Anaesthetic agents and their effect on tissue protein synthesis in the rat

1. Rates of protein synthesis were measured, in vivo, in lung, liver, heart and skeletal muscle of young male rats. Groups of rats were exposed for 1 h duration to one of the following anaesthetic regimens: 1.4% halothane, 2.2% halothane, 1.4% halothane in 66% nitrous oxide, intravenous pentobarbitone (20 mg/kg) and intravenous midazolam (18 mg/kg) combined with fentanyl (2 micrograms/kg). Fractional rates of protein synthesis were determined by injecting [3H]phenylalanine (150 mumol/100 g body weight). 2. Liver protein synthesis was depressed significantly by all regimens, except midazolam/fentanyl, by up to 37.7% of control values. Lung protein synthesis was significantly reduced by all the anaesthetic agents by up to 30% of control rates. 3. The effects of the anaesthetic agents on skeletal muscle and heart were small and not statistically significant. 4. There was no evidence of ventilatory depression as manifested by changes in arterial blood gas partial pressures of CO2 and O2, except in the group treated with 2.2% halothane.     

Effect of the cyclo-oxygenase inhibitor fenbufen on muscle and liver protein metabolism, muscle glutamine and plasma insulin in endotoxaemic rats

1. The effect of fenbufen (gamma-oxo-[1,1'-biphenyl]-4-butanoic acid), a known cyclo-oxygenase inhibitor, on the changes in muscle and liver protein metabolism in response to Escherichia coli endotoxin has been investigated in the rat. 2. Young male rats were fed a purified diet [18% (w/w) casein], with or without fenbufen (1.2 g/kg of diet). Groups of animals were injected with either endotoxin (LPS; Escherichia coli lipopolysaccharide 0.127 B8; 3 mg/kg body weight) or saline. Rectal temperature and food intake were measured over the following 24 h period, after which time measurements were made of muscle and liver protein content and synthesis in vivo, muscle protein degradation as the difference between protein synthesis and growth rates, muscle glutamine concentration and plasma insulin. 3. Fenbufen treatment alone tended to lower rectal temperature. It also reduced plasma insulin, slightly reduced food intake and slowed growth and muscle protein turnover, although muscle glutamine concentrations were unchanged. The slower protein synthesis mainly reflected reduced translational activity, which was consistent with the reduced insulin concentration. 4. LPS treatment increased rectal temperature by 1.6 degrees C, and this was abolished by fenbufen, indicating that the dose of the drug was sufficient to block prostaglandin production in the hypothalamus. 5. LPS treatment induced similar losses in body weight and muscle protein in both control and fenbufen groups, despite a 50% lower food intake in the LPS plus fenbufen group compared with the LPS-only group. The loss of muscle protein in both groups reflected reduced protein synthesis and increased protein degradation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Whole-body and tissue protein synthesis during brief and prolonged fasting in the rat.

1. Little information is currently available on protein turnover during chronic protein loss situations. We have thus measured the whole-body and tissue protein fractional synthesis rates (ks), the whole-body fractional protein degradation rate (kd), the capacity for protein synthesis (Cs) and the efficiency of protein synthesis (kRNA) in vivo in fed and fasted (1, 5 and about 9 days) 400 g rats. 2. One day of starvation resulted in a reduced ks and an increased kd in the whole body. ks was selectively depressed in skeletal muscles, mainly owing to a reduced kRNA, and was not modified in heart, liver and skin. The contribution of skin to whole-body protein synthesis increased by 39%. 3. During the phase of protein sparing (5 days of fasting), kd in the whole body decreased below the control fed level. ks in skeletal muscles was sustained because kRNA was restored to 82-98% of the control value. 4. Rats were in a protein-wasting phase after 9 days of starvation. kd in the whole body did not increase and was actually 78% of the value observed in fed animals. By contrast, ks in the whole body and tissues decreased to 14-34% of the control values, owing to reductions in both Cs and kRNA. Whatever the duration of the fast, the contribution of the skin to whole-body protein synthesis largely exceeded that of skeletal muscle. 5. The present findings suggest that the main goal in the treatment of chronic protein loss should be to sustain protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of chronic ethanol ingestion on tissue RNA and blood flow in skeletal muscle with comparative reference to bone and tissues of the gastrointestinal tract of the rat

