Kyphoscoliosis peptidase ( em Ky /em ), a cytoskeleton-associated protease essential for normal muscle growth, maturation and stabilization of neuromuscular junction and required for a hypertrophic response in muscle , was down-regulated 4-fold (0.25-4d), 30-fold (5-8d) and 15-fold (9-14d). Embigin homolog mouse ( em Emb /em ) was recently identified as a nerve terminal sprouting factor at the neuromuscular junction that is up-regulated in denervated muscle . days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals. Results During the observation period, 1583 genes were significantly up- or down-regulated by factors of two or greater. A significant temporal gene expression pattern was constructed at short (6 h-4 days), intermediate (5-8 days) and long (9-14 days) durations. A striking early and maintained up-regulation (6 h-14d) of muscle atrogenes (muscle ring-finger 1/tripartite motif-containing 63 and F-box protein 32/atrogin-1) was observed, followed by an up-regulation of the proteolytic systems at intermediate and long durations (5-14d). Oxidative stress response genes and genes that take part in amino acid catabolism, cell cycle arrest, apoptosis, muscle development, and protein synthesis together with myogenic factors were significantly up-regulated from 5 to 14 days. At 9-14 d, genes involved in immune response and the caspase cascade were up-regulated. At 5-14d, genes related to contractile (myosin heavy chain and myosin binding protein C), regulatory (troponin, tropomyosin), developmental, caveolin-3, extracellular matrix, glycolysis/gluconeogenesis, cytoskeleton/sarcomere regulation and mitochondrial proteins were down-regulated. An activation of genes related to muscle growth and new muscle fiber formation (increase of myogenic factors and JunB and down-regulation of myostatin) and up-regulation of genes that code protein synthesis and translation factors were found from 5 to 14 days. Conclusions Novel temporal patterns of gene expression Rabbit Polyclonal to Cox2 have been uncovered, suggesting a unique, coordinated Cevimeline hydrochloride and highly complex mechanism underlying the muscle wasting associated with AQM in ICU patients and providing new target Cevimeline hydrochloride genes and avenues for intervention studies. Background All critically ICU patients suffer from severe wasting and impaired muscle function, which delay respirator weaning and persist long after hospital discharge; thus reducing quality of life [1,2]. Although muscle wasting in ICU patients may be related to the primary disease, it also devolves from the interventions used in modern anaesthesiology and intensive care: Prolonged mechanical ventilation, post-synaptic neuromuscular transmission blockade (NMB), sedation, and systemic corticosteroid hormone treatment have all been proposed as factors triggering the severe muscle wasting, paralysis, impaired respiratory function, and partial or complete loss of the motor protein myosin in ICU patients who develop Acute Quadriplegic Myopathy (AQM). Sepsis, organ transplantation, multi-organ failure, and hyperglycemia are also hypothesized risk factors for AQM [3-6]. We have recently demonstrated that complete mechanical silencing, i.e., absence of weight bearing and internal strain in the muscle caused by muscle contraction, induces a phenotype which closely resembles that of AQM in ICU patients . The myosin loss and muscle wasting follows a temporal sequence with an initial sparing of both muscle function, mass and myosin content followed by a progressive loss of muscle force that exceeds the loss in muscle mass due to a preferential loss of the motor protein myosin [7-9]. Acute quadriplegic myopathy, also known as critical illness myopathy (CIM), thick filament myosin myopathy, acute myopathy in Cevimeline hydrochloride severe asthma and myopathy of intensive care , was for many years considered to be rare and of limited clinical significance, but in the past two decades the number of reported cases with AQM has substantially increased. Recent studies show that approximately 50% of ICU patients with sepsis, multi-organ failure or prolonged mechanical ventilation present significant neuromuscular dysfunction . This muscles spending Cevimeline hydrochloride and weakness Cevimeline hydrochloride might persist 5 years after medical center release, impairing standard of living drastically.