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Biomedical subjects

D J Millward

Publications and source records attributed to D J Millward.

At least 73 records · Page 4Linked to original sources
PubMed1987

The effects of severe zinc deficiency on protein turnover in muscle and thymus.

Measurements have been made of protein turnover, RNA and DNA in thymus and skeletal muscle from rats fed on a zinc-deficient diet (ZD) for 10 and 17 d, in pair-fed controls (CI) and in muscle from rats fed on the ZD diet for 24 d and then fed on restricted amounts of the deficient diet with (RIZS) or without (RIZD) Zn supplementation, for 8 d. In thymus the ZD diet induced a loss of DNA and protein which was not observed with the CI rats. Accumulation of RNA was less affected but protein synthesis was reduced. In muscle the accumulation of DNA and protein was slowed by the ZD diet, particularly in glycolytic muscles compared with oxidative muscles, and Zn supplementation increased DNA and protein. Protein synthesis and RNA concentrations were reduced in the ZD rats compared with the CI rats, but Zn supplementation at constant restricted food intake did not increase protein synthesis. Muscle protein synthesis per unit RNA varied markedly in the ZD rats after 10 d when the characteristic cycling of the food intakes and body-weight was most pronounced, the highest values being observed in the anabolic phase of the cycle although these were less than values for well-fed controls. The variability was inversely correlated with the plasma Zn levels. The extent of the variability was much less after 17 d and was not apparent in the food-restricted ZD animals. Protein degradation in muscle, assessed as the difference between overall and net protein synthesis, was faster in the ZD rats compared with the CI rats and fluctuated considerably, partly accounting for the cyclic changes in muscle after 10 d, and was entirely responsible after 17 d. The concentration of muscle-free 3-methylhistidine and its urinary excretion rate indicated inconsistent results which could not be satisfactorily interpreted. Plasma insulin was reduced in the ZD rats compared with the CI rats and was insensitive to food intake in contrast to urinary corticosterone excretion which was inversely correlated with the cyclic changes in body-weight and food intake. Furthermore, adrenalectomized rats exhibited increased mortality and reduced cycling of body-weight and food intake. Thus Zn deficiency impairs growth by a combination of reduced food intake, a reduced anabolic response to food due to a reduced capacity for protein synthesis and reduced activation of protein synthesis, possibly reflecting impaired insulin secretion, and an increased catabolic response to the reduced intake in which corticosterone may play a role.

Adrenalectomy↗
PubMed1987

The effect of dietary protein and energy restriction on heat production and growth costs in the young rat.

1. The effect of dietary protein and energy restriction on heat production and growth costs has been examined in rats fed on a marginal (MP) or high (HP) protein diet, containing 9.2% or 22% respectively of the gross energy content as casein. Diets were given either ad lib. or at approximately 25, 50 or 75% of the ad lib. intake. 2. Heat production (kJ/kg body-weight (W)0.75 per d) was increased by 23% in rats fed on the MP diet ad lib., as compared with their HP controls (P less than 0.01). 3. Factorial analysis of the data showed that the overall cost of energy deposition (kJ/kJ; Ee) was elevated on the MP diet (MP 1.7, HP 1.28; P less than 0.001). Maintenance requirements (kJ/kg W0.75 per d) for zero energy balance were unchanged (MP 562, HP 573). 4. The partial energy cost of protein deposition (Ep) varied with dietary manipulation. If the partial energy cost of fat deposition (Ef) was assumed constant at 1.25 kJ/kJ, and maintenance requirements were assumed to vary with metabolic body size (W0.75), Ep was elevated on the MP diet. On both diets, Ep was reduced at low energy intakes. 5. The significance of these results is discussed in the context of current approaches to the analysis and interpretation of findings describing dietary induced changes in the rate of heat production.

Animals↗
PubMed1987

Regional blood flow and skeletal muscle energy status in endotoxemic rats.

Endotoxins induce muscle wasting in part as a result of depressed protein synthesis. To investigate whether these changes reflect impaired energy transduction, blood flow, O2 extraction, and high-energy phosphates in muscle and whole-body O2 consumption (VO2) have been measured. VO2 was measured for 6h after an initial sublethal dose of endotoxin (Escherichia coli lipopolysaccharide 0.3 mg/100 g body wt sc) or saline and during 6h after a second dose 24 h later. In fed or fasted rats, VO2 was either increased or better maintained after endotoxin. In anesthetized fed rats 3-4 after the second dose of endotoxin VO2 was increased, and this was accompanied by increased blood flow to liver (hepatic arterial supply), kidney, and perirenal brown adipose tissue and a 57 and 64% decrease in flow to back and hindlimb muscle, respectively, with no change in any other organ. Hindlimb arteriovenous O2 was unchanged, indicating markedly decreased aerobic metabolism in muscle, and the contribution of the hindlimb to whole-body VO2 decreased by 46%. Adenosine 5'-triphosphate levels in muscle were unchanged in endotoxin-treated rats, and this was confirmed by topical nuclear magnetic resonance spectroscopy, which also showed muscle pH to be unchanged. These results show that although there is decreased blood flow and aerobic oxidation in muscle, adenosine 5'-triphosphate availability does not appear to be compromised so that the endotoxin-induced muscle catabolism and decreased protein synthesis must reflex some other mechanism.

