Leucine Rate Of Appearance Research Articles

A potent liver-mediated mechanism for loss of muscle mass during androgen deprivation therapy.

ContextAndrogen deprivation therapy (ADT) in prostate cancer results in muscular atrophy, due to loss of the anabolic actions of testosterone. Recently, we discovered that testosterone acts on the hepatic urea cycle to reduce amino acid nitrogen elimination. We now hypothesize that ADT enhances protein oxidative losses by increasing hepatic urea production, resulting in muscle catabolism. We also investigated whether progressive resistance training (PRT) can offset ADT-induced changes in protein metabolism.ObjectiveTo investigate the effect of ADT on whole-body protein metabolism and hepatic urea production with and without a home-based PRT program.DesignA randomized controlled trial.Patients and interventionTwenty-four prostate cancer patients were studied before and after 6 weeks of ADT. Patients were randomized into either usual care (UC) (n = 11) or PRT (n = 13) starting immediately after ADT.Main outcome measuresThe rate of hepatic urea production was measured by the urea turnover technique using 15N2-urea. Whole-body leucine turnover was measured, and leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, was calculated.ResultsADT resulted in a significant mean increase in hepatic urea production (from 427.6 ± 18.8 to 486.5 ± 21.3; P < 0.01) regardless of the exercise intervention. Net protein loss, as measured by Lox/Lra, increased by 12.6 ± 4.9% (P < 0.05). PRT preserved lean body mass without affecting hepatic urea production.ConclusionAs early as 6 weeks after initiation of ADT, the suppression of testosterone increases protein loss through elevated hepatic urea production. Short-term PRT was unable to offset changes in protein metabolism during a state of profound testosterone deficiency.

Effect of oral citrulline supplementation on whole body protein metabolism in adult patients with short bowel syndrome: A pilot, randomized, double-blind, cross-over study

As citrulline is produced by small intestine, plasma citrulline concentration is decreased and may become essential in patients with short bowel syndrome (SBS). In a rat model of SBS, citrulline supplementation enhanced muscle protein synthesis. The aim of the study was to determine whether citrulline impacts whole body protein metabolism in patients with SBS. Nine adults with non-malignant SBS (residual small bowel 90±48cm; mean±SD) who were in near-normal nutritional status without any artificial nutrition, were recruited long after surgery. They received 7-day oral supplementation with citrulline (0.18g/kg/day), or an iso-nitrogenous placebo in a randomized, double-blind, cross-over design with a 13-day wash-out between regimens, and an intravenous 5-h infusion of L-[1-13C]-leucine in the postabsorptive state to assess protein metabolism after each regimen. Plasma citrulline concentration rose 17-fold (25±9 vs. 384±95μmol/L) and plasma arginine 3-fold after oral citrulline supplementation (both p<4×10-6). Supplementation did not alter leucine appearance rate (97±5 vs. 97±5μmolkg-1.h-1; p=0.88), leucine oxidation (14±1 vs. 12±1μmolkg-1.h-1; p=0.22), or non-oxidative leucine disposal (NOLD), an index of whole-body protein synthesis (83±4 vs. 85±5μmolkg-1.h-1; p=0.36), nor insulin or IGF-1 plasma concentrations. In each of the 3 patients with baseline citrulline<20μmol/L, citrulline supplementation increased NOLD. Among the 7 patients with plasma citrulline <30μmol/L, the effect of supplementation on NOLD correlated inversely (r2=0.81) with baseline plasma citrulline concentration. 1) Oral citrulline supplementation enhances citrulline and arginine bioavailability in SBS patients. 2) Oral citrulline supplementation does not have any anabolic effect on whole body protein metabolism in patients with SBS in good nutritional status, in the late phase of intestinal adaptation, and with near-normal baseline citrulline homeostasis. 3) Whether oral citrulline would impact whole body protein anabolism in severely malnourished SBS patients in the early adaptive period, and with baseline plasma citrulline below 20μmol/L, warrants further study. Registered under ClinicalTrials.gov Identifier no. NCT01386034.

