AJP - Endo Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 291: E1044-E1050, 2006. First published June 27, 2006; doi:10.1152/ajpendo.00218.2006
0193-1849/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow A corrigendum has been published
Right arrow All Versions of this Article:
291/5/E1044    most recent
00218.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (7)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fredriksson, K.
Right arrow Articles by Rooyackers, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fredriksson, K.
Right arrow Articles by Rooyackers, O.

Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure

Katarina Fredriksson,1 Folke Hammarqvist,2 Karin Strigård,2 Kjell Hultenby,3 Olle Ljungqvist,4 Jan Wernerman,1 and Olav Rooyackers1

1Department of Anesthesiology and Intensive Care, 2Gastrocentrum, Department of Surgery, 3Clinical Research Center at Karolinska University Hospital, Huddinge; and 4Center for Gastrointestinal Disease at Ersta Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden

Submitted 8 May 2006 ; accepted in final form 22 June 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Critically ill patients treated for multiple organ failure often develop muscle dysfunction. Here we test the hypothesis that mitochondrial and energy metabolism are deranged in leg and intercostal muscle of critically ill patients with sepsis-induced multiple organ failure. Ten critically ill patients suffering from sepsis-induced multiple organ failure and requiring mechanical ventilation were included in the study. A group (n = 10) of metabolically healthy age- and sex-matched patients undergoing elective surgery were used as controls. Muscle biopsies were obtained from the vastus lateralis (leg) and intercostal muscle. The activities of citrate synthase and mitochondrial respiratory chain complexes I and IV and concentrations of ATP, creatine phosphate, and lactate were analyzed. Morphological evaluation of mitochondria was performed by electron microscopy. Activities of citrate synthase and complex I were 53 and 60% lower, respectively, in intercostal muscle of the patients but not in leg muscle compared with controls. The activity of complex IV was 30% lower in leg muscle but not in intercostal muscle. Concentrations of ATP and creatine phosphate were, respectively, 40 and 34% lower, and lactate concentrations were 43% higher in leg muscle but not in intercostal muscle. We conclude that both leg and intercostal muscle show a twofold decrease in mitochondrial content in intensive care unit patients with multiple organ failure, which is associated with lower concentrations of energy-rich phosphates and an increased anaerobic energy production in leg muscle but not in intercostal muscle.

mitochondrial respiratory chain; energy-rich phosphates; skeletal muscle; intensive care unit; oxidative stress

SEPTIC PATIENTS TREATED IN the intensive care unit (ICU) frequently develop skeletal muscle dysfunction. This dysfunction can be because of muscle weakness (decreased muscle strength), muscle fatigability (reduced capacity to continue muscle contractions), or other causes such as acquired neuropathy (1, 6, 13, 25, 26).

This muscle dysfunction often persists after ICU discharge. For instance, patients treated in the ICU for acute respiratory distress syndrome showed a persistent functional limitation up to one year after discharge from the ICU, which was associated with muscle fatigue by most patients (22). Also, respiratory muscles are susceptible to muscle dysfunction in critically ill patients. The majority of critically ill patients treated in ICUs in Northern Europe suffer from respiratory dysfunction and need mechanical ventilation. As much as 20% of all mechanically ventilated patients have problems with weaning from the ventilator, prolonging their ICU treatment (27, 32, 33). Both the respiratory dysfunction and the prolonged weaning are thought to be related to respiratory muscle weakness and fatigue.

In several animal models for severe sepsis and septic shock, decreased mitochondrial function and a consequent decrease in energy supplies in skeletal muscle have been shown (4, 9, 12, 30, 31). Because mitochondria are the main producers of cellular energy, a decreased mitochondrial function will interfere with muscle performance. Studies on skeletal muscle of septic patients are, however, limited. Three studies have shown decreased mitochondrial function in skeletal muscle of patients with acute cardiogenic or septic shock (8, 11, 17). These studies show an acute effect of shock on the mitochondrial membrane-bound enzymes of the respiratory chain. As discussed by Brealey at al. (8), this decreased respiratory chain activity might be related to the high mortality seen with acute shock. This mortality is most likely not the result of muscle dysfunction but more the result of a bioenergetic failure in more vital organs. Whether a similar derangement of mitochondrial function is present during a later phase of sepsis, where muscle dysfunction is more apparent, is not known. Septic patients surviving the initial shock phase often require prolonged ICU treatment and develop multiple organ failure (MOF). It is during this prolonged ICU treatment that muscle dysfunction develops and interferes with respiration and mobility during recovery. In the present study, we hypothesize that patients treated in the ICU for sepsis-related MOF are characterized by mitochondrial derangements and bioenergetic failure in both leg and intercostal muscle.

