Muscle wasting and the temporal gene expresion pattern in a novel rat ICU model
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
SUBMITTER: Monica Llano-Diez
PROVIDER: E-GEOD-30848 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Critically ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decrease quality of life of survivors. Acute Quadriplegic Myopathy (AQM) is one of the most common neuromuscular disorders associated with ICU-acquired muscle weakness. Although there are no available treatments for the ICU-acquired muscle weakness, it has been demonstrated that early mobilization can improve its prognosis and functional outcomes. This study aims at improving our understanding of the effects of passive mechanical loading on skeletal muscle structure and function by using a unique experimental rat ICU model allowing analyses of the temporal sequence of changes in mechanically ventilated and pharmacologically paralyzed animals at durations varying from 6 h to 14 days. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle structure and function is likely a consequence of a reduced oxidative stress, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle structure and function associated with mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients. This study aims to unravel the effects of passive mechanical loading on skeletal muscle structure and function in an experimental rat ICU model at duration varying between 6h and 14 days. A total of 23 experimental female Sprague-Dawley rats were included in this study. The experimental rats were anaesthetized, treated with the neuromuscular blocking agent (NMBA) M-NM-1-cobrotoxin, mechanically ventilated and monitored for durations varying from 6h to 4 days (n=13), from 5 to 8 days (n=4), and from 9 to 14 days (n=6). The left leg of the animal was activated for 6 hours at the shortest duration and 12 hours per day at durations 12 hours and longer throughout the experiment, using a mechanical lever arm that produced a continuous passive maximal ankle joint flexions-extensions at a speed of 13.3 cycles per minute. Muscle biopsies were obtained from gastrocnemius muscle (proximal part) immediately after euthanasia, were quickly frozen in liquid propane cooled by liquid nitrogen, and stored at -80M-BM-0C. RNA was extracted.
2012-05-11 | E-GEOD-37944 | biostudies-arrayexpress
Project description:Background: The aim of this study is to improve our understanding of the mechanisms underlying the sparing of masticatory muscles in ICU patients with acute quadriplegic myopathy (AQM) by using a unique porcine ICU model, i.e., 5-day longitudinal experiments where animals are sedated, mechanically ventilated and exposed to factors triggering AQM, such as muscle unloading, endotoxin-induced sepsis, and systemic exposure to CS and NMBA. Results: An increased expression was notably observed in atrogin-1, cathepsins, FoxO1a, runx1 and heat-shock proteins genes. A decreased expression in some sarcomeric proteins and myostatin genes was also noticed. Hence, modifications in heat-shock proteins and myostatin genes are in sharp contrast to alterations in the limb muscles and it is postulated that elevated heat-shock proteins and decreased myostatin genes play a protective role in the masticatory muscle in ICU patients with AQM. Conclusions: We have observed a general down-regulation of muscle proteins and myostatin. Genes involved in the UPS system, cathepsins, RUNX1, TBX1, TIMP2 and transcripts of heat-shock proteins were up-regulated. However, we have neither observed a decrease in fiber CSA or force generation, suggesting that the expected atrophic changes have been countered by a protective mechanism and myostatin downregulation. Five female domestic piglets were treated with non-depolarizing neuromuscular blocking agents (NMBA), corticosteroids(CS) and sepsis. Five female piglets were untreated.
2010-09-21 | E-GEOD-24239 | biostudies-arrayexpress
Project description:This study was undertaken to examine differential gene expression across the whole genome during short-term ventilator-induced lung injury in mice, a commonly used model of acute lung injury, as compared with spontaneous ventilation. Experiment Overall Design: Mice were anesthetized with isoflurane followed by ketamine/xylaxine. Saline (0.25 ml) was given every hour ip. A tracheotomy tube was placed and the mice were ventilated with an initial peak airway pressure of 20 cmH2O approximating a tidal volume of 20 ml/kg and without end-expiratory pressure. Ventilation was continued for 3h. Tidal volume was not adjusted. Body temperature was monitored with a digital rectal thermometer and maintained at 37C with a heating table and external heating lamp. Control mice were treated identically, but were not mechanically ventilated (i.e. breathed spontaneously). There were 5 biological relicates in each group.
2008-06-20 | E-GEOD-11434 | biostudies-arrayexpress
Project description:Gene expression profiling was performed in lung tissues from an animal model of sepsis challenged with injurious and non-injurious mechanical ventilation to unravel the molecular pathways involved in acute lung injury. Sepsis was induced in male Sprague Dawley rats by means of cecal ligation and puncture. Septic rats were randomly allocated to three distinct groups: spontaneous breathing, mechanically ventilated with high tidal volume with zero positive end expiratory pressure (PEEP) and with low tidal volume and 10 cmH2O of PEEP. Comparisons were performed against an unventilated control group.
