scholarly journals Effects of a Caspase and a Calpain Inhibitor on Resting Energy Expenditures in Normal and Hypermetabolic Rats: a Pilot Study

2016 ◽  
pp. 537-541 ◽  
Author(s):  
P. G. VANA ◽  
H. M. LAPORTE ◽  
R. H. KENNEDY ◽  
R. L. GAMELLI ◽  
M. MAJETSCHAK
Keyword(s):  
Whole Body ◽  
Calpain Inhibitor ◽  
Protein Loss ◽  
Body Protein ◽  
Physiological Conditions ◽  
Energy Expenditures ◽  
Calpain Inhibitors ◽  
Caspase Cascades ◽  
Observation Period ◽  
Resting Energy

Several diseases induce hypermetabolism, which is characterized by increases in resting energy expenditures (REE) and whole body protein loss. Exaggerated protein degradation is thought to be the driving force underlying this response. The effects of caspase and calpain inhibitors on REE in physiological and hypermetabolic conditions, however, are unknown. Thus, we studied whether MDL28170 (calpain inhibitor) or z-VAD-fmk (caspase inhibitor) affect REE under physiological conditions and during hypermetabolism post-burn. Rats were treated five times weekly and observed for 6 weeks. Treatment was started 2 h (early) or 48 h (late) after burn. In normal rats, MDL28170 transiently increased REE to 130 % of normal during week 2-4. z-VAD-fmk reduced REE by 20-25 % throughout the observation period. Within 14 days after burns, REE increased to 130±5 %. Whereas MDL28170/early treatment did not affect REE, MDL28170/late transiently increased REE to 180±10 % of normal by week 4 post-burn. In contrast, with z-VAD-fmk/early REE remained between 90-110 % of normal post-burn. z-VAD-fmk/late did not affect burn-induced increases in REE. These data suggest that caspase cascades contribute to the development of hypermetabolism and that burn-induced hypermetabolism can be pharmacologically modulated. Our data point towards caspase cascades as possible therapeutic targets to attenuate hypermetabolism after burns, and possibly in other catabolic disease processes.

Leucine kinetics in endurance-trained humans

1990 ◽  
Vol 69 (1) ◽  
pp. 1-6 ◽  
Author(s):  
L. S. Lamont ◽  
D. G. Patel ◽  
S. C. Kalhan
Keyword(s):  
Energy Expenditure ◽  
Protein Turnover ◽  
Resting Energy Expenditure ◽  
Whole Body ◽  
Body Protein ◽  
Energy Expenditures ◽  
Leucine Kinetics ◽  
Constant Rate ◽  
Tracer Dilution ◽  
Resting Energy

This study compared whole-body leucine kinetics in endurance-trained (TRN) and sedentary (SED) control subjects. Eleven men and women (6 TRN, 5 SED) underwent a 6-h primed, constant-rate infusion of L-[1-13C]leucine. Leucine turnover and oxidation were measured using tracer dilution and by measuring 13C enrichment of expired CO2 combined with respiratory calorimetry. Whole-body leucine turnover was greater in the TRN subjects (P less than 0.004; TRN 98.3 +/- 5.0, SED 75.3 +/- 4.2 mumol.kg-1.h-1; mean +/- SE), but there was no difference between groups in leucine oxidation (TRN 13.1 +/- 0.97, SED 11.5 +/- 0.48 mumol.kg-1.h-1). Thus more leucine turnover was available for nonoxidative utilization. In addition, the TRN subjects had higher resting energy expenditures compared with the SED group, and when all subjects were included in the analysis, there was a significant correlation between energy expenditure and protein turnover (n = 11, R = 0.61, P = 0.05). Therefore the heightened resting energy expenditure in the TRN subjects may be accounted for by an increased whole-body protein turnover. These results suggest that endurance training results in increased leucine and/or protein turnover, which may contribute to the increased resting energy expenditure observed in these subjects.

Whole body protein metabolism and resting energy expenditure in pregnant Gambian women

1992 ◽  
Vol 263 (4) ◽  
pp. E624-E631 ◽  
Author(s):  
L. Willommet ◽  
Y. Schutz ◽  
R. Whitehead ◽  
E. Jequier ◽  
E. B. Fern
Keyword(s):  
Protein Synthesis ◽  
Energy Expenditure ◽  
Protein Metabolism ◽  
Resting Energy Expenditure ◽  
First Trimester ◽  
Significant Rise ◽  
Whole Body ◽  
Body Protein ◽  
Fed State ◽  
Resting Energy

Whole body protein metabolism and resting energy expenditure (REE) were measured at 11, 23, and 33 wk of pregnancy in nine pregnant (not malnourished) Gambian women and in eight matched nonpregnant nonlactating (NPNL) matched controls. Rates of whole body nitrogen flux, protein synthesis, and protein breakdown were determined in the fed state from the level of isotope enrichment of urinary urea and ammonia during a period of 9 h after a single oral dose of [15N]glycine. At regular intervals, REE was measured by indirect calorimetry (hood system). Based on the arithmetic end-product average of values obtained with urea and ammonia, a significant increase in whole body protein synthesis was observed during the second trimester (5.8 +/- 0.4 g.kg-1.day-1) relative to values obtained both for the NPNL controls (4.5 +/- 0.3 g.kg-1.day-1) and those during the first trimester (4.7 +/- 0.3 g.kg-1.day-1). There was a significant rise in REE during the third trimester both in the preprandial and postprandial states. No correlation was found between REE after meal ingestion and the rate of whole body protein synthesis.