In this descriptive pilot study, for the first time, we measured mitochondrial enzyme activities, energy-rich phosphates, and a marker of oxidative stress in leg and intercostal muscle of mechanically ventilated ICU patients with sepsis-induced MOF. Intercostal muscle was used as a representative of respiratory muscle. Metabolically healthy, age- and sex-matched patients undergoing elective surgery served as controls.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. Ten mechanically ventilated patients with MOF admitted to the general ICU at Karolinska University Hospital Huddinge were included in the study. All patients had sepsis according to the criteria of Bone et al. (7) but were stabilized and had MOF with two or more organs failing. Patients with known preexisting neuromuscular disease, chronic obstructive pulmonary disorder (COPD), or severe coagulopathies not enabling muscle biopsies were excluded. Treatment and nutrition were according to the ICU routines and the discretion of the attending intensivist. None of the patients was treated with muscle relaxants. As a control group, 10 metabolically healthy age- and sex-matched patients undergoing elective surgery were included. Muscle biopsies were taken from leg (vastus lateralis) muscle using a Bergström biopsy needle and from the lateral external intercostal muscle between the fifth and sixth rib by open surgery. In the control patients, muscle biopsies were obtained just after induction of anesthesia but before surgery was started. Control patients were normoventilated. A small portion of the muscle biopsies was immediately fixed (2% glutaraldehyde and 0.5% paraformaldehyde in 0.1 M sodium cacodylate buffer containing 0.1 M sucrose and 3 mM CaCl2, pH 7.4) for morphological examination by electron microscopy. The rest of the biopsy specimens were quickly weighed, frozen in liquid nitrogen, and stored at –80°C until analysis. All patients or close relatives gave informed consent to participate in the study. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and had received an a priori approval by the Ethical Committee of Karolinska Institutet, Stockholm, Sweden.

Enzymatic measurements. Muscle samples were homogenized in a Potter-Elvhjem homogenizer in KCl buffer (100 mM KCl, 50 mM Tris·HCl, 5 mM MgCl2, 1.8 mM ATP, and 1 mM EDTA) to obtain a 5% homogenate (16). Parts of the homogenate were frozen, and the rest was used to isolate mitochondria by subsequent centrifugation. The homogenate was centrifuged at 700 g at 4°C for 10 min. The supernatant was decanted and centrifuged at 15,000 g at 4°C for another 10 min. Thereafter, the mitochondrial pellet was washed two times in the KCl buffer. The final mitochondrial pellet was suspended in 0.25 M sucrose, 2 mM EDTA, and 10 mM Tris (pH 7.4) and stored frozen at –80°C until analysis (16). Mitochondrial enzyme activities (citrate synthase, complex I and IV of the mitochondrial respiratory chain) were measured in both total muscle homogenate and the isolated mitochondria. All enzymes were analyzed using spectrophotometric assays (16) adapted for analyses on a Konelab 20 Analyzer (Thermo Clinical Labsystems, Vantaa, Finland). The limit of detection in the Konelab 20 analyzer is 0.0005 absorbance units.

Total muscle and mitochondrial superoxide dismutase (SOD) activities were also measured in both muscle homogenate and isolated mitochondria using a Ransod kit (Randox Laboratories) on a Konelab 20 spectrophotometric analyzer.

Energy-rich phosphates and lactate. Muscle samples were freeze-dried. The dried muscle pieces were dissected free from visible fat, blood, and connective tissue and pulverized in a mortar. The sample was subsequently suspended in 0.5 M perchloric acid, kept on ice for 10 min, and neutralized using 2 M KHCO3. A portion of the neutralized samples was frozen for later lactate analysis, and the other part was used for immediate analysis of ATP and creatine phosphate.

