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R R Wolfe

Publications and source records attributed to R R Wolfe.

At least 73 records · Page 4Linked to original sources
PubMed1999

Short-term oxandrolone administration stimulates net muscle protein synthesis in young men.

Short term administration of testosterone stimulates net protein synthesis in healthy men. We investigated whether oxandrolone [Oxandrin (OX)], a synthetic analog of testosterone, would improve net muscle protein synthesis and transport of amino acids across the leg. Six healthy men [22+/-1 (+/-SE) yr] were studied in the postabsorptive state before and after 5 days of oral OX (15 mg/day). Muscle protein synthesis and breakdown were determined by a three-compartment model using stable isotopic data obtained from femoral arterio-venous sampling and muscle biopsy. The precursor-product method was used to determine muscle protein fractional synthetic rates. Fractional breakdown rates were also directly calculated. Total messenger ribonucleic acid (mRNA) concentrations of skeletal muscle insulin-like growth factor I and androgen receptor (AR) were determined using RT-PCR. Model-derived muscle protein synthesis increased from 53.5+/-3 to 68.3+/-5 (mean+/-SE) nmol/min.100 mL/leg (P < 0.05), whereas protein breakdown was unchanged. Inward transport of amino acids remained unchanged with OX, whereas outward transport decreased (P < 0.05). The fractional synthetic rate increased 44% (P < 0.05) after OX administration, with no change in fractional breakdown rate. Therefore, the net balance between synthesis and breakdown became more positive with both methodologies (P < 0.05) and was not different from zero. Further, RT-PCR showed that OX administration significantly increased mRNA concentrations of skeletal muscle AR without changing insulin-like growth factor I mRNA concentrations. We conclude that short term OX administration stimulated an increase in skeletal muscle protein synthesis and improved intracellular reutilization of amino acids. The mechanism for this stimulation may be related to an OX-induced increase in AR expression in skeletal muscle.

Adult↗
PubMed1999

Insulin action on muscle protein kinetics and amino acid transport during recovery after resistance exercise.

We have determined the individual and combined effects of insulin and prior exercise on leg muscle protein synthesis and degradation, amino acid transport, glucose uptake, and alanine metabolism. Normal volunteers were studied in the postabsorptive state at rest and about 3 h after a heavy leg resistance exercise routine. The leg arteriovenous balance technique was used in combination with stable isotopic tracers of amino acids and biopsies of the vastus lateralis muscle. Insulin was infused into a femoral artery to increase the leg insulin concentrations to high physiologic levels without substantively affecting the whole-body level. Protein synthesis and degradation were determined as rates of intramuscular phenylalanine utilization and appearance, and muscle fractional synthetic rate (FSR) was also determined. Leg blood flow was greater after exercise than at rest (P<0.05). Insulin accelerated blood flow at rest but not after exercise (P<0.05). The rates of protein synthesis and degradation were greater during the postexercise recovery (65+/-10 and 74+/-10 nmol x min(-1) x 100 ml(-1) leg volume, respectively) than at rest (30+/-7 and 46+/-8 nmol x min(-1) x 100 ml(-1) leg volume, respectively; P<0.05). Insulin infusion increased protein synthesis at rest (51+/-4 nmol x min(-1) x 100 ml(-1) leg volume) but not during the postexercise recovery (64+/-9 nmol x min(-1) x 100 ml(-1) leg volume; P<0.05). Insulin infusion at rest did not change the rate of protein degradation (48+/-3 nmol x min(-1) 100 ml(-1) leg volume). In contrast, insulin infusion after exercise significantly decreased the rate of protein degradation (52+/-9 nmol x min(-1) x 100 ml(-1) leg volume). The insulin stimulatory effects on inward alanine transport and glucose uptake were three times greater during the postexercise recovery than at rest (P<0.05). In contrast, the insulin effects on phenylalanine, leucine, and lysine transport were similar at rest and after exercise. In conclusion, the ability of insulin to stimulate glucose uptake and alanine transport and to suppress protein degradation in skeletal muscle is increased after resistance exercise. Decreased amino acid availability may limit the stimulatory effect of insulin on muscle protein synthesis after exercise.