1. The effects of feeding a diet containing ethanol as 36% of total calories for 4-5 weeks on muscle RNA content and blood flow was investigated in male rats weighing 150-250 g. Control animals were pair-fed the same diet in which ethanol was substituted by isocaloric glucose. 2. Chronic ethanol consumption reduced the capacity for type II (anaerobic, fast-twitch) fibre-rich skeletal muscles to synthesize protein as reflected by a decreased RNA/protein ratio. Type I (aerobic, slow-twitch) fibre-rich muscles were unaffected. 3. Ethanol feeding had no significant effect on cardiac output. Furthermore, the percentage of cardiac output to type I and type II fibre-rich muscles, bone and tissues of the gastrointestinal tract, i.e. stomach, small intestine and large intestine, was unaffected by ethanol consumption. Similarly, ethanol feeding had no effect on blood flow when it was calculated on the basis of tissue weight (ml min-1 g-1). 4. It was concluded that chronic ethanol feeding in the rat was associated with selective skeletal muscle dysfunction in the absence of changes in blood supply.     

Altered protein metabolism following coronary artery bypass graft (CABG) surgery

The aim of the present study was to investigate the acute effect of CABG (coronary artery bypass graft) surgery on the rates of synthesis of muscle protein, the positive acute-phase protein fibrinogen and the negative acute-phase protein albumin. Synthesis rates of muscle protein, fibrinogen and albumin were measured simultaneously before and 4 h after the end of surgery from the incorporation of L-[(2)H(5)]phenylalanine (given at 43 mg/kg of body weight) in 12 patients undergoing CABG surgery. Surgery was performed either with the use of extracorporeal circulation with cardiopulmonary bypass (on-pump; n=5) or with the beating heart procedure without cardiopulmonary bypass (off-pump; n=7). Post-surgical muscle protein fractional synthesis rates were decreased by 36+/-6.5% compared with pre-surgical values (1.59+/-0.10 compared with 0.97+/-0.08%/day respectively; P<0.001). In contrast, the synthesis rates of both fibrinogen (36+/-4 compared with 100+/-11 mg.day(-1).kg(-1) of body weight; P<0.0001) and albumin (123+/-12 compared with 178+/-19 mg.day(-1).kg(-1) of body weight; P<0.001) were both significantly increased after surgery. No significant differences were found between surgery performed with or without cardiopulmonary bypass. In conclusion, the results demonstrate that CABG surgery has a profound effect on protein metabolism, with a differential response of protein synthesis in muscle and liver.     

Mechanism of IL-1 induced inhibition of protein synthesis in skeletal muscle

Chronic interleukin (IL)-1 administration is associated with negative nitrogen balance and the loss of lean body mass. To elucidate the molecular mechanism(s) by which IL-1 modulates protein metabolism in muscle, we investigated the effects of chronic (6 day) IL-1alpha infusion on protein synthesis in Individual muscles (gastrocnemius, soleus, heart) compared with saline-infused control rats. IL-1 significantly decreased muscle weight, protein content, and the rate of protein synthesis in gastrocnemius (fast-twitch muscle). IL-1 had no effect on these parameters in the heart, whereas only the rate of protein synthesis was reduced in soleus (slow-twitch muscle). The reduction in gastrocnemius protein synthesis was not the result of a decrease in total RNA content, but was associated with a diminished translational efficiency. The diminished translational efficiency correlated with a 40% reduction in the epsilon-subunit of eukaryotic initiation factor 2B (elF2Bepsilon) in gastrocnemius from IL-1 -treated animals. However, the content of the alpha-subunit of elF2 (elF2alpha) was unaffected. In contrast, the elF2alpha content in heart was increased by IL-1, although elF2Bepsilon levels were unchanged. Reductions in skeletal muscle protein synthesis were not associated with a concomitant reduction in circulating or tissue content of insulin-like growth factor I. In summary, the IL-1-induced decrease in gastrocnemius protein synthesis appears to be regulated at the level of RNA translation via a reduction in elF2Bepsilon. These findings support a regulatory role for IL-1 as a mediator of muscle protein synthesis and the alterations in body composition observed in catabolic states where this cytokine is overexpressed.     