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

2008 ◽  
Vol 93 (3) ◽  
pp. 688-695 ◽  
Author(s):  
Morton G. Burt ◽  
Gudmundur Johannsson ◽  
A. Margot Umpleby ◽  
Donald J. Chisholm ◽  
Ken K. Y. Ho
Keyword(s):  
Protein Metabolism ◽  
Dose Finding ◽  
Whole Body ◽  
Constant Infusion ◽  
Leucine Incorporation ◽  
Protein Loss ◽  
Body Protein ◽  
Prednisone Dose ◽  
Leucine Oxidation

Abstract Context: 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. Objective: Our objective was to assess the effect of GH and dehydroepiandrosterone (DHEA) on protein metabolism in subjects on long-term GC therapy. Design: This was an open, stepwise GH dose-finding study (study 1), followed by a randomized cross-over intervention study (study 2). Setting: The studies were performed at a clinical research facility. Patients and Intervention: 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). Main Outcome Measure: 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. Results: 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. Conclusion: 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.

scholarly journals Testosterone prevents protein loss via the hepatic urea cycle in human

2017 ◽  
Vol 176 (4) ◽  
pp. 489-496 ◽  
Author(s):  
Teresa Lam ◽  
Anne Poljak ◽  
Mark McLean ◽  
Neha Bahl ◽  
Ken K Y Ho ◽  
...  
Keyword(s):  
Urea Cycle ◽  
Nitrogen Loss ◽  
Testosterone Replacement ◽  
Whole Body ◽  
Urea Synthesis ◽  
Protein Loss ◽  
Open Label ◽  
Body Protein ◽  
Urea Production ◽  
Testosterone Administration

ContextThe 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.ObjectiveTo determine whether testosterone reduces hepatic urea production.DesignAn open-label study.Patients and interventionEight hypogonadal men were studied at baseline, and after two weeks of transdermal testosterone replacement (Testogel, 100 mg/day).Main outcomes measuresThe rate of hepatic urea synthesis was measured by the urea turnover technique using stable isotope methodology, with15N2-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.ResultsTestosterone 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).ConclusionTestosterone replacement reduces protein loss and hepatic urea synthesis. We conclude that testosterone regulates whole-body protein metabolism by suppressing the urea cycle.

Energy Not Protein Or Carbohydrate Intake Attenuates Whole-body Protein Loss During 4-d Arctic Military Training

2016 ◽  
Vol 48 ◽  
pp. 444
Author(s):  
Lee M. Margolis ◽  
Nancy E. Murphy ◽  
Svein Martini ◽  
Yngvar Gundersen ◽  
John W. Castellani ◽  
...  
Keyword(s):  
Military Training ◽  
Carbohydrate Intake ◽  
Whole Body ◽  
Protein Loss ◽  
Body Protein

Hemodialysis stimulates muscle and whole body protein loss and alters substrate oxidation

2002 ◽  
Vol 282 (1) ◽  
pp. E107-E116 ◽  
Author(s):  
T. Alp Ikizler ◽  
Lara B. Pupim ◽  
John R. Brouillette ◽  
Deanna K. Levenhagen ◽  
Kali Farmer ◽  
...  
Keyword(s):  
Amino Acids ◽  
Muscle Protein ◽  
Substrate Oxidation ◽  
Whole Body ◽  
Constant Infusion ◽  
Acid Oxidation ◽  
Protein Breakdown ◽  
Protein Loss ◽  
Body Protein ◽  
Protein Calorie Malnutrition

The hemodialysis (HD) procedure has been implicated as a potential catabolic factor predisposing the chronic HD (CHD) patients to protein calorie malnutrition. To assess the potential effects of HD on protein and energy metabolism, we studied 11 CHD patients 2 h before, during, and 2 h after HD by use of primed constant infusion of l-[1-13C]leucine andl-[ ring-2H5]phenylalanine. Our results showed that HD led to increased whole body (10%) and muscle protein (133%) proteolysis. Simultaneously, whole body protein synthesis did not change, and forearm synthesis increased (120%). The net result was increased net whole body protein loss (96%) and net forearm protein loss (164%). During the 2-h post-HD period, the muscle protein breakdown trended toward baseline, whereas whole body protein breakdown increased further. Substrate oxidation during the post-HD was significantly altered, with diminished carbohydrate and accelerated lipid and amino acid oxidation. These data demonstrate that hemodialysis is an overall catabolic event, decreasing the circulating amino acids, accelerating rates of whole body and muscle proteolysis, stimulating muscle release of amino acids, and elevating net whole body and muscle protein loss.