Endurance Exercise Attenuates Postprandial Whole-Body Leucine Balance in Trained Men.

Endurance exercise increases indices of small intestinal damage and leucine oxidation, which may attenuate dietary amino acid appearance and postprandial leucine balance during postexercise recovery. Therefore, the purpose of this study was to examine the effect of an acute bout of endurance exercise on postprandial leucine kinetics and net leucine balance. In a crossover design, seven trained young men (age = 25.6 ± 2.3 yr; V˙O2peak = 61.4 ± 2.9 mL·kg·min; mean ± SEM) received a primed constant infusion of L-[1-C]leucine before and after ingesting a mixed macronutrient meal containing 18 g whole egg protein intrinsically labeled with L-[5,5,5-H3]leucine, 17 g fat, and 60 g carbohydrate at rest and after 60 min of treadmill running at 70% V˙O2peak. Plasma intestinal fatty acid binding protein concentrations and leucine oxidation both increased (P < 0.01) to peaks that were ~2.5-fold above baseline values during exercise with a concomitant decrease (P < 0.01) in nonoxidative leucine disposal. Meal ingestion attenuated (P < 0.01) endogenous leucine rates of appearance at rest and after exercise. There were no differences (both, P > 0.05) in dietary leucine appearance rates or in the amount of dietary protein-derived leucine that appeared into circulation over the 5-h postprandial period at rest and after exercise (62% ± 2% and 63% ± 2%, respectively). Leucine balance over the 5-h postprandial period was positive (P < 0.01) in both conditions but was negative (P < 0.01) during the exercise trial after accounting for exercise-induced leucine oxidation. We demonstrate that endurance exercise does not modulate dietary leucine availability from a mixed meal but attenuates postprandial whole-body leucine balance in trained young men.

Leucine Transamination Is Lower in Middle-Aged Compared with Younger Adults

Background: Insulin and age affect leucine (and protein) kinetics in vivo. However, to our knowledge, leucine transamination and the effects of insulin have not been studied in participants of different ages.Objective: The aims of the study were to measure whole-body leucine deamination to α-ketoisocaproate (KIC) and KIC reamination to leucine in middle-aged and younger healthy adults, both in the postabsorptive state and after hyperinsulinemia.Methods: Younger (mean ± SE age: 26 ± 2 y) and middle-aged (54 ± 3 y) healthy men and women were enrolled. Isotope dilution methods with 2 independent leucine and KIC tracers, a dual isotope model and the euglycemic, hyperinsulinemic clamp technique, were used.Results: Leucine deamination [expressed as μmol/(kg × min)] was consistently greater than KIC reamination. In middle-aged adults, postabsorptive leucine deamination (0.77 ± 0.05), reamination (0.49 ± 0.04), and net deamination (0.28 ± 0.04) were ∼30% lower than in the younger group (deamination: 1.12 ± 0.07; reamination: 0.70 ± 0.09; net deamination: 0.42 ± 0.04) (P < 0.002, P < 0.05, and P < 0.015, respectively). After the hyperinsulinemic clamp, plasma leucine and KIC concentrations were reduced by ∼50% in both groups. Deamination and reamination also were suppressed by ∼40-50% in both groups (P < 0.001); however, they remained lower [-35% (P = 0.02) and -25% (P = 0.036), respectively] in the middle-aged than in the younger participants. The leucine rate of appearance and its suppression by insulin were similar in the middle-aged and in the younger subjects. By using both the basal and the clamp data, deamination was directly correlated with the plasma leucine concentration (r = 0.61, P < 0.0025) and reamination to that of plasma KIC (r = 0.79, P < 0.00002). Expressing the data relative to lean body mass did not substantially alter the results.Conclusions: Leucine deamination and reamination are lower in middle-aged than in younger adults, both in the postabsorptive and in the insulin-stimulated state. In middle age, a decreased net leucine transamination may represent a mechanism to spare this essential amino acid.

Testosterone prevents protein loss via the hepatic urea cycle in human.

