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The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy
Insights
Tripartite motif-containing 62 (TRIM62) is elevated in ICU-acquired weakness (ICUAW) skeletal muscle. This protein may drive ICUAW by promoting inflammation within myocytes.
Area of Science:
- Molecular biology
- Critical care medicine
- Skeletal muscle physiology
Background:
- ICU-acquired weakness (ICUAW) is a common complication in critically ill patients.
- Inflammation and acute-phase response in myocytes contribute to ICUAW.
- Increased tripartite motif-containing 62 (TRIM62), an E3 ubiquitin ligase, is observed in ICUAW patients' skeletal muscle.
Purpose of the Study:
- To investigate the regulation of muscular TRIM62 during critical illness.
- To elucidate the function of TRIM62 in the pathogenesis of ICUAW.
Main Methods:
- Skeletal muscle biopsies from 26 critically ill patients and 4 controls were analyzed for TRIM62 expression.
- Mouse models of inflammation, denervation, and starvation-induced muscle atrophy were used to study Trim62 kinetics.
- Mechanistic studies were performed in cultured myocytes.
Main Results:
- TRIM62 expression and protein content were significantly elevated early and persistently in critically ill patients' muscles.
- Muscular Trim62 expression increased early and continuously across all three mouse models of muscle atrophy.
- Overexpression of Trim62 in myocytes activated the atrophy-inducing activator protein 1 pathway and inhibited LPS-induced IL-6.
Conclusions:
- TRIM62 is activated in the skeletal muscle of critically ill patients.
- TRIM62 may contribute to ICUAW pathogenesis by activating and sustaining myocyte inflammation.
Introduction:
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.
Trial Registration:
Current Controlled Trials ID: ISRCTN77569430 (registered 13 February 2008).
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