Muslce mitochondria in sepsis

Patients treated in the intensive care unit (ICU) for sepsis induced multiple organ failure often suffer from skeletal muscle fatigue after ICU discharge. Since mitochondria are the main determinants of muscle fatigability, their function in muscle of these patients was the theme of this thesis. Decreased muscle mitochondrial activity has been related to mortality in patients suffering from acute sepsis. The present thesis has two major aims. The first is to describe mitochondrial derangements in muscle from septic patients and the second one was to elucidate the underlying mechanisms for these mitochondrial problems. To describe the mitochondrial derangements in muscle from septic patients, muscle biopsies were obtained from respiratory and leg muscle of mechanically ventilated septic patients and healthy control patients. In both muscle tissues a decreased mitochondrial content was found in comparison to controls. In addition, leg muscle had lower concentrations of energy rich phosphates and an increased lactate concentration. The second study relating to this problem was performed in a human model for studying the very early phase of sepsis. In this study leg muscle biopsies were obtained at baseline and 2 and 4 hours after an intravenous endotoxin injection. Mitochondrial enzyme activities increased 2 hours after endotoxin and went back to baseline at 4 hours. The concentration of ATP did not change between baseline and the two consecutive biopsies, however an increase in activity was found between 2 and 4 hours after endotoxin. The second aim was to characterize underlying mechanisms that may cause mitochondrial derangements in septic patients. The effect of inactivity on muscle mitochondria was evaluated in diaphragm muscle from mechanically ventilated piglets. The mitochondrial enzyme activity of complex IV was significantly decreased after 5 days of mechanical ventilation while the other mitochondrial enzymes and content did not change. In the last study mitochondrial protein turnover and biogenesis were evaluated in leg muscle from septic ICU patients. Mitochondrial protein synthesis and mRNA levels of mitochondrial proteins were not different between patients and controls. Some of the mitochondrial transcription factors increased in mRNA levels, whereas the others did not change in comparison to controls. The mRNA levels of the active subunits of two mitochondrial matrix proteases increased significantly while the membrane bound proteases did not change. In summary, the mitochondrial content is decreased in respiratory and leg muscle from septic ICU patients. In leg the lower mitochondrial content was accompanied by low concentrations of energetic phosphates. A human model of sepsis indicated a biphasic development of mitochondrial derangements were an initial increase in mitochondrial enzyme activity is followed by a decrease. The cause of the decrease in mitochondrial content does not seem to be related to inactivation by mechanical ventilation as evaluated in piglets. Decreased mitochondrial content cannot be explained by a decreased mitochondrial protein synthesis or biogenesis. It is more likely that an increased mitochondrial protein breakdown is responsible for the decreased mitochondrial content in patients with sepsis induced multiple organ failure. LIST OF PUBLICATIONS I. Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure. Fredriksson K, Hammarqvist F, Strigard K, Hultenby K, Ljungqvist O, Wernerman J, Rooyackers O. Am J Physiol Endocrinol Metab 291:E1044-E1050, 2006 II. Muscle mitochondrial activity and energetic status in a human model of sepsis. Fredriksson K, Flaring U, Guillet C, Wernerman J, Rooyackers O. Manuscript III. Effect of prolonged mechanical ventilation on diaphragm muscle mitochondria in piglets. Fredriksson K, Radell P, Eriksson LI, Hultenby K, Rooyackers O. Acta Anaesthesiol Scand 49: 1101-1107, 2005 IV. Mitochondrial protein turnover in muscle from patients with sepsis induced multiple organ failure. Fredriksson K, Tjader I, Ahlman B, Scheele C, Wernerman J, Timmons JA, Rooyackers O. Manuscript CONTENTS