ATP and creatine phosphate concentrations were measured enzymatically, as has been described previously (21), and adapted for analysis on a Konelab 20 Analyzer. The neutral samples were mixed with a reagent (89 mM imidazole buffer, 1.4 mM EDTA, 13.4 mM MgCl2·6H2O, 1.4 mM dithiothreitol, 0.5 mM ADP, 1.3 mM NADP, and 3.3 mM glucose, pH 7.2). The samples were incubated for 10 min with glucose-6-phosphate dehydrogenase at 37°C. The absorbance was measured at 340 nm, and hexokinase was added. After another 10 min, the absorbance was measured again at 340 nm, and creatine phosphokinase was added. After another 10 min, the absorbance was again measured at 340 nm. The concentration of ATP was calculated using the difference in absorbance between the first and second measurement, and creatine phosphate was calculated using the difference in absorbance between the second and third measurement.

To measure concentrations of lactate, an EnzyPlus L-lactitic acid kit (Diffchamb, Gothenburg, Sweden) was used.

Morphological evaluation. Morphological evaluation of the subsarcolemmal mitochondria (i.e., the mitochondria that are located just beneath the muscular cell membrane) and the intermyofibrillar mitochondria (located in between the myofibrils of the muscle cell) was performed blindly by a trained pathologist, using randomized muscle samples on a Tecnai 10 electron microscope. The fixed muscle samples were rinsed (0.15 M sodium cacodylate buffer containing 3 mM CaCl2, pH 7.4), postfixed for 2 h (2% osmium tetroxide in 0.07 mM sodium cacodylate buffer containing 1.5 M CaCl2, pH 7.4, 4°C), dehydrated (ethanol followed by acetone), and embedded in LX-112 (Ladd, Burlington, VT). Semithin sections were cut and stained with toluidine blue and used for light microscopic analysis. Ultrathin sections (~40–50 nm) were cut and contrasted with uranyl acetate followed by lead citrate and examined blindly in a Tecnai 10 electron microscope at 80 kV.

A score from two to zero was given, where two was normal/not influenced, one was influenced, and zero was bad. Both the matrix and the membrane cristae were evaluated. Mitochondria displaying a homogenous density in the matrix were scored as two. Well-defined, tightly connected membrane cristae of mitochondria were also scored as two. Thus a maximum score of four could be obtained for the subsarcolemmal and the intermyofibrillar mitochondria, respectively (Fig. 1).


Figure 1
View larger version (64K):
[in this window]
[in a new window]
  		Fig. 1. Examples of mitochondrial morphology scoring. A: normal mitochondria with intact membrane cristae (scoring = 2) and smooth matrix (scoring = 2). B: deranged mitochondria with disrupted cristae (scoring = 0) and slightly damaged matrix (scoring = 1). C: deranged mitochondria with disrupted cristae (scoring = 0) and damaged matrix (scoring = 0). The bar corresponds to 5 µm.

 
Statistical analysis. Results are presented as median and range. All data were analyzed using nonparametric Mann-Whitney U-test (Statistica; StatSoft, Tulsa, OK). A statistical level of significance of 0.05 was used for all analyses (n = 10 patients and 10 controls).


   RESULTS
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Patients. Characteristics of the ICU patients are given in Table 1. All ICU patients suffered from respiratory dysfunction as indicated by the PaO2/fraction of inspired oxygen ratio and MOF as indicated by the Sepsis-related Organ Failure Assessment (37) scores on the day of the study. All ICU patients had sepsis according to the criteria of Bone et al. (7). At the time of the study, all patients were stable and were given no or small doses of vasoactive drugs. Control subjects underwent elective surgery for hernia repair, ileostomy closure, recurrent diverticulitis, or colorectal resection. One control patient had a malignant disease. Three women and seven men were included as controls with a median age of 67 (range 45–87) yr. All control patients were sedated using propofol, and they were all given small doses of rokuronium, a nonpolarizing muscle relaxant, just before the muscle biopsies were obtained.


