Time Resolved Analyses of Gene Expression in a Rodent Icu Model

Abstract

Intensive care unit (ICU) patients commonly develop severe skeletal muscle wasting that aggravate the recovery from the primary disease and weaning from respirator. The modern treatment in anesthesiology and intensive care can progress in Acute Quadriplegic Myopathy (AQM). This study aims at improving our understanding of the mechanisms underlying the muscle wasting and weakness in ICU patients with AQM. Specific interest is focused on duration-dependent effects on intracellular signaling and myofibrillar gene and protein expression. For that reason, a unique experimental rat model mimicking ICU such as mechanical ventilation, muscle unloading, neuromuscular blocking agents (NMBA) administration and monitoring at different time points from 6h to 14 days, was used. Gene expression profile was analyzed in gastrocnemius muscle, showing an increased expression in the muscle-specific ubiquitin ligases, atrogin-1 and MuRF-1 after 6 h, as well as other genes involved in translational repression, authophagic/lysosomal genes (LC3b, cathepsins), oxidative stress response and up-regulation of pro-apoptosis signaling, except caspase-3 that increased after 9 days of intervention. Metalloproteins, GST, cystatins and cell cycle repressors were up-regulated in the early stages in response to oxidative stress and cellular damage among other genes, while LIM and sarcomeric proteins, collagen, extracellular matrix transcripts, carbohydrate metabolism, mitochondrial genes and the muscle-specific calpain-3 were down-regulated mainly after 5 days. These results suggest a very complex, unique and highly temporally coordinated activation of protein synthesis, degradation, protective mechanisms and intracellular signaling activation at different time points during ICU conditions.