2015-07-01 | E-MTAB-2673 | biostudies-arrayexpress
Project description:Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. In order to elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness in AQM, gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals.
2011-07-23 | GSE30848 | GEO
Project description:Background: The aim of this study is to improve our understanding of the mechanisms underlying the function of corticosteriods in the limb muscles of ICU patients with acute quadriplegic myopathy (AQM) by using a unique porcine ICU model, i.e., 5-day longitudinal experiments where animals are sedated, mechanically ventilated and exposed to factor triggering AQM that is hydrocortisone. Results: An increased expression of genes involved in kinase activity, cell cycle regulation and transcriptional regulation. A decreased expression in genes regulating heat shock proteins, cytoskeletal & sarcomeric and oxidative stress response were also apparent. Therefore, it appears that CS has an additive deleterious role in acute quadriplegic myopathywere also apparent. Conclusions: CS induced molecular mechanisms involving kinase activity and heat shock protein genes were forwarded as probable mechanisms underlying the decreased force generating capacity. Eight female domestic piglets (Sus scrofa, average body weight 26.4 kg) were used in this study. Piglets were immobilized by anesthesia and mechanically ventilated via a tracheotomy for a period of five days. During this study period, the animals were sedated using isoflurane inhalation (Abbott Laboratories, Chicago, Il, USA, 0.8 - 1.3% end-tidal concentration) supplemented by intravenous bolus doses of morphine and ketamine as needed. Core body temperature (blood) was maintained in the range of 38.5 - 40M-BM-0C by a servo controlled heating pad. The animals received intravenous crystalloid fluid (Ringeracetat) to maintain stable blood pressure and urinary output and a glucose infusion (Rehydrex, Fresenius Kabi, Stockholm, Sweden, 25 mg glucose /mL) in the range of 0.5 - 1.5 mg/kg/minute to decrease the effects of catabolism. Each animal received prophylactic streptomycin 750 mg/d and bensylpenicillin 600 mg/d (Streptocillin Vet, Boeringer-Ingelheim, Hellerup, Denmark). Arterial blood gas analysis as well as electrolytes and blood glucose levels were monitored regularly and kept in the normal range throughout the study period. A neuromuscular blocking agent (NMBA) was administered as a continuous infusion of pancuronium bromide 0.1mg/kg/h (Pavolun; Organon, Boxtel, The Netherlands) for 5days while a corticosteroid (CS) was given as bolus doses of hydrocortisone. Keywords: Treatment, immobilization, muscle function.
2012-04-11 | E-GEOD-37166 | biostudies-arrayexpress
Project description:Background: The aim of this study is to improve our understanding of the mechanisms underlying the function of corticosteriods in the limb muscles of ICU patients with acute quadriplegic myopathy (AQM) by using a unique porcine ICU model, i.e., 5-day longitudinal experiments where animals are sedated, mechanically ventilated and exposed to factor triggering AQM that is hydrocortisone. Results: An increased expression of genes involved in kinase activity, cell cycle regulation and transcriptional regulation. A decreased expression in genes regulating heat shock proteins, cytoskeletal & sarcomeric and oxidative stress response were also apparent. Therefore, it appears that CS has an additive deleterious role in acute quadriplegic myopathywere also apparent. Conclusions: CS induced molecular mechanisms involving kinase activity and heat shock protein genes were forwarded as probable mechanisms underlying the decreased force generating capacity.