Adult↗
PubMed1998

Insulin therapy in burn patients does not contribute to hepatic triglyceride production.

Lipid kinetics were studied in six severely burned patients who were treated with a high dose of exogenous insulin plus glucose to promote protein metabolism. The patients were 20+/-2-yr-old (SD) with 63+/-8% total body surface area burned. They were studied in a randomized order (a) in the fed state on the seventh day of a control period (C) of continuous high-carbohydrate enteral feeding alone, and (b) on the seventh day of enteral feeding plus exogenous insulin (200 pmol/h = 28 U/h) with extra glucose given as needed to avoid hypoglycemia (I+G). Despite a glucose delivery rate approximately 100% in excess of energy requirements, the following lipid parameters were unchanged: (a) total hepatic VLDL triglyceride (TG) secretion rate (0.165+/-0.138 [C] vs. 0.154+/- 0.138 mmol/kg . d-1 [I+G]), (b) plasma TG concentration (1.58+/-0.66 [C] vs. 1. 36+/-0.41 mmol/liter [I+G]), and (c) plasma VLDL TG concentration (0. 68+/-0.79 [C] vs. 0.67+/- 0.63 mmol/liter [I+G]). Instead, the high-carbohydrate delivery in conjunction with insulin therapy increased the proportion of de novo-synthesized palmitate in VLDL TG from 13+/-5% (C) to 34+/-14% (I+G), with a corresponding decreased amount of palmitate from lipolysis. In association with the doubling of the secretion rate of de novo-synthesized fatty acid (FA) in VLDL TG during insulin therapy (P > 0.5), the relative amount of palmitate and stearate increased from 35+/-5 to 44+/-8% and 4+/-1 to 7+/-2%, respectively, in VLDL TG, while the relative concentration of oleate and linoleate decreased from 43+/-5 to 37+/-6% and 8+/-4% to 2+/-2%, respectively. A 15-fold increase in plasma insulin concentration did not change the rate of release of FA into plasma (8.22+/-2.86 [C] vs. 8.72+/-6.68 mmol/kg.d-1 [I+G]. The peripheral release of FA represents a far greater potential for hepatic lipid accumulation in burn patients than the endogenous hepatic fat synthesis, even during excessive carbohydrate intake in conjunction with insulin therapy.

Adolescent↗
PubMed1998

Exogenous amino acids stimulate net muscle protein synthesis in the elderly.

We have investigated the response of amino acid transport and protein synthesis in healthy elderly individuals (age 71+/-2 yr) to the stimulatory effect of increased amino acid availability. Muscle protein synthesis and breakdown, and amino acid transport were measured in the postabsorptive state and during the intravenous infusion of an amino acid mixture. Muscle-free amino acid kinetics were calculated by means of a three compartment model using data obtained by femoral arterio-venous catheterization and muscle biopsies from the vastus lateralis during the infusion of stable isotope tracers of amino acids. In addition, muscle protein fractional synthetic rate (FSR) was measured. Peripheral amino acid infusion significantly increased amino acid delivery to the leg, amino acid transport, and muscle protein synthesis when measured either with the three compartment model (P < 0.05) or with the traditional precursor-product approach (FSR increased from 0. 0474+/-0.0054 to 0.0940+/-0.0143%/h, P < 0.05). Because protein breakdown did not change during amino acid infusion, a positive net balance of amino acids across the muscle was achieved. We conclude that, although muscle mass is decreased in the elderly, muscle protein anabolism can nonetheless be stimulated by increased amino acid availability. We thus hypothesize that muscle mass could be better maintained with an increased intake of protein or amino acids.

Aged↗
PubMed1998

Fat metabolism in exercise.

