTRIM62 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.Trial registrationCurrent Controlled Trials ID: ISRCTN77569430 (registered 13 February 2008)Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0545-6) contains supplementary material, which is available to authorized users.

Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy

“…Atrogin 1 and MuRF1 are key “atrogenes” in this process [10, 22, 38, 52]. Our finding that atrogene expression was not increased in Nlrp3 KO indicates that atrogene expression is regulated by Nlrp3-dependent IL-1β activation.…”

“…C2C12 myoblasts were originally isolated from wild-type mice [39] and selected for its ability to differentiate to myotubes expressing characteristic muscle proteins [40]. Others [41–43] and we [36, 38, 44] have used this cell line earlier to investigate mechanisms of inflammation-induced myocyte atrophy. Using immunocytochemistry, we found that 30 min of IL-1β treatment resulted in an increased cytoplasmic-to-nuclear shift of IRAK-1 in C2C12 myocytes (Fig.…”

“…An imbalanced muscular protein homeostasis plays a dominant role in muscle failure of critically ill patients [4, 10, 38]. Atrogin 1 and MuRF1 are key “atrogenes” in this process [10, 22, 38, 52].…”

“…Nlrp3 knockout (KO) mice were kindly provided by Aubry Tardivel and Nicolas Fasel (University of Lausanne) [35]. Cecal ligation and puncture (CLP) surgery was performed to induce polymicrobial sepsis in 12- to 16-week-old male Nlrp3 KO or wild-type (WT) mice as recently described [36–38]. Sham mice were treated identically except for the ligation and puncture of the cecum.…”

Cancer cachexia—when proteasomal inhibition is not enough

“…This hypothesis is strengthened by data from non‐cancer patients and animal models. For example, the UPS is activated in muscle of patients with intensive care unit‐acquired weakness and mice with polymicrobial sepsis . Accordingly, mice exposed to endotoxin, a cell wall component of gram‐negative bacteria, display enhanced proteolytic activity in the diaphragm leading to a reduction in muscle mass, force, and protein content.…”