The urea cycle is a rate-limiting step for amino acid nitrogen elimination. The rate of urea synthesis is a true indicator of whole-body protein catabolism. Testosterone reduces protein and nitrogen loss. The effect of testosterone on hepatic urea synthesis in humans has not been studied. To determine whether testosterone reduces hepatic urea production. An open-label study. Eight hypogonadal men were studied at baseline, and after two weeks of transdermal testosterone replacement (Testogel, 100 mg/day). The rate of hepatic urea synthesis was measured by the urea turnover technique using stable isotope methodology, with 15N2-urea as tracer. Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, were calculated. Testosterone administration significantly reduced the rate of hepatic urea production (from 544.4 ± 71.8 to 431.7 ± 68.3 µmol/min; P < 0.01), which was paralleled by a significant reduction in serum urea concentration. Testosterone treatment significantly reduced net protein loss, as measured by percent Lox/LRa, by 19.3 ± 5.8% (P < 0.05). There was a positive association between Lox and hepatic urea production at baseline (r2 = 0.60, P < 0.05) and after testosterone administration (r2 = 0.59, P < 0.05). Testosterone replacement reduces protein loss and hepatic urea synthesis. We conclude that testosterone regulates whole-body protein metabolism by suppressing the urea cycle.

Oral low-dose testosterone administration induces whole-body protein anabolism in postmenopausal women: a novel liver-targeted therapy

In hypopituitary men, oral delivery of unesterified testosterone in doses that result in a solely hepatic androgen effect enhances protein anabolism during GH treatment. In this study, we aimed to determine whether liver-targeted androgen supplementation induces protein anabolism in GH-replete normal women. Eight healthy postmenopausal women received 2-week treatment with oral testosterone at a dose of 40 mg/day (crystalline testosterone USP). This dose increases portal concentrations of testosterone, exerting androgenic effects on the liver without a spillover into the systemic circulation. The outcome measures were whole-body leucine turnover, from which leucine rate of appearance (LRa, an index of protein breakdown) and leucine oxidation (Lox, a measure of irreversible protein loss) were estimated, energy expenditure and substrate utilization. We measured the concentration of liver transaminases as well as of testosterone, SHBG and IGF1. Testosterone treatment significantly reduced LRa by 7.1 ± 2.5% and Lox by 14.6 ± 4.5% (P<0.05). The concentration of liver transaminases did not change significantly, while that of serum SHBG fell within the normal range by 16.8 ± 4.0% and that of IGF1 increased by 18.4 ± 7.7% (P<0.05). The concentration of peripheral testosterone increased from 0.4 ± 0.1 to 1.1 ± 0.2 nmol/l (P<0.05), without exceeding the upper normal limit. There was no change in energy expenditure and fat and carbohydrate utilization. Hepatic exposure to unesterified testosterone by oral delivery stimulates protein anabolism by reducing protein breakdown and oxidation without inducing systemic androgen excess in women. We conclude that a small oral dose of unesterified testosterone holds promise as a simple novel treatment of protein catabolism and muscle wasting.

Positive muscle protein net balance and differential regulation of atrogene expression after resistance exercise and milk protein supplementation

Resistance exercise and amino acid availability are positive regulators of muscle protein net balance (NB). However, anabolic responses to resistance exercise and protein supplementation deserve further elucidation. The purpose was to compare intakes of whey, caseinate (both: 0.30 g/kg lean body mass), or a non-caloric control after heavy resistance exercise on protein turnover and mRNA expressions of forkhead homeobox type O (FOXO) isoforms, muscle RING finger 1 (MuRF1), and Atrogin1 in young healthy males. Protein turnover was determined by stable isotope-labeled leucine and femoral arteriovenous blood samples at rest and during 6-h recovery. Muscle biopsies were collected at -60 min (rest) and at 60, 210, and 360 min in the recovery period. During recovery, leucine NB was significantly higher in the protein groups compared to control (P < 0.001). Differences in leucine NB, rate of disappearance, and oxidation were observed in the early recovery period between whey and caseinate. FOXO1A and MuRF1 were upregulated at 60 and 210 min, and, in contrast, FOXO3 and Atrogin1 were downregulated at 210 and 360 min. For leucine rate of appearance and all FOXO and atrogene mRNA expressions, no differences were observed between groups. Whey and caseinate were equally superior to control in the 6-h recovery period and displayed temporal differences with whey having a fast and superior effect in the early part of the recovery period. Effects on mRNA expressions indicate different regulatory mechanisms on the ubiquitin ligases MuRF1 and Atrogin1 in recovery from heavy resistance exercise.

