The response of muscle and liver protein metabolism to either a single or three successive daily injections of an endotoxin (Escherichia coli lipopolysaccharide, serotype 0127 B8; 1 mg/ml, 0.3 mg/100 g body wt.) was studied in vivo in the fed rat, and at 24 and 30 h after endotoxin treatment during fasting. In the fed rats there was a catabolic response in muscle, owing to a 60-100% increase in muscle protein degradation rate, and a 52% fall in the synthesis rate. Although there was a 20% decrease in food intake, the decrease in protein synthesis was to some extent independent of this, since rats treated with endotoxin and fasted also showed a lower rate of muscle protein synthesis, which was in excess of the decrease caused by fasting alone. The mechanism of this decreased protein synthesis involved decreased translational activity, since in both fed and fasted rats there was a decreased rate of synthesis per unit of RNA. This occurred despite the fact that insulin concentrations were either maintained or increased, in the fasted rats, to those observed in fed rats. In the liver total protein mass was increased in the fed rats by 16% at 24 h, and the fractional synthesis rate at that time was increased by 35%. In rats fasted after endotoxin treatment the liver protein mass was not decreased as it was in the control fasted rats, and the fractional synthesis rate was increased by 22%. In both cases the increased synthesis rate reflected an elevated hepatic RNA concentration. The extent of this increase in hepatic protein synthesis was sufficient at one point to compensate for the fall in estimated muscle protein synthesis, so that the sum total in the two tissues was maintained.

Muscle glutamine concentration ([GLN]) and protein synthesis rate (Ks) have been examined in vivo in well-fed, protein-deficient, starved, and endotoxemic rats. With protein deficiency (8 or 5% casein diet), [GLN] fell from 7.70 to 5.58 and 3.56 mmol/kg in the 8 and 5% diet groups, with Ks falling from 15.42 to 9.1 and 6.84%/day. Three-day starvation reduced [GLN] and Ks to 2.38 mmol/kg and 5.6%/day, respectively. In all these groups food intakes and insulin were generally well maintained (except in the starved group), whereas free 3,5,3'-triiodothyronine (T3) was depressed in the starved and 5% protein group. The E. coli lipopolysaccharide endotoxin (3 mg/kg) reduced [GLN] to 5.85 and 4.72 mmol/kg and Ks to 10.5 and 9.10%/day in two well-fed groups. Insulin levels were increased, and free T3 levels fell. Combined protein deficiency and endotoxemia further reduced [GLN] and Ks to 1.88 mmol/kg and 4.01%/day, respectively, in the 5% protein rats. Changes in both ribosomal activity (KRNA) and concentration (RNA/protein) contributed to the fall in Ks in malnutrition and endotoxemia, although reductions in the RNA concentration were most marked with protein deficiency and reductions in the KRNA dominated the response to the endotoxin. The changes in [GLN] and Ks were highly correlated as were [GLN] and both KRNA and the RNA concentration, and these relationships were unique to glutamine. These relationships could reflect sensitivity of glutamine transport and protein synthesis to the same regulatory influences, and the particular roles of insulin and T3 are discussed, as well as any direct influence of glutamine on protein synthesis.

1. We have investigated the relations between changes in plasma insulin and 3,5,3'-triiodothyronine (T,), and muscle growth and protein turnover in the rat in response to diets of varying protein concentrations.2. Young rats were fed ad lib. on a control (180 g casein/kg) diet or low-protein diets containing 80, 45 and 0 g casein/kg in four separate experiments. Measurements were made of food intakes, muscle and body-weight growth rates, muscle protein turnover in vivo, plasma insulin, and plasma free and total T,.3. The food intakes of the 80 and 45 g casein/kg diet groups were variable, with the 80 g casein/kg diet group consuming either the same or more than the controls, and the 45 g casein/kg diet group consuming less or more than the controls. Body-weight and skeletal-muscle growth rates varied with the protein but not energy intakes, which in turn reflected both dietary composition and the food intake, with the hyperphagic 80 g casein/kg diet group of rats growing almost normally and the 0 g caseinlkg diet group losing body-weight and muscle mass. 4. Changes in rates of muscle growth were accompanied by parallel changes in rates of protein synthesis and degradation, as well as parallel changes in concentrations of plasma insulin and free T,, to the extent that all these variables were highly correlated with each other.5. Partial correlation analysis was used to separate interactions between variables. This indicated that dietary energy had no identifiable influence on muscle growth. In contrast dietary protein appeared to stimulate muscle growth directly by increasing muscle RNA content and inhibiting proteolysis, as well as increasing insulin and free T, levels. Insulin and free T, stimulated each other as well as muscle protein turnover; insulin stimulating the RNA activity particularly at low insulin levels, free T, stimulating the RNA content and both hormones stimulating proteolysis.6 . These apparent relations are shown to be consistent in the main part with previous studies of the mechanism of action of insulin and T,, but the possibility cannot be discounted that other anabolic hormones not measured in these studies are involved, particularly in the apparent direct influence of dietary protein on muscle.

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