View this table:
[in this window]
[in a new window]
  		Table 1. ICU patient characteristics at the time of biopsy

 
Intercostal muscle. In muscle homogenate, the activity of citrate synthase was 53% lower in the ICU patients compared with controls (P = 0.003; Fig. 2). The activities of complexes I and IV expressed per dry weight of muscle showed a 60% lower complex I activity (P = 0.03), but no difference was found in the activity of complex IV (P = 0.06; Fig. 2). The activities of complex I and IV were not significantly different from controls when expressed per citrate synthase activity (i.e., mitochondrial content; complex I: patient median 0.12, range 0.03–0.31, control median 0.16, range 0.01–0.30, P = 0.25; complex IV: patient median 0.26, range 0.09–0.44, control median 0.31, range 0.01–0.41, P = 0.62). In the isolated mitochondria from intercostals muscle, activities of complex I and IV (expressed per citrate synthase activity) were not significantly different from control values (complex I: patient median 0.59, range 0.34–0.82, control median 0.51, range 0.33–0.86, P = 0.55; complex IV: patient median 0.76, range 0.11–1.09, control median 0.69, range 0.59–0.99, P = 0.45).


Figure 2
View larger version (9K):
[in this window]
[in a new window]
  		Fig. 2. Activities of mitochondrial enzyme citrate synthase and complexes I and IV in human intercostal and leg muscle of intensive care unit (ICU) patients and controls, expressed per muscle weight. The long bar represents the median value. dw, Dry weight. *P < 0.05.

 
The concentrations of ATP, creatine phosphate, and lactate were not significantly different from controls in intercostal muscle of the ICU patients (ATP: P = 0.096; creatine phosphate: P = 0.50; lactate: P = 0.41; Fig. 3).


Figure 3
View larger version (8K):
[in this window]
[in a new window]
  		Fig. 3. Concentrations of creatine phosphate, ATP, and lactate in human intercostal and leg muscle from ICU patients and controls. The long bar represents the median value. *P < 0.05.

 
In muscle homogenates, there were no significant differences in the activity of SOD (P = 0.82), but when the same activity was measured in isolated mitochondria a 230% higher activity was detected in the patients (P = 0.00004; Table 2).


View this table:
[in this window]
[in a new window]
  		Table 2. Markers of oxidative stress in different muscle groups in ICU patients and matched controls

 
No significant difference in the morphology of the mitochondria was seen in intercostal muscle. The subsarcolemmal mitochondria had a scoring ranging from zero to four with a median value of three in both ICU patients and controls. The intermyofibrillar mitochondria scored from two to four with a median value of three in ICU patients and from zero to four with a median value of two in the controls.

Leg (vastus lateralis) muscle. In leg muscle homogenates, there was no significant difference in citrate synthase activity between the ICU patients and controls (P = 0.11; Fig. 2). When the activities of the mitochondrial complexes I and IV were expressed per dry weight of leg muscle, complex I activity was not significantly different from controls (P = 0.45), but complex IV activity was 38% lower in the ICU patients (P = 0.05; Fig. 2). Complexes I and IV in leg muscle were not significantly different in patients compared with controls when expressed per citrate synthase activity (i.e., mitochondrial content; complex I: patients median 0.2, range 0.01–0.80, controls median 0.18, range 0.02–0.27, P = 0.70; complex IV: patients median 0.34, range 0.01–0.51, controls median 0.46, range 0.10–0.88, P = 0.06).

In the isolated mitochondria, the activities of complexes I and IV (expressed per citrate synthase) in the ICU patients were not significantly different from those in the control subjects (complex I: patients median 0.55, range 0.14–1.93; controls median 0.56, range 0.29–0.67, P = 0.76; complex IV: patients median 0.72, range 0.06–1.30, controls median 0.70, range 0.25–0.85, P = 0.82).

Compared with controls, the ICU patients had a 40% lower ATP concentration (P < 0.01), a 34% lower creatine phosphate concentration (P < 0.01), and a 43% higher lactate concentration (P < 0.01) in leg muscle (Fig. 3).

There was no significant difference in the activity of SOD in leg muscle homogenate (P = 0.11), but when the activity was measured in isolated mitochondria, a 411% higher activity was detected in patients compared with controls (P = 0.004; Table 2).