Responsiveness of muscle protein synthesis to growth hormone administration in HIV-infected individuals declines with severity of disease.

This study was undertaken to determine if human recombinant growth hormone (hrGH, 6 mg/d for 2 wk) would stimulate muscle protein synthesis in AIDS wasting. Healthy controls were compared with patients who were HIV+, had AIDS without weight loss, and had AIDS with > 10% weight loss. Before hrGH, rates of skeletal muscle protein synthesis, measured with l-[2H5]phenylalanine, were the same in controls and in all stages of disease. Rates of myofibrillar protein degradation, however, assessed from urinary excretion of 3-methyl histidine, were higher in AIDS and AIDS wasting than in HIV+ or healthy individuals. The group with weight loss had significantly higher TNFalpha levels but not higher HIV viral loads. Muscle function, as determined by isokinetic knee extension and shoulder flexion, was significantly higher in controls than all infected individuals. After GH, rates of protein synthesis were stimulated 27% in controls, with a smaller increase (11%) in HIV+, and a significant depression (42%) in AIDS with weight loss, despite fourfold elevation in insulin-like growth factor-I in all groups. There was a significant correlation of hrGH-induced changes in muscle protein synthesis with severity of disease (P = 0.002). The results indicate increased basal muscle protein degradation and decreased responsiveness of muscle protein synthesis to GH in the later stages of disease.     

Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism.

Metabolic acidosis is associated with enhanced renal ammonia-genesis which is regulated, in part, by glucocorticoids. The interaction between glucocorticoids and chronic metabolic acidosis on nitrogen utilization and muscle protein metabolism is unknown. In rats pair-fed by gavage, we found that chronic acidosis stunted growth and caused a 43% increase in urinary nitrogen and an 87% increase in urinary corticosterone. Net protein degradation in incubated epitrochlearis muscles from chronically acidotic rats was stimulated at all concentrations of insulin from 0 to 10(4) microU/ml. This effect of acidosis persisted despite supplementation of the media with amino acids with or without insulin, indomethacin, and inhibitors of lysosomal thiol cathepsins. Acidosis did not change protein synthesis; hence, the increase in net protein degradation was caused by stimulation of proteolysis. Acidosis did not increase glutamine production in muscle. The protein catabolic effect of acidosis required glucocorticoids; protein degradation was stimulated in muscle of acidotic, adrenalectomized rats only if they were treated with dexamethasone. Moreover, when nonacidotic animals were given 3 micrograms/100 g of body weight dexamethasone twice a day, muscle protein degradation was increased if the muscles were simply incubated in acidified media. We conclude that chronic metabolic acidosis depresses nitrogen utilization and increases glucocorticoid production. The combination of increased glucocorticoids and acidosis stimulates muscle proteolysis but does not affect protein synthesis. These changes in muscle protein metabolism may play a role in the defense against acidosis by providing amino acid nitrogen to support the glutamine production necessary for renal ammoniagenesis.     

Chronic alpha-tocopherol supplementation in rats does not ameliorate either chronic or acute alcohol-induced changes in muscle protein metabolism

Chronic alcohol muscle disease is characterized by reduced skeletal muscle mass precipitated by acute reduction in protein synthesis. The pathogenic mechanisms remain obscure, but several lines of evidence suggest that increased oxidative stress occurs in muscle in response to alcohol and this may be associated with impaired alpha-tocopherol status. Potentially, this implies a therapeutic role for alpha-tocopherol, especially as we have shown that supplemental alpha-tocopherol may increase the rate of protein synthesis in normal rats [Reilly, Patel, Peters and Preedy (2000) J. Nutr. 130, 3045-3049]. We investigated the therapeutic effect of alpha-tocopherol on plantaris muscle protein synthesis in rats treated either acutely, chronically or chronically+acutely with ethanol. Protein synthesis rates were measured with a flooding dose of L-[4-(3)H]phenylalanine. Protein, RNA and DNA contents were determined by standard laboratory methods. Ethanol caused defined metabolic changes in muscle, including decreased protein, RNA and DNA contents in chronically treated rats. In acute or chronic+acute studies, ethanol suppressed fractional rates of protein synthesis. alpha-Tocopherol supplementation did not ameliorate the effects of either acute, chronic or chronic+acute alcohol on plantaris muscle protein content or rates of protein synthesis. In control animals (not treated with alcohol), alpha-tocopherol supplementation decreased muscle protein content owing to increases in protein turnover (both synthesis and degradation). alpha-Tocopherol supplementation is not protective against the deleterious effects of alcohol on protein metabolism in skeletal muscle.     