Fatty acids are the most abundant source of endogenous energy substrate. They can be mobilized from peripheral adipose tissue and transported via the blood to active muscle. During higher intensity exercise, triglyceride within the muscle can also be hydrolyzed to release fatty acids for subsequent direct oxidation. Control of fatty acid oxidation in exercise can potentially occur via changes in availability, or via changes in the ability of the muscle to oxidize fatty acids. We have performed a series of experiments to distinguish the relative importance of these potential sites of control. The process of lipolysis normally provides free fatty acids (FFA) at a rate in excess of that required to supply resting energy requirements. At the start of low intensity exercise, lipolysis increases further, thereby providing sufficient FFA to provide energy substrates in excess of requirements. However, lipolysis does not increase further as exercise intensity increases, and fatty acid oxidation becomes approximately equal to the total amount of fatty acids available at 65% of VO2 max. When plasma FFA concentration is increased by lipid infusion during exercise at 85% VO2 max, fat oxidation is significantly increased. Taken together, these observations indicate that fatty acid availability can be a determinant of the rate of their oxidation during exercise. However, even when lipid is infused well in excess of requirements during high-intensity exercise, less than half the energy is derived from fat. This is because the muscle itself is a major site of control of the rate of fat oxidation during exercise. We have demonstrated that the mechanism of control of fatty acid oxidation in the muscle is the rate of entry into the mitochondria. We hypothesize that the rate of glycolysis is the predominant regulator of the rate of carbohydrate metabolism in muscle, and that a rapid rate of carbohydrate oxidation caused by mobilization of muscle glycogen during high intensity exercise inhibits fatty acid oxidation by limiting transport into the mitochondria. During low intensity exercise, glycogen breakdown and thus glycolysis is not markedly stimulated, so the increased availability of fatty acids allows their oxidation to serve as the predominant energy source. At higher intensity exercise, stimulation of glycogen breakdown and glycolysis cause increased pyruvate entry into the TCA cycle for oxidation, and as a consequence the inhibition of fatty acid oxidation by limiting their transport into the mitochondria.

Animals↗
PubMed1998

Exercise-induced changes in protein metabolism.

Exercise has a profound acute effect on protein metabolism. Whereas reports on whole body responses to exercise have varied results, it is generally agreed leucine oxidation is increased during exercise, thus indicating increased net protein breakdown. Following endurance exercise, whole body protein breakdown is generally reduced from resting levels, while following eccentric exercise, both whole body protein breakdown and leucine oxidation are increased. Whole body protein synthesis, on the other hand, is either increased or unchanged. Much of the disagreement in the results of studies on the response of whole body protein metabolism to exercise may be attributed to the limitations of the available methods. Even if the methodology accurately reflects whole body metabolism, this may not reflect changes in the protein metabolism of muscle. Although endurance exercise has not been studied, muscle protein breakdown is increased following resistance exercise. There is a concomitant, and qualitatively greater, increase in muscle protein synthesis following resistance exercise, which may last for as long as 48 h. Increased muscle protein synthesis is linked to increased intramuscular availability of amino acids, and thus, to increased blood flow and increased amino acid delivery to the muscle, as well as increased amino acid transport. Administration of exogenous amino acids after exercise increases protein synthesis while ameliorating protein breakdown, thus improving net muscle protein balance. While it is clear that muscle protein synthesis and protein breakdown increase in a qualitatively similar manner following exercise, the mechanisms of stimulation have yet to be determined. However, we propose that the intracellular availability of amino acids is the link between these processes.

Animals↗
PubMed1998

Fatal maternal beta-hemolytic group B streptococcal meningitis: a case report.

Meningitis secondary to beta-hemolytic group B streptococcus is rare and represents less than 1% of cases of adult meningitis. We report the first known case of maternal mortality attributed to beta-hemolytic group B streptococcal meningitis. A 23-year-old African-American woman with a benign prenatal course delivered a viable male infant at term. Labor was complicated by thick meconium for which a saline amnioinfusion was utilized. On postpartum Day 1, the patient complained of right hip pain and a headache. Within 12 hr the patient was comatose with fixed and dilated pupils. Life support measures were discontinued secondary to absence of electrocortical activity. Postmortem examination revealed endomyometritis and fulminant meningitis with gram-positive cocci. Placental histologic sections demonstrated acute chorioamnionitis and bateriological cultures noted beta-hemolytic group B streptococcus. The virulence of beta-hemolytic group B streptococcus in the neonate is well recognized. This case demonstrates that beta-hemolytic group B streptococcus is also a potentially fatal maternal pathogen.

Adult↗
PubMed1998

Metabolic interactions between glucose and fatty acids in humans.

