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Gene expression and muscle fiber function in a porcine ICU model

ABSTRACT: Background: Skeletal muscle wasting and impaired muscle function in response to mechanical ventilation and immobilization in intensive care unit (ICU) patients are clinically challenging partly due to (i) the poorly understood intricate cellular and molecular networks; and (ii) the unavailability of an animal model mimicking this condition. By employing a unique porcine model mimicking the conditions in the ICU with long-term mechanical ventilation and immobilization, we have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a five-day period. Results: We have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a five-day period. Among the differentially regulated transcripts, extracellular matrix, energy metabolism, sarcomeric proteins and LIM protein mRNA levels were down-regulated while ubiquitin proteasome system, cathepsins, oxidative stress responsive genes and heat shock proteins (HSP) mRNAs were up-regulated Conclusions: We conclude that induction of HSPs may play an inherent temporary protective mechanism in skeletal muscle in the early stages of immobilization and mechanical ventilation. The proposed molecular events leading to our final hypothesis are illustrated in the manuscript. Keywords: Treatment, immobilization, muscle function.

ORGANISM(S): Sus scrofa

PROVIDER: GSE16348 | GEO | 2009/08/31

SECONDARY ACCESSION(S): PRJNA115301

REPOSITORIES: GEO

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Project description:Background: Skeletal muscle wasting and impaired muscle function in response to mechanical ventilation and immobilization in intensive care unit (ICU) patients are clinically challenging partly due to (i) the poorly understood intricate cellular and molecular networks; and (ii) the unavailability of an animal model mimicking this condition. By employing a unique porcine model mimicking the conditions in the ICU with long-term mechanical ventilation and immobilization, we have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a five-day period. Results: We have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a five-day period. Among the differentially regulated transcripts, extracellular matrix, energy metabolism, sarcomeric proteins and LIM protein mRNA levels were down-regulated while ubiquitin proteasome system, cathepsins, oxidative stress responsive genes and heat shock proteins (HSP) mRNAs were up-regulated Conclusions: We conclude that induction of HSPs may play an inherent temporary protective mechanism in skeletal muscle in the early stages of immobilization and mechanical ventilation. The proposed molecular events leading to our final hypothesis are illustrated in the manuscript. Keywords: Treatment, immobilization, muscle function. Sixteen female domestic piglets (Sus scrofa, average body weight 26.5 kg) were used in this study. All piglets were immobilized by anesthesia and mechanically ventilated (Servo 900C, Siemens-Elema, Solna, Sweden). The first m. biceps femoris biopsies (day 1) were obtained from all animals, after administering anesthetics. During the five day study period, four 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. Biopsies from the m. biceps femoris were obtained on two further separate occasions (days 3 and 5) in these animals. Core body temperature (blood) was maintained in the range of 38.5 – 40°C by a servocontrolled heating pad. The animals received intravenous crystalloid fluid (Ringer’s acetate) 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 benzylpenicillin 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.

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.

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Gene expression and muscle fiber function in a porcine ICU model

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