Ethanol impairs post-prandial hepatic protein metabolism.

The effects of acute ethanol ingestion on whole body and hepatic protein metabolism in humans are not known. To simulate social drinking, we compared the effects of the association of a mixed meal (632 kcal, 17% amino acids, 50% glucose, 33% lipids) with a bottle of either table wine (ethanol content 71 g) or water on the estimates ([1-14C]-leucine infusion) of whole body protein breakdown, oxidation, and synthesis, and on the intravascular fractional secretory rates (FSR) of hepatically (albumin, fibrinogen) and extrahepatically (IgG) synthesized plasma proteins in two randomized groups (ethanol n = 7, water n = 7) of healthy nonalcoholic volunteers. Each study was carried out for 8 h. Protein kinetics were measured in the overnight post-absorptive state, over the first 4 h, and during a meal infusion (via a nasogastric feeding tube at constant rate) combined with the oral ingestion of wine or water, over the last 4 h. When compared with water, wine ingestion during the meal reduced (P < 0.03) by 24% the rate of leucine oxidation, did not modify the estimates of whole body protein breakdown and synthesis, reduced (P < 0.01) by approximately 30% the FSR of albumin and fibrinogen, but did not affect IgG FSR. In conclusion, 70 g of ethanol, an amount usual among social drinkers, impairs hepatic protein metabolism. The habitual consumption of such amounts by reducing the synthesis and/or secretion of hepatic proteins might lead to the progressive development of liver injury and to hypoalbuminemia also in the absence of protein malnutrition.     

Glutamine synthetase in experimental meningitis: increased ratio of the subunits 3 and 2 may indicate enhanced activity

Rats were acutely injected with alcohol (75 mmol/kg body weight) and at the end of 2.5 h changes in cardiac synthesis rates were assessed with a 'flooding dose' of L-[4-(3)H]phenylalanine. The results showed that acute alcohol dosage reduced the fractional rates of cardiac protein synthesis (k(S), %/day). This effect was also seen when data were expressed relative to either RNA (i.e. k(RNA), mg protein/day/mg RNA) or DNA (i.e. k(DNA), mg protein/day/mg DNA). Both left and right ventricles responded similarly to ethanol. However, propranolol pre-treatment (at doses of 17 and 170 micromol/kg body weight; i.p.) did not prevent these effect of ethanol in either the left or right ventricle. Indeed, there was evidence that propranolol per se perturbed cardiac protein synthesis in vivo in control (i.e. without ethanol) rats particularly in the right ventricle. In conclusion, the results suggest that alcohol is cardiotoxic to the myocardium, which may cause its effects on protein synthesis independently of beta-receptors and/or xanthine oxidase inhibition.     

Effect of parenteral nutrition on protein turnover in endotoxaemic rats

1. Intravenous infusion of endotoxin into rats over 18 h caused a reduction in food intake to 20% of normal levels, weight loss, hypoalbuminaemia and a fall in rates of protein synthesis in vivo in heart and skeletal muscle. 2. Measurements of protein turnover in vitro in skeletal muscle of endotoxaemic animals, showed a 50% fall in protein synthesis rates and a 200% increase in rates of protein degradation. 3. Total parenteral nutrition was only partially able to reverse endotoxin-induced weight loss. Total parenteral nutrition did not reverse endotoxin-induced catabolism in cardiac or skeletal muscle, but was able to reverse the catabolism of protein in skeletal muscle produced by starvation. 4. Endotoxin treatment elevated rates of protein synthesis in vivo in liver. The combination of parenteral nutrition and endotoxaemia further increased the rate of protein synthesis in the liver. Parenteral nutrition did not influence endotoxin-induced hypoalbuminaemia.     