Substrate metabolism during basal and hyperinsulinemic conditions in adolescents and young‐adults with Barth syndrome

Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by mitochondrial abnormalities, infantile or childhood onset of cardioskeletal myopathy, and high mortality rates. It is currently unknown if BTHS related mitochondrial dysfunction results in substrate metabolism abnormalities and thereby contributes to cardioskeletal myopathy in patients with BTHS. Adolescents and young adults with BTHS (n = 5, 20 ± 4 yrs) and age and activity matched healthy controls (n = 5, 18 ± 4 yrs) underwent an hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracers for measurement of lipolysis, fatty acid oxidation, glucose disposal, and whole-body proteolysis rates; dual energy x-ray absorptiometry for measurement of body composition and 2-D and strain echocardiography for measurement of left ventricular function. Participants with BTHS had lower fat-free mass (FFM) (BTHS: 31.4 ± 6.9 vs. 46.7 ± 5.3 kg, p < 0.005), lower systolic function (strain, BTHS: -15.2 ± 2.4 vs. -19.0 ± 2.4 %, p < 0.05), greater insulin-stimulated glucose disposal rate per kg FFM (BTHS: 96.5 ± 16.3 vs. 67.4 ± 17.6 μmol/kgFFM/min, p < 0.05), lower basal (BTHS: 4.6 ± 2.7 vs. 11.9 ± 4.4 μmol/kgFM/min, p < 0.05) and hyperinsulinemic (BTHS: 1.6 ± 0.4 vs. 3.6 ± 1.6 μmol/kgFM/min, p < 0.05) lipolytic rate per kg fat mass (FM), and a trend towards higher basal leucine rate of appearance per kg FFM (BTHS: 271.4 ± 69.3 vs. 193.1 ± 28.7 μmol/kgFFM/hr, p = 0.07) compared to controls. Higher basal leucine rate of appearance per kg FFM (i.e. whole-body proteolytic rate) tended to be associated with lower left ventricular systolic strain (r = -0.57, p = 0.09). Whole-body fatty acid, glucose and amino acid metabolism kinetics when expressed per unit of body composition are altered and appear to be related to cardioskeletal myopathy in humans with BTHS. Further studies examining myocardial substrate metabolism and whole-body substrate metabolism during increased energy demands (e.g., exercise) and their relationships to skeletal and cardiac function are recommended.

Oral citrulline does not affect whole body protein metabolism in healthy human volunteers: Results of a prospective, randomized, double-blind, cross-over study

Citrulline increases protein synthesis during refeeding in rodents with short bowel syndrome, aging and malnutrition, and improves nitrogen balance in fed healthy humans. The aim of the current study therefore was to determine whether citrulline had affected protein metabolism in healthy volunteers. In a randomized, double-blind, cross-over study, 12 healthy adults received a 5-h intravenous infusion of L-[1-(13)C]-leucine in the post-absorptive state, after a 7-day oral supplementation with 0.18 g/kg/day citrulline, or an iso-nitrogenous placebo. Treatment order was randomized, treatment periods were separated by 13-day wash out. Leucine appearance rate (Ra) was determined from plasma [1-(13)C]-keto-iso-caproate enrichment and leucine oxidation from expired (13)CO(2), and nitrogen balance was estimated from 6-h urinary urea excretion. Compared with placebo, oral citrulline supplementation increased plasma citrulline, arginine and ornithine concentrations, but failed to affect albumin, transthyretin, free insulin and insulin-like growth factor (IGF)-1 plasma concentrations, urinary nitrate excretion, or nitrogen balance. Citrulline supplementation did not alter leucine Ra, leucine oxidation, nor whole-body protein synthesis. In healthy, well nourished volunteers, oral citrulline increases plasma citrulline and arginine availability but does not affect whole-body protein kinetics in the post-absorptive state.