No significant differences in the morphology of the mitochondria were seen in leg muscle. The subsarcolemmal mitochondria in both groups had a score ranging from one to four with a median value of three for the ICU patients and of two for the controls. The intermyofibrillar mitochondria scored from zero to four with a median value of three in ICU patients and from zero to four with a median value of two in controls.


   DISCUSSION
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In this study, we found twofold decreases in mitochondrial enzyme activities in both intercostal and leg muscle of ICU patients suffering from sepsis-induced MOF compared with a group of metabolically healthy control patients. In leg muscle, the lower enzyme activities were accompanied by a lower concentration of ATP and creatine phosphate and by a higher lactate concentration, indicating a compromised energy production. A high activity of mitochondrial SOD in both intercostal and leg muscle of ICU patients suggests an increase in reactive oxygen species production. These results show, for the first time, a compromised mitochondrial content in both respiratory and leg muscle of critically ill patients with MOF.

In intercostal muscle of ICU patients, both citrate synthase and complex I activities were lower than in controls. In leg muscle, only the activity of complex IV was significantly lower, but citrate synthase activity showed a trend in the same direction. The changes in enzyme activities in both muscle groups were only present when the activities were expressed per muscle weight and not when expressed per citrate synthase activity. Expressing these respiratory chain complex activities per citrate synthase activity is a common way of correcting for mitochondrial density (39). Thus these results indicate that the ICU patients suffered from a lower mitochondrial density rather than a specific inhibition of the measured enzymes. This was supported by the fact that the enzyme activities in isolated mitochondria and the mitochondrial morphology in the ICU patients were not different from the controls. A similar observation was recently made in patients with acute septic shock studied during the initial 24 h of ICU stay (8). Both complex I and complex IV activities (expressed per citrate synthase activity) in skeletal muscle of the surviving patients were similar to that of age-matched control patients. On the other hand, the nonsurvivors had lower complex I activity and higher complex IV activity expressed per citrate synthase activity compared with both healthy controls and survivors of acute septic shock. However, the activities shown are all expressed per citrate synthase activity, and it is therefore not possible to conclude whether the surviving patients suffered from a decrease in mitochondrial content as shown in the present study. These results indicate that muscle mitochondria are differently affected during the acute phase of fatal septic shock compared with a later stage of sepsis-induced MOF as described in the present paper.

Mitochondria are the major site of energy production in the cell; therefore, the lower mitochondrial enzyme activities are the likely cause of the changes in the energy-rich phosphates. However, a decreased blood flow and thereby oxygen and substrate supply also will potentially decrease energy-rich phosphates and increase lactate contents. A decreased blood flow in these patients could be the result of their severe insulin resistance or an ongoing inflammatory response (38, 40). However, previous studies have shown that skeletal muscle oxygen tension is not decreased in patients similar to ours (5). In leg muscle, we found lower concentrations of ATP and creatine phosphate and higher lactate levels in the ICU patients compared with controls. However, in intercostal muscle, concentrations of these energy metabolites were not different between ICU patients and controls. Similar results have been obtained in a study on energy metabolism in intercostal and leg muscle in COPD patients suffering from acute respiratory distress syndrome (19). Also in that study, ATP and creatine levels were lower in intercostal muscle compared with leg muscle in healthy controls. The COPD patients had lower concentrations of both ATP and creatine in leg muscle compared with controls, but the concentrations in intercostal muscle did not change. The reason for the generally lower concentrations of energy-rich phosphates and the lack of depletion in intercostal muscle is not known. However, one explanation could be that the intercostal muscle is passively stretched during mechanical ventilation, while leg muscle is not activated at all. This stretching of the intercostal muscle may increase blood flow, and that in turn could preserve the levels of energy-rich phosphates. Another explanation may be that respiratory muscles are more protected than other muscle groups. Our results show that different skeletal muscles do not respond to metabolic stress in the same way and that care should be taken to extrapolate results obtained in one muscle to all skeletal muscles in the body.