The influence of functional electrical stimulation on the properties of vastus lateralis fibres following total knee arthroplasty.

The influence of functional electrical muscle stimulation (FES) on selected properties of vastus lateralis muscle fibres was studied in patients recovering from total knee arthroplasty for osteoarthritis. Prior to surgery, on the average, muscle biopsies from the vastus lateralis could be characterized as having a predominance of Type I fibres which were significantly larger in cross-sectional area than the Type II fibres in the same sample. Following surgery, muscle biopsies from a group of patients (n = 7) which received continuous passive motion and no FES, exhibited a marked increase in the proportion of Type II fibres along with a general atrophy of both the Type I and Type II fibres. Patients receiving passive motion and FES (n = 9) also showed an increase in the relative percentage of Type II fibres. Post-operatively, however, there was no significant reduction in fibre area in the stimulated muscles. These data suggest that FES was effective in attenuating the muscle atrophy associated with total knee arthroplasty but had no influence on those metabolic properties which were related to muscle fibre type classification criteria.     

Muscle morphology and enzymes in proximal and distal muscle groups of lower limb from patients with corticosteroid treated rheumatoid arthritis: the relationship to maximal isokinetic muscle strength

Abnormal morphological and enzymatic patterns in the lateral vastus muscle have been found in women with corticosteroid treated rheumatoid arthritis. By means of biopsies from the lateral heads of right gastrocnemius muscles, the histology and enzyme activities were compared with those found in right vastus lateralis biopsies. The findings were correlated with isometric and isokinetic strength of the plantar flexors. The relative occurrence of type I fibres in the gastrocnemius muscle was 46.4 +/- 18.7 (SD) %, which is significantly higher than found in the vastus lateralis [35.7 +/- 13.3 (SD) %] (P less than 0.03). The relatively lower percentage of type II fibres in the gastrocnemius muscle was due to a relatively low percentage of type II A fibres [mean 27.9 +/- 16.4 (SD) %] (P less than 0.05). The area of type I fibres in the gastrocnemius muscle was 26.1 X 10(2) +/- 10.0 (SD) micron 2, which is 74% of the mean area for type I fibres found in the vastus lateralis (P less than 0.01). The area of type II fibres in the gastrocnemius was 14.9 X 10(2) +/- 7.1 (SD) micron 2, which is 77% of the mean area for type II fibres found in the vastus lateralis. The isokinetic muscle strength of the plantar flexors in corticosteroid treated patients with rheumatoid arthritis was reduced to less than 50% at all angular velocities when compared with healthy women. The same difference was found in the knee extensors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects in vivo of decreased plasma and intracellular muscle glutamine concentration on whole-body and hindquarter protein kinetics in rats.

Glutamine is considered to be a 'conditionally' essential amino acid. During situations of severe stress like sepsis or after trauma there is a fall in plasma glutamine levels, enhanced glutamine turnover and intracellular muscle glutamine depletion. Under these conditions, decreased intramuscular glutamine concentration correlates with reduced rates of protein synthesis. It has therefore been hypothesized that intracellular muscle glutamine levels have a regulatory role in muscle protein turnover rates. Administration of the glutamine synthetase inhibitor methionine sulphoximine (MSO) was used to decrease glutamine levels in male Wistar rats. Immediately after the MSO treatment (t=0 h), and at t=6 h and t=12 h, rats received intraperitoneal injections (10 ml/100 g body weight) with glutamine (200 mM) to test whether this attenuated the fall in plasma and intracellular muscle glutamine. Control animals received alanine and saline after MSO treatment, while saline was also given to a group of normal rats. At t=18 h rats received a primed constant infusion of L-[2,6-3H]phenylalanine. A three-pool compartment tracer model was used to measure whole-body protein turnover and muscle protein kinetics. Administration of MSO resulted in a 40% decrease in plasma glutamine and a 60% decrease in intracellular muscle glutamine, both of which were successfully attenuated by glutamine infusions. The decreased intracellular muscle glutamine levels had no effect on whole-body protein turnover or muscle protein kinetics. Also, glutamine supplementation did not alter these parameters. Alanine supplementation increased both hindquarter protein synthesis and breakdown but the net balance of phenylalanine remained unchanged. In conclusion, our results show that decreased plasma and muscle glutamine levels have no effect on whole-body protein turnover or muscle protein kinetics. Therefore, it is unlikely that, in vivo, the intracellular muscle concentration of glutamine is a major regulating factor in muscle protein kinetics.     