In vivo energy production results largely from the oxidative metabolism of either glucose or fatty acids. Under diverse physiologic and nutritional conditions, the oxidation of either glucose or fatty acids may predominate. The nature of the control of the availability and oxidation of each substrate has been studied extensively for > or = 30 y. The most popular and enduring hypothesis was proposed by Randle et al in 1963 and is termed the glucose-fatty acid cycle. This proposal places great significance on the regulation of lipolysis as a factor controlling substrate metabolism. Our work has led to an opposite perspective, which could be called the glucose-fatty acid cycle reversed. According to our hypothesis, the rate of glycolysis, determined by the intracellular availability of glucose-6-phosphate, is the predominant factor determining the rate of glucose oxidation. Whereas the rate of lipolysis may have some effect on the availability of glucose, both via a fatty acid-mediated inhibition of plasma glucose uptake and also by supplying glycerol for gluconeogenesis, there is little evidence for a direct inhibitory effect of fatty acid oxidation on the intracellular oxidation of glucose. In contrast, increased glucose oxidation limits oxidation of long-chain fatty acids directly by inhibiting their transport into the mitochondria. Consequently, whereas there is a close coupling between glucose availability and oxidation, fatty acids are generally available in greater quantities than are required for oxidation. We propose that fatty acid oxidation is largely controlled at the site of oxidation, which is in turn determined by the availability of glucose, rather than by its availability via lipolysis.

Dietary Carbohydrates↗
PubMed1998

Acute dichloroacetate administration increases skeletal muscle free glutamine concentrations after burn injury.

OBJECTIVE: To investigate the hypothesis that the stimulation of pyruvate oxidation by dichloroacetate (DCA) administration would increase the level of intramuscular glutamine in severely burned patients. SUMMARY BACKGROUND DATA: The level of intramuscular glutamine decreases in response to severe injury, and the rate of intramuscular glycolysis and pyruvate oxidation is elevated. Intramuscular glutamine concentrations have been correlated to muscle protein synthesis. METHODS: Six studies were conducted on five patients with burns >40% total body surface area. Patients were studied in the fed state during an 8-hour stable isotope infusion. After 5 hours, DCA (30 mg/kg) was administered for 30 minutes. RESULTS: Analysis of muscle biopsy samples taken at 5 and 8 hours of the study revealed a 32% increase in intracellular glutamine levels after DCA administration. Increased intracellular glutamine concentrations did not affect skeletal muscle protein synthesis as determined by a three-pool arteriovenous model or by the direct incorporation of isotope into skeletal muscle protein. DCA administration resulted in a decrease in plasma lactate but no change in alanine de novo synthesis or intracellular concentration. CONCLUSIONS: These results suggest that acute DCA administration can increase intramuscular glutamine concentration, but that this acute elevation does not affect muscle protein metabolism.

Adult↗
PubMed1998

Effects of insulin on wound healing.

BACKGROUND: Insulin plus glucose, given for 7 days to hypermetabolic burn patients, has been shown to stimulate limb protein anabolism. We hypothesized that insulin plus glucose given to burn patients would also stimulate wound healing. METHODS: Six patients with burns >40% total body surface area were randomized to receive insulin or placebo in a crossover study during the healing of their first and second donor sites. Insulin treatment was titrated at 25 to 49 U/h to achieve a plasma insulin level of 400 to 900 microU/mL for 7 days. Patients receiving insulin received dextrose 50 at 20 to 50 mL/h, titrated to maintain euglycemia. Donor-site biopsies were taken at 7 days and evaluated by three observers blinded to the treatment. RESULTS: The mean (+/-SD) donor-site healing time was reduced from 6.5 +/- 1.0 days with placebo to 4.7 +/- 1.2 days during insulin infusion (p < 0.05). Laminin showed intense staining along the basal lamina and blood vessels. Collagen type IV staining also increased after insulin therapy compared with placebo. CONCLUSION: Data indicate that high doses of insulin and glucose can be safely administered to massively burned patients to improve wound matrix formation.

Adolescent↗
PubMed1998

Alanine and glutamine kinetics at rest and during exercise in humans.