Interaction between Testosterone and Growth Hormone on Whole-Body Protein Anabolism Occurs in the Liver

GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism. Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic. In this open-label randomized crossover study, the impact on whole-body protein metabolism of oral (solely hepatic testosterone exposure) and transdermal (systemic testosterone exposure) testosterone replacement in the presence or absence of GH was compared. Eleven hypopituitary men with GH and testosterone deficiency were randomized to 2-wk treatments with transdermal testosterone (10 mg) or oral testosterone (40 mg), with or without GH replacement (0.6 mg/d). The dose of testosterone administered orally achieves physiological portal testosterone concentrations without spillover into the systemic circulation. Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown, and leucine oxidation (Lox), a measure of irreversible protein loss, were estimated at the end of each treatment. In the absence of GH, neither transdermal nor oral testosterone affected LRa or Lox. GH therapy significantly increased LRa, an effect equally reduced by transdermal and oral testosterone administration. GH replacement alone did not significantly change Lox, whereas addition of testosterone treatment reduced Lox, with the effect not significantly different between transdermal and oral testosterone. In the doses used, testosterone stimulates protein anabolism by reducing protein breakdown and oxidation only in the presence of GH. Because the net effect on protein metabolism during GH therapy is not different between systemic and solely hepatic testosterone administration, we conclude that the liver is the primary site of this hormonal interaction.

Protein consumption following aerobic exercise increases whole-body protein turnover in older adults

Research measuring whole-body protein turnover (WBPT) after both exercise and nutrition has generally focused on resistance exercise; however, there is a paucity of data regarding the effect of postaerobic exercise nutrition, especially in older adults. It is not known if postexercise protein feeding has a beneficial effect on protein turnover after low- to moderate-intensity exercise. We investigated whether consuming protein plus carbohydrate (PRO) immediately after an acute bout of aerobic exercise has an additive effect over carbohydrate alone (CHO) on WBPT in older individuals. Twelve healthy older adults (age, 59 ± 4 years) were studied on 2 separate occasions after 1 h of exercise at approximately 50% of maximal rate of oxygen uptake, followed by 4 h of recovery. Immediately following exercise, subjects ingested a CHO (60 g) or an isocaloric PRO beverage (40 g carbohydrate, 20 g whey protein). Whole-body protein metabolism was determined using [1-13C]leucine infusion (60 mg prime; 75 mgh(-1) continuous), and sampling blood and expired breath. Rates of whole-body leucine appearance and oxidation, and nonoxidative leucine disposal during the third and fourth hours of postexercise recovery were higher in the PRO group (2.51 ± 0.55, 0.78 ± 0.37, and 1.71 ± 0.44 micromol kg(-1)·min(-1), respectively) than in the CHO group (1.81 ± 0.27, 0.33 ± 0.14, and 1.47 ± 0.25 micromol kg(-1)·min-1, respectively; p = 0.001). Our results indicate that consumption of a PRO beverage after aerobic exercise increased WBPT to a greater extent than a CHO beverage.

The effect of a cycling stage race on whole-body protein turnover

Marked energy expenditure, independent of energy balance, could change whole-body protein turnover. The aims of the present study were to determine the effect of participation in a 6-day, 10-stage cycling stage tour on whole-body protein turnover in elite male cyclists, and to determine whether energy and protein turnover are related to fatigue and over-reaching. 13C-leucine was used to determine 18-h whole-body protein turnover in cyclists both before and immediately after a cycling stage race. The 18-h period included two feeding periods to simulate a normal evening meal and a normal breakfast meal, and two fasted periods including overnight. Blood was drawn for the determination of plasma cortisol and serum ferritin on days 2, 4, and 6 and a Profile of Mood States questionnaire was administered on alternate days during the tour event for determination of markers of over-reaching. Mean leucine rate of appearance was unchanged from pre- to post-tour during both fed and fasted conditions and mean energy balance was maintained. Serum ferritin concentration declined and plasma cortisol concentration remained stable over the 6 days. Markers of overtraining were evident in one athlete who pulled out of the tour event due to fatigue on the second to last day. Our main finding was that high energy output over a 6-day period did not significantly change protein turnover during fed, fasted or overnight conditions.