The combined effects of infection and malnutrition on protein metabolism in children

Twenty-two children were studied as inpatients at a Nigerian Hospital. They were divided into four groups on the basis of weight for age: I, adequately nourished, acutely infected; II, moderately under weight, acutely infected; III, malnourished, chronically infected; IV, malnourished, uninfected. Urinary nitrogen excretion was highest in group I and lowest in groups III and IV. Urinary creatinine was highest in group I, but did not differ significantly in groups II, III and IV. The excretion of 3-methylhistidine closely paralleled that of creatinine. It is suggested that the high rates of creatinine and methylhistidine excretion in group I resulted in part from destruction of muscle. Rates of whole body protein turnover were measured by administration of a single dose of [15N]glycine with measurement of the excretion of 15N in urinary NH3 for the next 9 h. Rates of protein synthesis and breakdown were very high in infected children of groups I and II. Although rates were lower in the malnourished groups, in infected children of group III they were nearly twice as high as in the uninfected group IV. The net balance of protein (synthesis minus breakdown) was negative in group I, less negative in group II, zero in group III and positive in group IV. Repeat measurements in group I during recovery from infection showed a decline in rates of excretion of nitrogen, creatinine and 3-methylhistidine. Rates of protein synthesis and breakdown declined and the protein balance became less negative, but these changes were not statistically significant. Multiple regression analysis of the results of all groups taken together showed independent contributions to rates of protein metabolism from infection and nutritional state, especially plasma albumin. It was concluded that infection caused a rise in protein breakdown which was larger than the concomitant rise in synthesis, leading to net loss of protein, and that these responses were reduced by malnutrition.     

Systemic response to thermal injury in rats. Accelerated protein degradation and altered glucose utilization in muscle.

Negative nitrogen balance and increased oxygen consumption after thermal injury in humans and experimental animals is related to the extent of the burn. To determine whether defective muscle metabolism is restricted to the region of injury, we studied protein and glucose metabolism in forelimb muscles of rats 48 h after a scalding injury of their hindquarters. This injury increased muscle protein degradation (PD) from 140 +/- 5 to 225 +/- 5 nmol tyrosine/g per h, but did not alter protein synthesis. Muscle lactate release was increased greater than 70%, even though plasma catecholamines and muscle cyclic AMP were not increased. Insulin dose-response studies revealed that the burn decreased the responsiveness of muscle glycogen synthesis to insulin but did not alter its sensitivity to insulin. Rates of net glycolysis and glucose oxidation were increased and substrate cycling of fructose-6-phosphate was decreased at all levels of insulin. The burn-induced increase in protein and glucose catabolism was not mediated by adrenal hormones, since they persisted despite adrenalectomy. Muscle PGE2 production was not increased by the burn and inhibition of prostaglandin synthesis by indomethacin did not inhibit proteolysis. The increase in PD required lysosomal proteolysis, since inhibition of cathepsin B with EP475 reduced PD. Insulin reduced PD 20% and the effects of EP475 and insulin were additive, reducing PD 41%. An inhibitor of muscle PD, alpha-ketoisocaproate, reduced burn-induced proteolysis 28% and lactate release 56%. The rate of PD in muscle of burned and unburned rats was correlated with the percentage of glucose uptake that was directed into lactate production (r = +0.82, P less than 0.01). Thus, a major thermal injury causes hypercatabolism of protein and glucose in muscle that is distant from the injury, and these responses may be linked to a single metabolic defect.     

Motoneuron activity and muscle fibre type composition in hemiparesis.