PURPOSE: The purpose of this study was to quantify both alanine and glutamine kinetics during exercise of moderate intensity to determine the sum total of alanine and glutamine flux. METHODS: Tracer methods were used to quantify alanine and glutamine rates of appearance (Ra) in plasma at rest and during 180 min of approximately 45% VO2max treadmill exercise in six normal volunteers (25 +/- 2 yr, 68 +/- 2.5 kg, VO2max 43 +/- 2.4 mL.min-1.kg-1; means +/- SE). Bolus injections (N = 3) or primed-constant infusions (N = 3) of 2H5-glutamine and 3-13C-alanine were given at rest on 1 d and 10-15 min after the onset of exercise on a separate day less than 2 wk later. Plasma enrichment decay curves and plateau enrichments were used to estimate alanine and glutamine kinetics. RESULTS: Whereas alanine Ra increased significantly from rest to exercise (5.72 +/- 0.31 vs 13.5 +/- 1.9 mumol.min-1.kg-1, respectively; P < 0.01), glutamine Ra was not significantly altered by exercise (6.11 +/- 0.44 and 6.40 +/- 0.69 mumol.min-1.kg-1 at rest and during exercise, respectively). The total of alanine and glutamine flux increased from 17.93 +/- 0.88 to 25.98 +/- 3.04 (P < 0.05). CONCLUSIONS: Since most muscle amino-N is released as alanine and glutamine, these findings provide strong evidence that amino-N delivery from muscle to the liver is increased during exercise. In addition, it appears that alanine, rather than glutamine, is the predominant N carrier involved in the transfer of N from muscle to the liver during moderate intensity exercise.

Adult↗
PubMed1998

Metabolism of skin and muscle protein is regulated differently in response to nutrition.

We have measured skin and muscle protein kinetics and amino acid (AA) transport in anesthetized rabbits during 1) 64-h fast, 2) AA infusion, 3) AA plus fat emulsion infusion, and 4) AA plus hyperinsulinemia. L-[ring-13C6]phenylalanine was infused as the tracer, and the ear and hindlimb were used as arteriovenous units to reflect skin and muscle protein kinetics, respectively. Skin protein net balance was not different from zero in all groups, indicating a maintenance of protein mass. In contrast, the muscle net balance differed over a range from -1.6 +/- 0.6 after fasting to 0.2 +/- 0.2 mumol.100 g-1.h-1 during hyperinsulinemia. In the skin, 59-66% of intracellular free phenylalanine came from proteolysis, and phenylalanine availability from proteolysis was positively correlated to the protein synthesis rate. In conclusion, normal skin maintains its constant protein mass by efficient reutilization of AAs from proteolysis. In contrast to muscle, skin protein is relatively insensitive to control by nutritional and hormonal factors. Because of the metabolic differences, when limb models are used for muscle protein metabolism, the potential contribution by limb skin should be considered.

Animal Nutritional Physiological Phenomena↗
PubMed1998

Regulation of fatty acid oxidation in untrained vs. trained men during exercise.

We have recently shown that increased carbohydrate flux decreases fat oxidation during exercise by inhibition of fatty acid entry into the mitochondria. Because endurance training reduces the rate of carbohydrate flux during exercise, we hypothesized that training increases fat oxidation by relieving this inhibition. To test this hypothesis, five sedentary and five endurance-trained men exercised on a cycle ergometer at an oxygen consumption (VO2) of approximately 2.0 l/min, representing 80 and 40% peak VO2, respectively. [1-13C]oleate and [1-14C]octanoate, long- and medium-chain fatty acids, respectively, were infused for the duration of the studies. Carbohydrate oxidation was significantly higher in the sedentary group (196 +/- 9 vs. 102 +/- 17 mumol.kg-1.min-1, P < 0.05). Oleate oxidation was higher in the trained group (3.8 +/- 0.6 vs. 1.9 +/- 0.3 mumol.kg-1.min-1, P < 0.05), whereas octanoate oxidation was not different between the two groups. The percentage of oleate that was taken up by tissues and oxidized was higher in the trained group (76 +/- 7 vs. 58 +/- 3%, P < 0.05). However, the percentage of octanoate taken up and oxidized was not different (82 +/- 3 vs. 85 +/- 4%, not significant). Because octanoate, unlike oleate, can freely diffuse across the mitochondrial membrane, the present results suggest that the difference in fatty acid oxidation between trained and untrained individuals may be due to enhanced fatty acid entry into the mitochondria.

