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

Schmidt F, Kny M, Zhu X, Wollersheim T, Persicke K, Langhans C, Lodka D, Kleber C, Weber-Carstens S, Fielitz J - Crit Care (2014)

Bottom Line: 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.It could play a role in the pathogenesis of ICUAW by activating and maintaining inflammation in myocytes.

View Article: PubMed Central - PubMed

ABSTRACT

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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Related in: MedlinePlus

Trim62expression is increased during inflammation-, denervation- and starvation-induced muscle atrophy. (A) Quantitative RT-PCR (qRT-PCR) analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles at 24 hours, 48 hours, 72 hours and 96 hours after surgery, as indicated. CLP, Cecal ligation and puncture surgery. (B) qRT-PCR analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles 7 days, 14 days and 21 days after denervation or sham surgery. (C) qRT-PCR analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles of control mice (–, n =6) and mice deprived of food for 24 hours (n =6) or 48 hours (n =6), as indicated. Glyceraldehyde 3-phosphate dehydrogenase (Gapdh) expression was used as the reference in all assays. Data shown are fold changes of expression in sham-operated and untreated mice. Data are presented as mean ± SEM. **P <0.01, *P <0.05.
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Fig3: Trim62expression is increased during inflammation-, denervation- and starvation-induced muscle atrophy. (A) Quantitative RT-PCR (qRT-PCR) analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles at 24 hours, 48 hours, 72 hours and 96 hours after surgery, as indicated. CLP, Cecal ligation and puncture surgery. (B) qRT-PCR analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles 7 days, 14 days and 21 days after denervation or sham surgery. (C) qRT-PCR analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles of control mice (–, n =6) and mice deprived of food for 24 hours (n =6) or 48 hours (n =6), as indicated. Glyceraldehyde 3-phosphate dehydrogenase (Gapdh) expression was used as the reference in all assays. Data shown are fold changes of expression in sham-operated and untreated mice. Data are presented as mean ± SEM. **P <0.01, *P <0.05.

Mentions: Muscular Trim62 expression was measured by qRT-PCR. It was significantly increased in gastrocnemius/plantaris and tibialis anterior muscles at 48 hours and 72 hours after CLP surgery. Throughout the experiment, Trim62 expression levels were persistently elevated in both muscle types (Figure 3A).Figure 3


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

Schmidt F, Kny M, Zhu X, Wollersheim T, Persicke K, Langhans C, Lodka D, Kleber C, Weber-Carstens S, Fielitz J - Crit Care (2014)

Trim62expression is increased during inflammation-, denervation- and starvation-induced muscle atrophy. (A) Quantitative RT-PCR (qRT-PCR) analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles at 24 hours, 48 hours, 72 hours and 96 hours after surgery, as indicated. CLP, Cecal ligation and puncture surgery. (B) qRT-PCR analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles 7 days, 14 days and 21 days after denervation or sham surgery. (C) qRT-PCR analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles of control mice (–, n =6) and mice deprived of food for 24 hours (n =6) or 48 hours (n =6), as indicated. Glyceraldehyde 3-phosphate dehydrogenase (Gapdh) expression was used as the reference in all assays. Data shown are fold changes of expression in sham-operated and untreated mice. Data are presented as mean ± SEM. **P <0.01, *P <0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4231194&req=5

Fig3: Trim62expression is increased during inflammation-, denervation- and starvation-induced muscle atrophy. (A) Quantitative RT-PCR (qRT-PCR) analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles at 24 hours, 48 hours, 72 hours and 96 hours after surgery, as indicated. CLP, Cecal ligation and puncture surgery. (B) qRT-PCR analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles 7 days, 14 days and 21 days after denervation or sham surgery. (C) qRT-PCR analyses of Trim62 expression in gastrocnemius/plantaris and tibialis anterior muscles of control mice (–, n =6) and mice deprived of food for 24 hours (n =6) or 48 hours (n =6), as indicated. Glyceraldehyde 3-phosphate dehydrogenase (Gapdh) expression was used as the reference in all assays. Data shown are fold changes of expression in sham-operated and untreated mice. Data are presented as mean ± SEM. **P <0.01, *P <0.05.
Mentions: Muscular Trim62 expression was measured by qRT-PCR. It was significantly increased in gastrocnemius/plantaris and tibialis anterior muscles at 48 hours and 72 hours after CLP surgery. Throughout the experiment, Trim62 expression levels were persistently elevated in both muscle types (Figure 3A).Figure 3

Bottom Line: 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.It could play a role in the pathogenesis of ICUAW by activating and maintaining inflammation in myocytes.

View Article: PubMed Central - PubMed

ABSTRACT

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).

Show MeSH
Related in: MedlinePlus