No difference in mitochondrial morphology was observed in our study, mainly because of the fact that the control subjects had more morphological changes than expected. These analyses were performed blindly by a trained pathologist and are therefore most likely not the result of the evaluation procedure itself. The most likely explanation is that these are the signs of aging. It is well established that aging has a negative effect on mitochondrial density, oxidative capacity, and morphology (2, 10, 18, 34–36). We therefore included control subjects carefully matched for age.

One of the main determinant factors of muscle mitochondrial density is physical activity (24). Critically ill patients lying in the ICU are always bed bound and often sedated, which most likely will influence mitochondrial density. Several human studies have shown that immobilization for 4–7 wk decreases mitochondrial enzyme activity in various muscle types by ~20% (3, 15, 23, 20, 28). The ICU patients included in the present study were immobilized for a shorter period of time (medium ICU stay of 7.5 days) and still had more pronounced mitochondrial derangements in skeletal muscle. Even though immobilization surely affects mitochondrial enzyme activity in critically ill patients, disease itself most likely plays a larger role.

Mitochondria produce energy for basal metabolism in all tissues. In skeletal muscle, the mitochondrial energy production is the rate-limiting step during endurance activity. It is therefore likely that the decreased mitochondrial content could lead to the muscle fatigue observed in ICU patients. Both during the recovery phase and during weaning of the ventilator, decreased endurance capacity is causing problems. However, it is not certain whether the observed decrease in mitochondrial enzyme activities in intercostal and leg muscle of the critically ill patients is sufficient to cause bioenergetic problems during rest. Two studies performed in rats have shown that a 25–40% decrease of muscle mitochondrial enzyme activity does not influence ATP and creatine phosphate levels at rest (14, 29). However, when the muscles were activated by electrical stimulation, ATP levels decreased much faster when the rats had decreased mitochondrial enzyme activities. In leg muscle of the critically ill patients in our study, ATP and creatine phosphate concentrations were already low and lactate levels high at rest, indicating that these patients probably will face great problems coping with the increased energy demand during muscle activation. No human data are, however, available to confirm this hypothesis, and more studies are needed.

In summary, in ICU patients suffering from sepsis-induced MOF, there was a twofold decrease in mitochondrial content in both leg and intercostal muscle. It is likely that these changes will lead to problems with muscle weakness and fatigue when the patients are activated again after ICU discharge. The decreased mitochondrial content without an accompanying effect on energy substrates in intercostal muscle might suggest that respiratory muscles are more protected.


   GRANTS
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This research project was sponsored by a grant from the Swedish Research Council (no: 14244), Karolinska Institute Funds, Stockholm County Council, and the Swedish National Board of Health and Welfare.