Adult↗
PubMed1998

Regional acetate kinetics and oxidation in human volunteers.

We have used a 3-h primed continuous infusion of [1,2-13C]acetate in five fasted (24 h) volunteers to quantify splanchnic and leg acetate metabolism (protocol 1). Fractional extraction of acetate by both tissues was high ( approximately 70%), and simultaneous uptake and release of acetate were observed. Labeled carbon recovery in CO2 was 37.9 +/- 2.3% at the whole body level, 37.7 +/- 1.5% across the splanchnic bed, and 37.3 +/- 2.9% across the leg. Furthermore, we calculated whole body labeled carbon recovery during 15 h of [1, 2-13C]acetate infusion in three volunteers (protocol 2). Whole body acetate carbon recovery in CO2 was significantly higher (66.7 +/- 4. 5%) after 15 h of tracer infusion than after 3 h. We conclude that acetate is rapidly taken up by the leg and splanchnic tissues and that the percent recovery of CO2 from the oxidation of acetate is heavily dependent on the length of acetate tracer infusion. In the postabsorptive state, labeled carbon recovery from acetate across the leg and the splanchnic region is similar to the whole body CO2 recovery.

Acetates↗
PubMed1998

Hyperglycemia-induced inhibition of splanchnic fatty acid oxidation increases hepatic triacylglycerol secretion.

The effect of hyperglycemia ( approximately 8 mmol/l) on splanchnic fatty acid oxidation and triacylglycerol (TG) secretion rates was investigated in five healthy men. U-13C-labeled fatty acids were infused to estimate fatty acid kinetics and oxidation across the splanchnic region, and in vivo labeled very low density lipoprotein (VLDL)-TG was infused to estimate TG secretion rate. Plasma fatty acid carbon enrichment and concentration were maintained constant by infusion of lipids and heparin in the hyperglycemia experiments. Fatty acid uptake by the splanchnic region was 1.4 +/- 0.2 and 2.2 +/- 0.9 micromol. kg-1. min-1 in the basal and clamp experiments, respectively, whereas fatty acid oxidation decreased from 0.4 +/- 0. 04 to 0.2 +/- 0.05 micromol. kg-1. min-1 (P < 0.05). Hepatic TG secretion increased from 0.35 +/- 0.07 micromol. kg-1. min-1 in the basal state to 0.53 +/- 0.11 micromol. kg-1. min-1 after 15 h of hyperglycemia (P < 0.05). Similarly, plasma VLDL-TG concentration increased from 0.28 +/- 0.06 to 0.43 +/- 0.05 mmol/l during the clamp (P < 0.05). In summary, hyperglycemia attenuates fatty acid oxidation in the splanchnic region in human volunteers, even when fatty acid availability is constant. This adaptation results in a significant increase in the VLDL-TG secretion rate and concentration in plasma.

Adult↗
PubMed1998

Testosterone injection stimulates net protein synthesis but not tissue amino acid transport.

Testosterone administration (T) increases lean body mass and muscle protein synthesis. We investigated the effects of short-term T on leg muscle protein kinetics and transport of selected amino acids by use of a model based on arteriovenous sampling and muscle biopsy. Fractional synthesis (FSR) and breakdown (FBR) rates of skeletal muscle protein were also directly calculated. Seven healthy men were studied before and 5 days after intramuscular injection of 200 mg of testosterone enanthate. Protein synthesis increased twofold after injection (P < 0.05), whereas protein breakdown was unchanged. FSR and FBR calculations were in accordance, because FSR increased twofold (P < 0.05) without a concomitant change in FBR. Net balance between synthesis and breakdown became more positive with both methodologies (P < 0.05) and was not different from zero. T injection increased arteriovenous essential and nonessential nitrogen balance across the leg (P < 0.05) in the fasted state, without increasing amino acid transport. Thus T administration leads to an increased net protein synthesis and reutilization of intracellular amino acids in skeletal muscle.

Adult↗