Animals↗
PubMed1987

Effects of the anabolic steroid stanozolol on growth and protein metabolism in the rat.

The effects of the anabolic steroid stanozolol on whole body and muscle growth and protein metabolism in the rat have been examined. No responses could be found in normal well-fed male rats. Female rats responded to 1 mg/kg per day with an increased body and skeletal muscle growth rate and an increase in muscle protein synthesis. The anabolic action on muscle protein synthesis was due to increased RNA concentration with no change in the rate of protein synthesis per unit RNA (KRNA). Investigation of any anticatabolic effects of stanozolol treatment in male rats deprived of food for 24 h indicated no response of protein balance and turnover. However, rats treated with catabolic doses of corticosterone (50 mg/kg per day) did respond to stanozolol with decreased muscle growth inhibition due to better-maintained muscle protein synthesis. The latter response was due to a reversal of the corticosterone-induced reduction of KRNA, but with no effect on RNA concentration. Thus there appear to be at least two effects of stanozolol; an anabolic action evident only in female rats, involving increased muscle RNA concentrations, and an anticatabolic action involving inhibition of the corticosterone-induced fall in muscle RNA activity. In both cases, stanozolol influenced muscle protein synthesis with no evident effects on protein degradation.

Animals↗
PubMed1986

Characteristics of a glutamine carrier in skeletal muscle have important consequences for nitrogen loss in injury, infection, and chronic disease.

A carrier for glutamine, identified in rat muscle, has properties in terms of kinetics, ion dependence and hormone sensitivity, and effects of endotoxin and branched-chain aminoacids that point to an important function in the control of whole-body aminoacid metabolism. The existence of a link between the size of the glutamine pool in muscle and the rate of muscle protein synthesis raises possibilities for therapeutic interventions to limit protein loss in injury, sepsis, and chronic disease.

Amino Acids, Branched-Chain↗
PubMed1986

The effects of endotoxaemia on protein metabolism in skeletal muscle and liver of fed and fasted rats.

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.

Animals↗
PubMed1985

The effect of catabolic doses of corticosterone on heat production in the growing rat.

The effect of corticosterone treatment on energy balance and heat production was investigated in growing rats. Animals were treated with daily subcutaneous injections of a vehicle containing 0, 50 or 100 mg corticosterone/kg for 5 d. Measurements of digestible energy intake and urinary energy losses showed that corticosterone treatment resulted in a depression of metabolizable energy intake due to elevated urinary energy losses resulting from massive glucosuria. Measurements of the metabolizable energy intake and the change in carcass energy indicated that at 50 mg/kg energy deposition and heat production were reduced, whilst at 100 mg/kg energy deposition was completely abolished with heat production increased. Postprandial oxygen consumption was unchanged at 50 mg/kg and increased at 100 mg/kg. Factorial analysis of these results based on reported values for the energy cost of protein and fat deposition indicated that (a) the depression of total heat production at 50 mg/kg could be entirely accounted for by the concomitant suppression of growth, and (b) the elevation of total and postprandial heat production at 100 mg/kg reflected a specific influence of corticosterone on thermogenesis. The significance of these findings is discussed in the light of reports that corticosterone in low doses suppresses heat production.

Adipose Tissue, Brown↗
PubMed1984

The measurement of whole body protein turnover in the preterm infant with intragastric infusion of L-[1-13C]leucine and sampling of the urinary leucine pool.

The measurement of whole body protein turnover in the preterm infant has been investigated with an intragastric infusion of L-[1-13C]-leucine and with sampling of the urinary leucine pool. Measurements have been made in seven preterm infants with body weights averaging 1733 g, fed with either human breast milk (n = 3) or proprietary formulae (n = 4), giving intakes of 541 (+/- 25) kJ/kg and 465 (+/- 42) mg of N day-1 kg-1 and growing satisfactorily (14.7 +/- 2.6 g day-1 kg-1). The measurement of the enrichment of urinary leucine was well within the capability of gas chromatography-spectrometry, and similar values for the enrichment of plasma and urinary leucine were observed (plasma/urinary ratio was 0.93 +/- 0.04, mean +/- 1 SEM, n = 13). Isotopic equilibrium, as indicated by a plateau in the urinary leucine and expired CO2 enrichment, was obtained within 8 h and was maintained for at least 48 h. Nitrogen retention, measured by nitrogen balance, was similar to that calculated from the leucine retention (determined as the leucine intake--oxidation), i.e. 310 +/- 45 and 301 +/- 38 mg of N day-1 kg-1 (means +/- 1 SEM). Because of this it is suggested that in this specific type of study the direct measurement of nitrogen retention dispenses with the need for measurement of leucine oxidation, thereby simplifying the measurements. From the leucine flux, leucine intake and nitrogen retention, rates of whole body protein synthesis and degradation were shown to be 11.32 (+/- 0.78) and 9.54 (+/- 0.55) g day-1 kg-1.