   ACKNOWLEDGMENTS
 
We thank Viveka Gustavsson for excellent nursing assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. Fredriksson, Dept. of Anesthesiology and Intensive Care, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden (e-mail: katarina.fredriksson{at}ki.se)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Banwell BL, Mildner RJ, Hassall AC, Becker LE, Vajsar J, and Shemie SD. Muscle weakness in critically ill children. Neurology 61: 1779–1782, 2003.[Abstract/Free Full Text]
  2. Barazzoni R. Skeletal muscle mitochondrial protein metabolism and function in ageing and type 2 diabetes. Curr Opin Clin Nutr Metab Care 7: 97–102, 2004.[ISI][Medline]
  3. Berg HE, Dudley GA, Hather B, and Tesch PA. Work capacity and metabolic and morphologic characteristics of the human quadriceps muscle in response to unloading. Clin Physiol 13: 337–347, 1993.[ISI][Medline]
  4. Boczkowski J, Lisdero CL, Lanone S, Samb A, Carreras MC, Boveris A, Aubier M, and Poderoso JJ. Endogenous peroxynitrite mediates mitochondrial dysfunction in rat diaphragm during endotoxemia. FASEB J 13: 1637–1646, 1999.[Abstract/Free Full Text]
  5. Boekstegers P, Weidenhofer S, Pilz G, and Werdan K. Peripheral oxygen availability within skeletal muscle in sepsis and septic shock: comparison to limited infection and cardiogenic shock. Infection 19: 317–323, 1991.[CrossRef][ISI][Medline]
  6. Bolton CF. Sepsis and the systemic inflammatory response syndrome: neuromuscular manifestations. Crit Care Med 24: 1408–1416, 1996.[CrossRef][ISI][Medline]
  7. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, and Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee American College of Chest Physicians/Society of Critical Care Medicine. Chest 101: 1644–1655, 1992.[Abstract/Free Full Text]
  8. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, and Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360: 219–223, 2002.[CrossRef][ISI][Medline]
  9. Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, Smolenski RT, and Singer M. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 286: R491–R497, 2004.[Abstract/Free Full Text]
  10. Conley KE, Jubrias SA, and Esselman PC. Oxidative capacity and ageing in human muscle. J Physiol 526: 203–210, 2000.[Abstract/Free Full Text]
  11. Corbucci GG, Gasparetto A, Candiani A, Crimi G, Antonelli M, Bufi M, De Blasi RA, Cooper MB, and Gohil K. Shock-induced damage to mitochondrial function and some cellular antioxidant mechanisms in humans. Circ Shock 15: 15–26, 1985.[ISI][Medline]
  12. Crouser ED, Julian MW, Blaho DV, and Pfeiffer DR. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med 30: 276–284, 2002.[CrossRef][ISI][Medline]
  13. De Jonghe B, Cook D, Sharshar T, Lefaucheur JP, Carlet J, and Outin H. Acquired neuromuscular disorders in critically ill patients: a systematic review. Groupe de Reflexion et d'Etude sur les Neuromyopathies En Reanimation. Intensive Care Med 24: 1242–1250, 1998.[CrossRef][ISI][Medline]
  14. Dudley GA, Tullson PC, and Terjung RL. Influence of mitochondrial content on the sensitivity of respiratory control. J Biol Chem 262: 9109–9114, 1987.[Abstract/Free Full Text]
  15. Ferretti G, Antonutto G, Denis C, Hoppeler H, Minetti AE, Narici MV, and Desplanches D. The interplay of central and peripheral factors in limiting maximal O2 consumption in man after prolonged bed rest. J Physiol 501: 677–686, 1997.[CrossRef][ISI][Medline]
  16. Fredriksson K, Radell P, Eriksson LI, Hultenby K, and Rooyackers O. Effect of prolonged mechanical ventilation on diaphragm muscle mitochondria in piglets. Acta Anaesthesiol Scand 49: 1101–1107, 2005.[CrossRef][ISI][Medline]
  17. Gasparetto A, Corbucci GG, Candiani A, Gohil K, and Edwards RH. Effect of tissue hypoxia and septic shock on human skeletal muscle mitochondria (Abstract). Lancet 2: 1486, 1983.[ISI][Medline]
  18. Genova ML, Pich MM, Bernacchia A, Bianchi C, Biondi A, Bovina C, Falasca AI, Formiggini G, Castelli GP, and Lenaz G. The mitochondrial production of reactive oxygen species in relation to aging and pathology. Ann NY Acad Sci 1011: 86–100, 2004.[Abstract/Free Full Text]
  19. Gertz I, Hedenstierna G, Hellers G, and Wahren J. Muscle metabolism in patients with chronic obstructive lung disease and acute respiratory failure. Clin Sci Mol Med 52: 396–403, 1977.[Medline]
  20. Häggmark T, Jansson E, and Eriksson E. Fiber type area and metabolic potential of the thigh muscle in man after knee surgery and immobilization. Int J Sports Med 2: 12–17, 1981.[ISI][Medline]