Effects of Adiposity and 30 Days of Caloric Restriction Upon Protein Metabolism in Moderately vs. Severely Obese Women

Protein metabolism adapts during caloric restriction (CR) to minimize protein loss, and it is unclear whether greater fat stores favorably affect this response. We sought to determine whether protein metabolism is related to degree of obesity and whether the response to CR is impacted by pre-CR adiposity level. Whole body protein metabolism was studied in 12 obese women over a wide range of BMI (30-53 kg/m(2)) as inpatients using [1-(13)C]leucine as a tracer following 5 days of a weight-maintaining diet and then after 30 days of CR (1,400 kcal deficit with maintained protein intake). When expressed as total rates, per body weight (BW) or per fat-free mass (FFM), leucine rate of appearance (Ra), and nonoxidative leucine disposal (NOLD) were significantly higher in the individuals with a greater degree of obesity (P < 0.05). Leucine oxidation (Rox) was also higher in more highly obese women when expressed as a total rate (P < 0.05) but not if expressed per BW or FFM. CR reduced BW, FFM, and fat mass (P < 0.001), and declines were relatively similar between individuals. CR reduced Ra (P < 0.001), NOLD (P < 0.01), and Rox (P < 0.05), and the relative decline was not affected by differences in fat mass. CR-induced declines were significant even when Ra and NOLD were normalized to BW or FFM. We conclude that fat mass, like FFM, is a key determinant of protein turnover. However, during CR, higher fat mass does not favorably alter the response of protein metabolism and does not mitigate the loss of FFM.

Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

The metabolic action of GH is attenuated by estrogens administered via the oral route. Selective estrogen receptor modulators lower IGF-I to a lesser degree than 17beta-estradiol in GH-deficient women, and their effect on fat and protein metabolism is unknown. The aim of the study was to compare the modulatory effects of 17beta-estradiol and raloxifene, a selective estrogen receptor modulator, on the metabolic action of GH. We conducted an open-label, two-group, randomized, two-period crossover study. Ten hypopituitary women received GH therapy alone (0.5 mg/d) and GH plus 17beta-estradiol (E(2); 2 mg/d). Eleven hypopituitary women received GH therapy alone and GH plus raloxifene (R; 60 mg/d). The treatment duration was 1 month, with a 4-wk washout period. IGF-I, IGFBP-3, resting energy expenditure, and fat oxidation were quantified by indirect calorimetry. We measured whole body leucine turnover from which leucine rate of appearance and leucine incorporation into protein were estimated. GH significantly stimulated all outcome measures. During GH treatment, addition of R significantly reduced mean IGF-I but not IGFBP-3, whereas E(2) reduced both IGF-I and IGFBP-3 levels. Cotreatment with R but not E(2) significantly attenuated the stimulatory effects of GH on fat oxidation. There was a strong trend (P = 0.08) toward a greater reduction in leucine incorporation into protein after R compared to E(2) cotreatment. The modulatory effects of E(2) and R at therapeutic doses on GH action are different. R during GH therapy exerts a greater inhibitory effect on lipid oxidation and protein anabolism compared to E(2).

Use of the insulin pump in treat cystic fibrosis related diabetes

Objectives This study was conducted to determine efficacy and tolerability of the continued subcutaneous insulin infusion (CSII) via an insulin pump for treatment of Cystic Fibrosis Related Diabetes (CFRD). We also tested the hypothesis that CSII would improve body weight, blood sugar control, lean body mass, whole body protein turnover, hepatic glucose production (HGP). Methods We recruited 9 CF patients with established diabetes and placed them on insulin pump therapy for six months. Each subject kept daily blood sugar records before and during pump use. Prior to the pump placement and at the end of six months, each patient underwent the following measurements: 1) whole body protein turnover using the stable isotope [1- 13C] leucine; 2) DEXA scan for measurement of lean body mass; 3) anthropometric measurements; 4) Hemoglobin A1c. Patient data was compared to baseline data and the mean change from baseline was analyzed. Results There was significant improvement in both fasting and post-prandial blood glucose levels, body weight, HbA1C, and lean mass. Protein catabolism as measured by leucine rate of appearance was significantly lower, as was hepatic glucose production. No patient developed hypoglycemia during the study. Conclusions This study demonstrates that CSII is safe and effective for treatment of CFRD and that metabolic benefits are also present.