Whole-body urea cycling and protein turnover during hyperphagia and dormancy in growing bears (Ursus americanus and U. arctos)

1997 ◽  
Vol 75 (12) ◽  
pp. 2129-2136 ◽  
Author(s):  
Perry S. Barboza ◽  
Sean D. Farley ◽  
Charles T. Robbins
Keyword(s):  
Protein Turnover ◽  
Whole Body ◽  
Turnover Rates ◽  
Protein Loss ◽  
Plasma Urea ◽  
Body Protein ◽  
Urea Production ◽  
Amino Acid Degradation ◽  
Urea Kinetics ◽  
N Resorption

Subadult bears were studied during their autumn hyperphagia (n = 3) and winter dormancy (n = 6). Urea kinetics were measured with 14C- and 15N-urea, protein turnover was estimated with 15N-glycine, and body composition was assessed with 3H-water. Reduced amino acid degradation in winter was indicated by declines in plasma urea and aminotransferase activities, and lower urea production than in autumn (4.7 vs. 27.5 mmol urea-N∙kg−0.75∙d−1). Only 7.5% of urea produced in hyperphagic bears was degraded and just 1.1% of the degraded N reutilized as amino-N. Dormant bears reutilized 99.7% of urea produced, indicating thorough microbial ureolysis and urea-N resorption. Low rates of body N loss during dormancy suggested losses of non-urea N as creatinine. Protein turnover rates (15.2–21.5 g∙kg−0.75∙d−1) were similar between seasons and reflected the apparent maintenance of hepatic, intestinal, and muscular functions through dormancy. Protein synthesis accounted for 32% of energy expended in dormancy, which was mainly (91.5%) derived from fat oxidation. Consistent organ function and body temperature in dormant bears enables recycling of urea-N, which minimizes body protein loss and conserves mobility. In comparison with heterothermic hibernation, ursid dormancy would provide greater flexibility during winter and facilitate rapid resumption of foraging and growth in spring.

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

1991 ◽  
Vol 81 (5) ◽  
pp. 611-619 ◽  
Author(s):  
Yves Cherel ◽  
Didier Attaix ◽  
Danuta Rosolowska-Huszcz ◽  
Rajae Belkhou ◽  
Jean-Patrice Robin ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Skeletal Muscles ◽  
Whole Body ◽  
Protein Loss ◽  
Body Protein ◽  
Tissue Protein ◽  
Control Value ◽  
Tissue Protein Synthesis ◽  
Fractional Synthesis

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. Our data also emphasize the importance of skin in whole-body protein synthesis in fasting and possibly in other protein loss situations.

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

2013 ◽  
Vol 169 (3) ◽  
pp. 321-327 ◽  
Author(s):  
Vita Birzniece ◽  
Margot A Umpleby ◽  
Anne Poljak ◽  
David J Handelsman ◽  
Ken K Y Ho
Keyword(s):  
Energy Expenditure ◽  
Postmenopausal Women ◽  
Outcome Measures ◽  
Oral Delivery ◽  
Whole Body ◽  
Protein Breakdown ◽  
Protein Loss ◽  
Carbohydrate Utilization ◽  
Body Protein ◽  
Liver Transaminases

ObjectiveIn 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.DesignEight 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.Outcome measuresThe 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.ResultsTestosterone 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.ConclusionsHepatic 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.

scholarly journals The Decisive Role of Free Fatty Acids for Protein Conservation during Fasting in Humans with and without Growth Hormone

2003 ◽  
Vol 88 (9) ◽  
pp. 4371-4378 ◽  
Author(s):  
Helene Nørrelund ◽  
K. Sreekumaran Nair ◽  
Steen Nielsen ◽  
Jan Frystyk ◽  
Per Ivarsen ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Muscle Protein ◽  
Decisive Role ◽  
Normal Subjects ◽  
Whole Body ◽  
Protein Loss ◽  
Body Protein ◽  
Gh Replacement ◽  
Protein Conservation ◽  
Underlying Mechanisms

During fasting, a lack of GH increases protein loss by close to 50%, but the underlying mechanisms remain uncertain. The present study tests the hypothesis that the anabolic actions of GH depend on mobilization of lipids. Seven normal subjects were examined on four occasions during a 37-h fast with infusion of somatostatin, insulin, and glucagon for the final 15 h: 1) with GH replacement, 2) with GH replacement and antilipolysis with acipimox, 3) without GH and with antilipolysis, and 4) with GH replacement, antilipolysis, and infusion of intralipid. Urinary urea excretion, serum urea concentrations, and muscle protein breakdown (assessed by labeled phenylalanine) increased by almost 50% during fasting with suppression of lipolysis. Addition of GH during fasting with antilipolysis did not influence indexes of protein degradation, whereas restoration of high FFA levels regenerated proportionally low concentrations of urea and decreased whole body protein degradation (phenylalanine to tyrosine conversion) by 10–15%, but failed to affect muscle protein metabolism. Thus, the present data provide strong evidence that FFA are important protein-sparing agents during fasting. The finding that inhibition of lipolysis eliminates the ability of GH to restrict fasting protein loss indicates that stimulation of lipolysis is the principal protein-conserving mechanism of GH.

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