  21. Harris RC, Hultman E, and Nordesjo LO. Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values. Scand J Clin Lab Invest 33: 109–120, 1974.[ISI][Medline]
  22. Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, Cooper AB, Guest CB, Mazer CD, Mehta S, Stewart TE, Barr A, Cook D, and Slutsky AS. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348: 683–693, 2003.[Abstract/Free Full Text]
  23. Hikida RS, Gollnick PD, Dudley GA, Convertino VA, and Buchanan P. Structural and metabolic characteristics of human skeletal muscle following 30 days of simulated microgravity. Aviat Space Environ Med 60: 664–670, 1989.[Medline]
  24. Holloszy JO and Coyle EF. Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol 56: 831–838, 1984.[Abstract/Free Full Text]
  25. Larsson L, Li X, Edstrom L, Eriksson LI, Zackrisson H, Argentini C, and Schiaffino S. Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels. Crit Care Med 28: 34–45, 2000.[CrossRef][ISI][Medline]
  26. Latronico N, Fenzi F, Recupero D, Guarneri B, Tomelleri G, Tonin P, De Maria G, Antonini L, Rizzuto N, and Candiani A. Critical illness myopathy and neuropathy. Lancet 347: 1579–1582, 1996.[CrossRef][ISI][Medline]
  27. Lemaire F. Difficult weaning. Intensive Care Med 19: S69–S73, 1993.
  28. Rifenberick DH, Gamble JG, and Max SR. Response of mitochondrial enzymes to decreased muscular activity. Am J Physiol 225: 1295–1299, 1973.[Free Full Text]
  29. Rooyackers OE, Gijsen AP, Saris WH, Soeters PB, and Wagenmakers AJ. Derangement in aerobic and anaerobic energy metabolism in skeletal muscle of critically ill and recovering rats. Biochim Biophys Acta 1315: 55–60, 1996.[Medline]
  30. Rooyackers OE, Kersten AH, and Wagenmakers AJ. Mitochondrial protein content and in vivo synthesis rates in skeletal muscle from critically ill rats. Clin Sci (Lond) 91: 475–481, 1996.[Medline]
  31. Schumer W, Erve PR, and Obernolte RP. Endotoxemic effect on cardiac and skeletal muscle mitochondria. Surg Gynecol Obstet 133: 433–436, 1971.[ISI][Medline]
  32. Shanely RA, Zergeroglu MA, Lennon SL, Sugiura T, Yimlamai T, Enns D, Belcastro A, and Powers SK. Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative injury and increased proteolytic activity. Am J Respir Crit Care Med 166: 1369–1374, 2002.[Abstract/Free Full Text]
  33. Tahvanainen J, Salmenpera M, and Nikki P. Extubation criteria after weaning from intermittent mandatory ventilation and continuous positive airway pressure. Crit Care Med 11: 702–707, 1983.[ISI][Medline]
  34. Terman A and Brunk UT. Myocyte aging and mitochondrial turnover. Exp Gerontol 39: 701–705, 2004.[CrossRef][ISI][Medline]
  35. Tonkonogi M, Fernstrom M, Walsh B, Ji LL, Rooyackers O, Hammarqvist F, Wernerman J, and Sahlin K. Reduced oxidative power but unchanged antioxidative capacity in skeletal muscle from aged humans. Pflugers Arch 446: 261–269, 2003.[ISI][Medline]
  36. Trounce I, Byrne E, and Marzuki S. Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet 1: 637–639, 1989.[ISI][Medline]
  37. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, and Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22: 707–710, 1996.[ISI][Medline]
  38. Vincent MA, Clerk LH, Lindner JR, Klibanov AL, Clark MG, Rattigan S, and Barrett EJ. Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes 53: 1418–1423, 2004.[Abstract/Free Full Text]
  39. Wibom R, Hultman E, Johansson M, Matherei K, Constantin-Teodosiu D, and Schantz PG. Adaptation of mitochondrial ATP production in human skeletal muscle to endurance training and detraining. J Appl Physiol 73: 2004–2010, 1992.[Abstract/Free Full Text]
  40. Youd JM, Rattigan S, and Clark MG. Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNF-alpha. Diabetes 49: 1904–1909, 2000.[Abstract]



This article has been cited by other articles:


Home page
 JPEN J Parenter Enteral NutrHome page
D. H. Herndon and J. Wernerman
Brussels 2007 Roundtable on Metabolism in Sepsis and Multiple Organ Failure
JPEN J Parenter Enteral Nutr, January 1, 2008; 32(1): 1 - 5.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow A corrigendum has been published
Right arrow All Versions of this Article:
291/5/E1044    most recent
00218.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (7)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fredriksson, K.
Right arrow Articles by Rooyackers, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fredriksson, K.
Right arrow Articles by Rooyackers, O.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.