Finally, network analysis was able to pin-point oxidative stress related pathway activation, modulation of the insulin signalling pathway and indicated that skeletal muscle in ICU patients was undergoing a de-differentiation process regardless of duration in the ICU. This suggests to us that suppressed microRNA processing or export may be occurring, representing a plausible mechanism explaining global loss of coordinated muscle gene expression and thus worthy of further investigation. This is especially plausible as Gene ontology analysis of the predicted targets of mir-21 suggest it should inhibit genes involved in ubiquitin ligase and JAK-STAT activity, both which were processes shown to be significantly up regulated in the transcriptomes of the patients. Thus failure to produce sufficient mir-21 may well have contributed to the activation of these pathways. However, the low activities of complexes I and IV were not present when expressed per citrate synthase activity, indicating a net decrease in mitochondrial content had occurred. Low activities of mitochondrial enzymes in skeletal musclehave been shown before inanimal models for sepsis and in critically ill patients. Most patient studies included patients in the acute septic or cardiogenic shock whereas our patients have been stabilized in the ICU and have developed multiple organ failure. During the acute critical phase results indicate a decreased function of the respiratory chain enzymes whereas the later phase of sepsis is characterized by a general decrease in mitochondrial content. One might assume that the loss of mitochondrial content reflects muscle inactivity resulting in decreased gene activation or sepsis induced atrophy disrupting mitochondrial biogenesis. However, neither appears to be true. Firstly, the in vivo mitochondrial protein Labetalol hydrochloride synthesis in the septic ICU patients was not different from thatin thecontrol Orbifloxacin subjects,indicating that sufficientmRNA template existed for translation. Secondly, targeted qPCR analysis demonstrated that the expression of several nuclear encoded oxidative phosphorylation genes did not differ between the groups, while there was a trend for up-regulation of mtDNA encoded oxidative phosphorylation genes and global analysis identified.80 modestly up regulated nuclear encoded mitochondrial related genes.