Intensive Care Unit Acquired Paresis (ICUAP) is a major health concern facing today’s critical care patients. This syndrome of severe muscle wasting and weakness is associated with significant morbidity and mortality, resulting in a substantial clinical and financial burden. However as yet, other than early mobilisation and rehabilitation, there are no available treatments. The aim of this work was to identify molecular mechanisms in the aetiology of ICUAP with a view to finding novel therapeutic targets. In a prospective study of high-risk elective cardiothoracic patients, prolonged elevation of circulating GDF-15, a stress-induced cytokine and TGF-β family member, was associated with acute muscle wasting. Following on from this work, the hypothesis that GDF-15 might be a driver of muscle wasting in ICUAP was tested in an observational study of 20 ICUAP patients and 7 elective cardiothoracic controls. Both circulating GDF-15 and muscle GDF-15 mRNA expression were elevated in patients compared to controls. In addition microRNAs essential for muscle homeostasis and protection against TGF-β signalling were found to be down-regulated. In vitro experiments demonstrated that GDF-15 could increase expression of muscle atrophy-related genes and supress these microRNAs. Increased sensitivity to TGF-β signalling secondary to down-regulation of muscle microRNAs driven by GDF-15 hypothesised as an aetiological mechanism of muscle wasting in critical illness. Supporting this hypothesis, transfection of miR-181a into C2C12 cells reduced the response to TGF-β1 and increased TGF-β signalling was found in the muscle of ICUAP patients. 9 An interventional study of neuromuscular electrical stimulation (NMES) in ICU demonstrated that although increased mobility in critical care patients can improve outcomes there is a risk that NMES may cause muscle damage. Finally preliminary data, suggested that miR-181a is a potential biomarker for ICUAP. GDF-15 and microRNAs are potential therapeutic targets and this work supports the need for further investigation into these pathways in ICUAP.