The firing of single motor units (MUs) in musculus tibialis anterior (TA) was studied during maximal voluntary effort and maximal speed of walking in 10 patients with severe chronic hemiparesis and the findings compared to normal data. As shown in a previous study, the paralysed TA exhibited an increase in proportion of type 2 fibres as compared with normal muscle. Thus, 57% of the muscle fibres were type 1 and 43% type 2, while the normal percentages were 80% and 20% respectively. The present findings indicate that in the paralysed muscles a little less than half of the fibres, i.e. roughly the equivalent of the type 2 population, was not tonically active either during sustained voluntary contraction or during locomotion. Normally high threshold MUs reached high rates during both modes of activation. The findings paralysed muscles also indicate that a little more than half of the fibres, i.e. roughly the equivalent of the type 1 population, could be brought into tonic firing during voluntary contraction as well as during walking. Their maximal firing rate was, however, no more than two thirds of that of normal low threshold MUs.     

Skeletal muscle fibre types and sizes in anorexia nervosa patients

Summary. Fibre type composition and fibre areas in skeletal muscle of anorexia patients were studied on biopsies from the m. quadriceps femoris in five male and five females, whose body weight was 2–3-5 SDs less than expected from the normal weight/height relationship. In two of the males, the muscle studies were also made after rehabilitation. A higher than normal percentage of type I fibres was found in the patients (male, 62 ±12, female, 69 ±7) whereas the percentage of type IIA fibres did not differ from normal individuals (male, 38 ±12, female 24 ±15). Of note was the observation that no type IIB fibres were found and some patients had an increased occurrence of the normally rare type IIC fibres. All muscle fibres were markedly atrophied with the mean cross-sectional area of type IIA fibres being significantly smaller (male, 26-1 ±3–7, female, 21-2 ±10-3, fi.m²×10^-2) than the mean area of type I fibres (male, 34-1 ±4–7, female, 35-3±7-4, (j.m²× 10^-2). In the two males studied after rehabilitation (body weight increased 12 and 19 kg), mean fibre area had increased by 40%. Our results suggested that a predominant part of the reduction in body weight and lean body mass, seen in adolescent children suffering from anorexia nervosa, could be accounted for by a loss of skeletal muscle mass. In the six subjects where marker enzymes of glycolytic (TPDH, LDH) and mitochondrial pathways (CS, HAD) were assayed, the former were 50% and the latter 10–20% below sedentary controls. Maximal oxygen uptake was only 35 (males) and 29 (females) ml/kg min^-1; this contrasted with the physical activity pattern of these patients, yet was in line with their small muscle mass with its low oxidative potential.     

Cyclic adenosine monophosphate-phosphodiesterase inhibitors reduce skeletal muscle protein catabolism in septic rats

We have previously shown that catecholamines exert an inhibitory effect on muscle protein degradation through a pathway involving the cyclic adenosine monophosphate (cAMP) cascade in normal rats. In the present work, we investigated in vivo and in vitro effects of cAMP-phosphodiesterase inhibitors on protein metabolism in skeletal muscle from rats submitted to a model of acute sepsis. The in vivo muscle protein metabolism was evaluated indirectly by measurements of the tyrosine interstitial concentration using microdialysis. Muscle blood flow (MBF) was monitored by ethanol perfusion technique. Sepsis was induced by cecal ligation and puncture and resulted in lactate acidosis, hypotension, and reduction in MBF (-30%; P < 0.05). Three-hour septic rats showed an increase in muscle interstitial tyrosine concentration (approximately 150%), in arterial plasma tyrosine levels (approximately 50%), and in interstitial-arterial tyrosine concentration difference (approximately 200%; P < 0.05). Pentoxifylline (50 mg/kg of body weight, i.v.) infusion during 1 h after cecal ligation and puncture prevented the tumor necrosis factor alpha increase and significantly reduced by 50% (P < 0.05) the interstitial-arterial tyrosine difference concentration. In situ perfusion with isobutylmethylxanthine (IBMX; 10(-3) M) reduced by 40% (P < 0.05) the muscle interstitial tyrosine in both sham-operated and septic rats. Neither pentoxifylline nor IBMX altered MBF. The addition of IBMX (10(-3) M) to the incubation medium increased (P < 0.05) muscle cAMP levels and reduced proteolysis in both groups. The in vitro addition of H89, a protein kinase A inhibitor, completely blocked the antiproteolytic effect of IBMX. The data show that activation of cAMP-dependent pathways and protein kinase A reduces muscle protein catabolism during basal and septic state.