Physical activity counteracts increased whole‐body protein breakdown in chronic obstructive pulmonary disease patients

Chronic obstructive pulmonary disease (COPD) is associated with increased whole body protein breakdown and low-grade systemic inflammation. We aimed to determine if physical training of patients with COPD induces anti-inflammatory effects and decreases whole-body protein breakdown. Nineteen subjects with severe (FEV(1)=31+/-1) COPD were randomized into a training group (n=9) and a control group (n=10). Twenty healthy subjects were studied for baseline comparison. The "COPD training" group participated in an outpatient rehabilitation program consisting of endurance training (walking at 85% of VO(2max)) twice weekly for 7 weeks plus daily home-based training. Maximum walking distance increased by almost 70% in the training group after 7 weeks of training. At baseline, the concentrations of C-reactive protein (CRP) and IL-18 in plasma were increased in subjects with COPD compared with healthy subjects (P<0.05) and leucine rate of appearance (R(a)) was approximately 15% greater (P<0.05) in subjects with COPD. Training had no effect on the plasma concentration of inflammatory markers but decreased leucine R(a) in subjects with COPD by approximately 10% (P<0.05). In conclusion, 7 weeks of physical training markedly improved endurance in patients with COPD and accelerated whole-body protein breakdown in patients with COPD was attenuated by physical training independent of changes in inflammatory markers.

The Effects of Growth Hormone and/or Testosterone on Whole Body Protein Kinetics and Skeletal Muscle Gene Expression in Healthy Elderly Men: A Randomized Controlled Trial

Alterations of protein turnover may contribute to the progressive decline of muscle mass with aging. Our objective was to examine the effects of near-physiological recombinant human GH and/or testosterone (T) administration to older men on whole body protein kinetics and muscle gene expression. A 6-month randomized, double-blind, placebo-controlled trial in 21 healthy elderly men aged 65-75 yr, was performed. Participants were randomized to receive placebo GH and placebo T, rhGH and placebo T (GH), T and placebo GH (T), or rhGH and T (GHT). The leucine rate of appearance (index of proteolysis), nonoxidative leucine disposal rate (an index of protein synthesis), and leucine oxidation rate were measured with an infusion of l-[1-(13)C] leucine. Muscle biopsies for the measurement of gene expression were performed. Body composition and aerobic capacity (maximal oxygen capacity) were measured. Serum IGF-I levels increased significantly with GH and GHT (P < 0.001) compared with placebo. T increased significantly only in the T group (P = 0.028). Leucine rate of appearance and nonoxidative leucine disposal rate increased with GH (P = 0.015, P = 0.019) and GHT (P = 0.017, P = 0.02), but leucine oxidation did not change significantly in any treatment group. Midthigh muscle mass and maximal oxygen capacity increased (P < 0.04) with GHT only. Expression of muscle function genes did not change significantly, but the within-group comparisons revealed a significant increase of androgen receptor expression in the GHT group (P = 0.001). This study showed that 6-month treatment with low-dose GH alone or with T in healthy elderly men produces comparable increments in whole body protein turnover and protein synthesis.