2012-04-12 | GSE37166 | GEO
Project description:Background : The aim of this study is to improve our understanding of the mechanisms underlying the role of sepsis in the limb muscles of ICU patients with acute quadriplegic myopathy (AQM) by using a unique porcine ICU model, i.e., 5-day longitudinal experiments where animals are sedated, mechanically ventilated and exposed to factor triggering AQM that is endotoxin-induced sepsis. Results : An increased expression of genes involved in chemokine activity and transcriptional regulation. A decreased expression in genes regulating heat shock proteins, cytoskeletal & sarcomeric and oxidative stress response were also apparent. Therefore, it appears that sepsis has an additive deleterious role in acute quadriplegic myopathy. Sepsis-induced molecular mechanisms involving chemokine/innate immunity and heat shock proteins are forwarded as probable mechanisms underlying the decreased force generating capacity. Conclusions : This sepsis had significant effect on biceps femoris muscle force-generation capacity but not on fiber size. However, significant differences were observed between the MV and MV+SEP in the transcriptional regulation of an increased expression of genes involved in chemokine activity genes like MCP-1 and transcriptional regulation genes like JUNB, STAT3 and BHLHB2. A decreased expression in genes regulating heat shock proteins like HSP 90, HSP 70 and αB-crystallin, cytoskeletal & sarcomeric like MAP1A, MyBP-C1 and MYH7 and oxidative stress response like SRXN1 and SOD2 were also apparent. Therefore, it appears that sepsis has an additive negative role in acute quadriplegic myopathy. Four female domestic piglets (Sus scrofa, average body weight 25.5 kg) were used in this study. Piglets were immobilized by anesthesia and mechanically ventilated via a tracheotomy for a period of five days. During this study period, the animals were sedated using isoflurane inhalation (Abbott Laboratories, Chicago, Il, USA, 0.8 – 1.3% end-tidal concentration) supplemented by intravenous bolus doses of morphine and ketamine as needed. Core body temperature (blood) was maintained in the range of 38.5 – 40°C by a servo controlled heating pad. The animals received intravenous crystalloid fluid (Ringeracetat) to maintain stable blood pressure and urinary output and a glucose infusion (Rehydrex, Fresenius Kabi, Stockholm, Sweden, 25 mg glucose /mL) in the range of 0.5 – 1.5 mg/kg/minute to decrease the effects of catabolism. Each animal received prophylactic streptomycin 750 mg/d and bensylpenicillin 600 mg/d (Streptocillin Vet, Boeringer-Ingelheim, Hellerup, Denmark). Arterial blood gas analysis as well as electrolytes and blood glucose levels were monitored regularly and kept in the normal range throughout the study period. A neuromuscular blocking agent (NMBA) was administered as a continuous infusion of pancuronium bromide 0.1mg/kg/h (Pavolun; Organon, Boxtel, The Netherlands) for 5days while a corticosteroid (CS) was given as bolus doses of betamethasone 0.1 mg/kg (Betapred; GSK, Slona, Sweden) twice daily for 5days. Endotoxemia was induced by a continuous infusion of Escherichia coli endotoxin, serotype O26:B6 (Sigma Labkemi, Stockholm, Sweden) at 36 µg/kg/h for 1h. Key words : Treatment, immobilization, muscle function.
2011-10-18 | E-GEOD-33037 | biostudies-arrayexpress
Project description:Background: The aim of this study is to improve our understanding of the mechanisms underlying the sparing of masticatory muscles relative to limb muscles in ICU patients with acute quadriplegic myopathy (AQM) by using a unique porcine ICU model, i.e., 5-day longitudinal experiments where animals are sedated, mechanically ventilated and exposed to factors triggering AQM, such as muscle unloading, endotoxin-induced sepsis, and systemic exposure to CS and NMBA. Results: An altered expression was notably observed in heat-shock proteins genes, sarcomeric proteins and myostatin genes were noticed. Hence, modifications in heat-shock proteins, sarcomeric proteins and myostatin genes are in sharp contrast to alterations in the limb muscles and it is postulated that elevated heat-shock proteins and decreased sarcomeric protein and myostatin genes play a protective role in the masticatory muscle relative to limb muscle in ICU patients with AQM. Conclusions: This intervention had no significant effect on masseter muscle fiber size or force-generation capacity. This is in sharp contrast to the dramatic decrease observed in specific force in limb muscle fibers from the same animals. However, significant differences were observed between the craniofacial and the limb muscle with a masseter muscle specific regulation of i) transcriptional and growth factors like RUNX1, FOXO1A, TBX1, PGC1-β and myostatin, ii) several heat shock protein genes like HSP 90, HSP 105/110 and αB-crystallin, iii) a matrix metalloproteinase inhibitor (TIMP2) and iv) oxidative stress responsive elements such as SRXN1 and SOD2. These muscle-type specific differences, the alterations in heat shock protein, sarcomeric protein and myostatin genes are forwarded as important factors underlying the sparing of masticatory muscles compared with limb muscles in critically ill ICU patients with Acute Quadriplegic Myopathy. Keywords: Treatment, immobilization, muscle function.
2010-09-21 | GSE24239 | GEO
Project description:Critically ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decrease quality of life of survivors. Acute Quadriplegic Myopathy (AQM) is one of the most common neuromuscular disorders associated with ICU-acquired muscle weakness. Although there are no available treatments for the ICU-acquired muscle weakness, it has been demonstrated that early mobilization can improve its prognosis and functional outcomes. This study aims at improving our understanding of the effects of passive mechanical loading on skeletal muscle structure and function by using a unique experimental rat ICU model allowing analyses of the temporal sequence of changes in mechanically ventilated and pharmacologically paralyzed animals at durations varying from 6 h to 14 days. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle structure and function is likely a consequence of a reduced oxidative stress, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle structure and function associated with mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients.
2012-05-12 | GSE37944 | GEO