Dataset Information

Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs.

ABSTRACT:

Rationale

The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs.

Objectives

To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro.

Methods

In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined.

Measurements and main results

Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-β (TGF-β) responses in C2C12 cells, suggesting increased sensitivity to TGF-β in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle.

Conclusions

GDF-15 may increase sensitivity to TGF-β signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets.

SUBMITTER: Bloch SA

PROVIDER: S-EPMC4345798 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Publications

Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs.

Bloch S A A SA Lee J Y JY Syburra T T Rosendahl U U Griffiths M J D MJ Kemp P R PR Polkey M I MI

Thorax 20141216 3

<h4>Rationale</h4>The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs.<h4>Objectives</h4>To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro.<h4>Method ...[more]

PMID: 25516419

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Project description:Over the last 10 years we have significantly reduced hospital mortality from sepsis and critical illness. However, the evidence reveals that over the same period we have tripled the number of patients being sent to rehabilitation settings. Further, given that as many as half of the deaths in the first year following ICU admission occur post ICU discharge, it is unclear how many of these patients ever returned home. For those who do survive, the latest data indicate that 50-70% of ICU "survivors" will suffer cognitive impairment and 60-80% of "survivors" will suffer functional impairment or ICU-acquired weakness (ICU-AW). These observations demand that we as intensive care providers ask the following questions: "Are we creating survivors ... or are we creating victims?" and "Do we accomplish 'Pyrrhic Victories' in the ICU?" Interventions to address ICU-AW must have a renewed focus on optimal nutrition, anabolic/anticatabolic strategies, and in the future employ the personalized muscle and exercise evaluation techniques utilized by elite athletes to optimize performance. Specifically, strategies must include optimal protein delivery (1.2-2.0 g/kg/day), as an athlete would routinely employ. However, as is clear in elite sports performance, optimal nutrition is fundamental but alone is often not enough. We know burn patients can remain catabolic for 2 years post burn; thus, anticatabolic agents (i.e., beta-blockers) and anabolic agents (i.e., oxandrolone) will probably also be essential. In the near future, evaluation techniques such as assessing lean body mass at the bedside using ultrasound to determine nutritional status and ultrasound-measured muscle glycogen as a marker of muscle injury and recovery could be utilized to help find the transition from the acute phase of critical illness to the recovery phase. Finally, exercise physiology testing that evaluates muscle substrate utilization during exercise can be used to diagnose muscle mitochondrial dysfunction and to guide a personalized ideal heart rate, assisting in recovery of muscle mitochondrial function and functional endurance post ICU. In the end, future ICU-AW research must focus on using a combination of modern performance-enhancing nutrition, anticatabolic/anabolic interventions, and muscle/exercise testing so we can begin to create more "survivors" and fewer victims post ICU care.

Project description:BACKGROUND:Whereas ICU-acquired weakness may delay extubation in mechanically ventilated patients, its influence on extubation failure is poorly known. This study aimed at assessing the role of ICU-acquired weakness on extubation failure and the relation between limb weakness and cough strength. METHODS:A secondary analysis of two previous prospective studies including patients at high risk of reintubation after a planned extubation, i.e., age greater than 65 years, with underlying cardiac or respiratory disease, or intubated for more than 7 days prior to extubation. Patients intubated less than 24 h and those with a do-not-reintubate order were not included. Limb and cough strength were assessed by a physiotherapist just before extubation. ICU-acquired weakness was clinically diagnosed as limb weakness defined as Medical Research Council (MRC) score < 48 points and severe weakness as MRC sum-score < 36. Cough strength was assessed using a semi-quantitative 5-Likert scale. Extubation failure was defined as reintubation or death within the first 7 days following extubation. RESULTS:Among 344 patients at high risk of reintubation, 16% experienced extubation failure (56/344). They had greater severity and lower MRC sum-score (41 ± 16 vs. 49 ± 13, p < 0.001) and were more likely to have ineffective cough than the others. The prevalence of ICU-acquired weakness at the time of extubation was 38% (130/244). The extubation failure rate was 12% (25/214) in patients with no limb weakness vs. 18% (12/65) and 29% (19/65) in those with moderate and severe limb weakness, respectively (p < 0.01). MRC sum-score and cough strength were weakly but significantly correlated (rho = 0.28, p < .001). After multivariate logistic regression analyses, the lower the MRC sum-score the greater the risk of reintubation; severe limb weakness was independently associated with extubation failure, even after adjustment on cough strength and severity at admission. CONCLUSION:ICU-acquired weakness was diagnosed in 38% in this population of patients at high risk at the time of extubation and was independently associated with extubation failure in the ICU.

Dataset Information

Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs.

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