Impact of Growth Hormone and Dehydroepiandrosterone on Protein Metabolism in Glucocorticoid-Treated Patients

Chronic pharmacological glucocorticoid (GC) use causes substantial morbidity from protein wasting. GH and androgens are anabolic agents that may potentially reverse GC-induced protein loss. Our objective was to assess the effect of GH and dehydroepiandrosterone (DHEA) on protein metabolism in subjects on long-term GC therapy. This was an open, stepwise GH dose-finding study (study 1), followed by a randomized cross-over intervention study (study 2). The studies were performed at a clinical research facility. In study 1, six subjects (age 69+/-4 yr) treated with long-term (>6 months) GCs (prednisone dose 8.3+/-0.8 mg/d) were studied before and after two sequential GH doses (0.8 and 1.6 mg/d) for 2 wk each. In study 2, 10 women (age 71+/-3 yr) treated with long-term GCs (prednisone dose 5.4+/-0.5 mg/d) were studied at baseline and after 2-wk treatment with GH 0.8 mg/d, DHEA 50 mg/d, or GH and DHEA (combination treatment). Changes in whole body protein metabolism were assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance, leucine oxidation, and leucine incorporation into protein were estimated. In study 1, GH 0.8 and 1.6 mg/d significantly reduced leucine oxidation by 19% (P=0.03) and 31% (P=0.02), and increased leucine incorporation into protein by 10% (P=0.13) and 19% (P=0.04), respectively. The lower GH dose did not cause hyperglycemia, whereas GH 1.6 mg/d resulted in fasting hyperglycemia in two of six subjects. In study 2, DHEA did not significantly change leucine metabolism alone or when combined with GH. Blood glucose was not affected by DHEA. GH, at a modest supraphysiological dose of 0.8 mg/d, induces protein anabolism in chronic GC users without causing diabetes. DHEA 50 mg/d does not enhance the effect of GH. GH may safely prevent or reverse protein loss induced by chronic GC therapy.

The Effects of Nutritional Supplementation Throughout an Endurance Run on Leucine Kinetics during Recovery

This study determined the effect of nutritional supplementation throughout endurance exercise on whole-body leucine kinetics (leucine rate of appearance [Ra], oxidation [Ox], and nonoxidative leucine disposal [NOLD]) during recovery. Five trained men underwent a 2-h run at 65% VO(2max), during which a carbohydrate (CHO), mixed protein-carbohydrate (milk), or placebo (PLA) drink was consumed. Leucine kinetics were assessed during recovery using a primed, continuous infusion of 1-13C leucine. Leucine Ra and NOLD were lower for milk than for PLA. Ox was higher after milk-supplemented exercise than after CHO or PLA. Although consuming milk during the run affected whole-body leucine kinetics, the benefits of such a practice for athletes remain unclear. Additional studies are needed to determine whether protein supplementation during exercise can optimize protein utilization during recovery.

Impact of Acute and Chronic Low-Dose Glucocorticoids on Protein Metabolism

High-dose glucocorticoids cause acute protein loss by increasing protein breakdown and oxidation. Whether lower glucocorticoid doses, typical of therapeutic use, induce sustained catabolism has not been studied. Our objective was to assess the effect of acute and chronic therapeutic glucocorticoid doses on protein metabolism. We conducted an open longitudinal and a cross-sectional study at a clinical research facility. Ten healthy subjects were studied before and after a short course of prednisolone (5 and 10 mg/d sequentially for 7 d each). Twelve subjects with inactive polymyalgia rheumatica receiving chronic (>12 months) prednisone (mean = 5.0 +/- 0.8 mg/d) were compared with 12 age- and gender-matched normal subjects. Whole-body protein metabolism was assessed using a 3-h primed constant infusion of 1-[(13)C]leucine, from which rates of leucine appearance (leucine Ra, an index of protein breakdown), leucine oxidation (Lox, index of protein oxidation) and leucine incorporation into protein (LIP, index of protein synthesis) were estimated. Prednisolone induced an acute significant increase in Lox (P = 0.008) and a fall in LIP (P = 0.08) but did not affect leucine Ra. There was no significant difference between the effects of the 5- and 10-mg prednisolone doses on leucine metabolism. In subjects receiving chronic prednisone therapy, leucine Ra, Lox, and LIP were not significantly different from normal subjects. Glucocorticoids stimulate protein oxidation after acute but not chronic administration. This time-related change suggests that glucocorticoid-induced stimulation of protein oxidation does not persist but that a metabolic adaptation occurs to limit protein loss.