Body Weight↗
PubMed1984

Growth and zinc homeostasis in the severely Zn-deficient rat.

Male weanling rats were fed on diets either adequate (55 mg/kg), or severely deficient (0.4 mg/kg) in zinc, either ad lib. or in restricted amounts in four experiments. Measurements were made of growth rates and Zn contents of muscle and several individual tissues. Zn-deficient rats exhibited the expected symptoms of deficiency including growth retardation, cyclic changes in food intake and body-weight. Zn deficiency specifically reduced whole body and muscle growth rates as indicated by the fact that (a) growth rates were lower in ad lib.-fed Zn-deficient rats compared with rats pair-fed on the control diet in two experiments, (b) Zn supplementation increased body-weights of Zn-deficient rats given a restricted amount of diet at a level at which they maintained weight if unsupplemented, (c) Zn supplementation maintained body-weights of Zn-deficient rats fed a restricted amount of diet at a level at which they lost weight if unsupplemented (d) since the ratio, muscle mass: body-weight was lower in the Zn-deficient rats than in the pair-fed control groups, the reduction in muscle mass was greater than the reduction in body-weight. Zn concentrations were maintained in muscle, spleen and thymus, reduced in comparison to some but not all control groups in liver, kidney, testis and intestine, and markedly reduced in plasma and bone. In plasma, Zn concentrations varied inversely with the rate of change of body-weight during the cyclic changes in body-weight. Calculation of the total Zn in the tissues examined showed a marked increase in muscle Zn with a similar loss from bone, indicating that Zn can be redistributed from bone to allow the growth of other tissues. The magnitude of the increase in muscle Zn in the severely Zn-deficient rat, together with the magnitude of the total losses of muscle tissue during the catabolic phases of the cycling, indicate that in the Zn-deficient rat Zn may be highly conserved in catabolic states.

Animals↗
PubMed1984

Metabolic rate and thyroid status in rats fed diets of different protein-energy value: the importance of free T3.

Oxygen consumption and thyroid hormone status have been investigated in relation to dietary protein and energy intake in young growing rats fed a control diet of 18% protein as well as diets containing 9 and 4.5% protein fed ad libitum and an 18% protein diet fed at a restricted intake for up to 14 days. Measurements of growth rate, food intake and oxygen consumption indicated that the rats fed a 4.5% protein diet ad libitum and those fed restricted amounts of an 18% protein diet have behaved similarly with severely arrested growth and reduced rates of oxygen consumption and food intake. However, the rats fed the 9% protein diet ad libitum differed from the control group only in terms of a reduced growth rate. Among all the rats thyroid hormone status was associated with the metabolic rate only in the case of the concentration of free L-3,3',5-triiodothyronine (T3), which was reduced in the groups fed 4.5% protein and 18% protein (restricted). Total T3 was actually increased in the rats fed 9% and 4.5% protein and unchanged in the restricted group. These differences in the concentrations of free and total T3 appeared to reflect the fact that the binding capacity for T3 increased with decreasing levels of dietary protein. It is concluded therefore that measurement of free rather than total T3 is the appropriate index of physiological thyroid status in protein-energy malnutrition, at least in the rat.

Animals↗
PubMed1983

The role of insulin, corticosterone and other factors in the acute recovery of muscle protein synthesis on refeeding food-deprived rats.

Measurements of changes in muscle protein synthesis, insulin and corticosterone in vivo in refed food-deprived rats, some after pretreatment with anti-insulin serum or corticosterone, indicate that the acute increase in protein synthesis (20-40 min) requires (a) insulin, (b) a fall in corticosterone, since corticosterone acts at least in part by blocking insulin action, and (c) at least one other independent anabolic factor.

Animals↗
PubMed1983

Myofibrillar protein turnover. Synthesis rates of myofibrillar and sarcoplasmic protein fractions in different muscles and the changes observed during postnatal development and in response to feeding and starvation.

Measurement of rates of synthesis of skeletal-muscle proteins in adult rats shows that the faster overall rate of turnover in diaphragm and soleus muscles compared with several other, more glycolytic, muscles is also exhibited by the myofibrillar proteins, since the ratio of sarcoplasmic to myofibrillar protein synthesis is similar for all muscles. Further, throughout postnatal development, when the overall turnover rate falls with age, parallel changes occur for the myofibrillar proteins, as indicated by a constant ratio of sarcoplasmic to myofibrillar protein synthesis (2.06) in the steady state after overnight starvation. Only in the youngest (4 weeks old) rats is a slightly lower ratio observed (1.72). These results indicate that, when changes in the overall turnover rate of muscle proteins occur, the relative turnover of the two major protein fractions stays constant. However, measurements in the non-steady state during growth and after starvation for 4 days show that the relative synthesis rates of the two fractions change as a result of a disproportionate increase in myofibrillar protein synthesis during growth and decrease during starvation. Thus the synthesis rate of the slower-turning-over myofibrillar protein fraction is more sensitive to nutritional state than is that of the sarcoplasmic protein. It is suggested that such responses may help to maintain constant tissue composition during non-steady-state conditions of growth and atrophy.

Animals↗