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.

Role of ovarian hormones in the regulation of protein metabolism in women: effects of menopausal status and hormone replacement therapy

2006 ◽  
Vol 291 (3) ◽  
pp. E639-E646 ◽  
Author(s):  
Michael J. Toth ◽  
Cynthia K. Sites ◽  
Dwight E. Matthews
Keyword(s):  
Postmenopausal Women ◽  
Protein Metabolism ◽  
Protein Turnover ◽  
Hormone Replacement ◽  
Menopausal Status ◽  
Ovarian Hormones ◽  
Hormone Deficiency ◽  
Whole Body ◽  
Protein Breakdown ◽  
Body Protein

The age-related decline in fat-free mass is accelerated in women after menopause, implying that ovarian hormone deficiency may have catabolic effects on lean tissue. Because fat-free tissue mass is largely determined by its protein content, alterations in ovarian hormones would likely exert regulatory control through effects on protein balance. To address the hypothesis that ovarian hormones regulate protein metabolism, we examined the effect of menopausal status and hormone replacement therapy (HRT) on protein turnover. Whole body protein breakdown, oxidation, and synthesis were measured under postabsorptive conditions using [13C]leucine in healthy premenopausal ( n = 15, 49 ± 1 yr) and postmenopausal ( n = 18, 53 ± 1 yr) women. In postmenopausal women, whole body protein turnover and plasma albumin synthesis rates (assessed using [13C]leucine and [2H]phenylalanine) were also measured following 2 mo of treatment with oral HRT (0.625 mg conjugated estrogens + 2.5 mg medroxyprogesterone acetate, n = 9) or placebo ( n = 9). No differences in whole body protein breakdown, oxidation, or synthesis were found between premenopausal and postmenopausal women. Protein metabolism remained similar between groups after statistical adjustment for differences in adiposity and when subgroups of women matched for percent body fat were compared. In postmenopausal women, no effect of HRT was found on whole body protein breakdown, synthesis, or oxidation. In contrast, our results support a stimulatory effect of HRT on albumin fractional synthesis rate, although this did not translate into alterations in circulating albumin concentrations. In conclusion, our results suggest no detrimental effect of ovarian hormone deficiency coincident with the postmenopausal state, and no salutary effect of hormone repletion with HRT, on rates of whole body protein turnover, although oral HRT regimens may increase the synthesis rates of albumin.

Increased bone turnover is associated with protein and energy metabolism in adolescents with sickle cell anemia

2001 ◽  
Vol 280 (3) ◽  
pp. E518-E527 ◽  
Author(s):  
Maciej S. Buchowski ◽  
F. Alexander de la Fuente ◽  
Paul J. Flakoll ◽  
Kong Y. Chen ◽  
Ernest A. Turner
Keyword(s):  
Energy Expenditure ◽  
Bone Turnover ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Protein Turnover ◽  
Type I Collagen ◽  
Whole Body ◽  
Type I ◽  
Protein Breakdown ◽  
Body Protein

Contribution of bone turnover to the hypercatabolic state observed in sickle cell anemia is unknown. We examined the association between markers of bone turnover and basal rates of whole body protein turnover and energy expenditure in 28 adolescents with homozygous sickle cell anemia (HbSS) and in 26 matched controls with normal phenotype (HbAA). Whole body protein breakdown and synthesis were measured using a stable isotope of [15N]glycine, resting energy expenditure was measured by whole room indirect calorimetry, and the rate of pyridinoline cross-link (PYD) excretion in urine and fasting serum levels of the type I procollagen carboxy-terminal propeptide (PICP) were measured with commercial kits. Urinary PYD and serum PICP were significantly elevated in HbSS patients. The increase in procollagen synthesis, indicated by high levels of PICP, was significantly correlated with increased whole body protein synthesis. The increase in type I collagen degradation, indicated by high PYD excretion, was significantly correlated with increased protein breakdown. We conclude that increased rates of bone turnover contribute to the increased rates of protein turnover and energy expenditure observed in adolescents with homozygous sickle cell anemia.

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.

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

2011 ◽  
Vol 96 (4) ◽  
pp. 1060-1067 ◽  
Author(s):  
Vita Birzniece ◽  
Udo J. Meinhardt ◽  
Margot A. Umpleby ◽  
David J. Handelsman ◽  
Ken K. Y. Ho
Keyword(s):  
Protein Metabolism ◽  
Whole Body ◽  
Protein Breakdown ◽  
Protein Loss ◽  
Open Label ◽  
Gh Therapy ◽  
Body Protein ◽  
Gh Replacement ◽  
Testosterone Administration ◽  
The Impact

Abstract Context: GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism. Objective: Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic. Design: 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. Patients and Intervention: 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. Main Outcome Measures: 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. Results: 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. Conclusions: 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.

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

2007 ◽  
Vol 92 (10) ◽  
pp. 3923-3929 ◽  
Author(s):  
Morton G. Burt ◽  
Gudmundur Johannsson ◽  
A. Margot Umpleby ◽  
Donald J. Chisholm ◽  
Ken K. Y. Ho
Keyword(s):  
Protein Oxidation ◽  
Protein Metabolism ◽  
Normal Subjects ◽  
Whole Body ◽  
Metabolic Adaptation ◽  
High Dose ◽  
Protein Breakdown ◽  
Protein Loss ◽  
Body Protein ◽  
Significant Difference

Abstract Context: 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. Objective: Our objective was to assess the effect of acute and chronic therapeutic glucocorticoid doses on protein metabolism. Design and Setting: We conducted an open longitudinal and a cross-sectional study at a clinical research facility. Patients and Intervention: 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 (&gt;12 months) prednisone (mean = 5.0 ± 0.8 mg/d) were compared with 12 age- and gender-matched normal subjects. Main Outcome Measure: Whole-body protein metabolism was assessed using a 3-h primed constant infusion of 1-[13C]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. Results: 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. Conclusion: 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.

scholarly journals Alterations in basal nutrient metabolism increase resting energy expenditure in sickle cell disease

1998 ◽  
Vol 274 (2) ◽  
pp. E357-E364 ◽  
Author(s):  
Myfanwy J. Borel ◽  
Maciej S. Buchowski ◽  
Ernest A. Turner ◽  
Benjamin B. Peeler ◽  
Richard E. Goldstein ◽  
...  
Keyword(s):  
African American ◽  
Lipid Metabolism ◽  
Sickle Cell Disease ◽  
Energy Expenditure ◽  
Resting Energy Expenditure ◽  
Whole Body ◽  
Protein Breakdown ◽  
Cell Disease ◽  
Body Protein ◽  
Glucose And Lipid Metabolism

Basal rates of whole body protein, glucose, and lipid metabolism and resting energy expenditure (REE) were measured in eight African-American sickle cell disease (SCD) patients and in six African-American controls. Catheters were placed 1) in an antecubital vein for stable isotope infusion and 2) in a heated hand vein for arterialized venous blood. Breath and blood were collected during the last 30 min of the 2.5-h study, and REE was measured by indirect calorimetry. REE [128 ± 5 vs. 111 ± 1 kJ ⋅ kg fat-free mass (FFM)−1 ⋅ day−1; P < 0.05 vs. controls] was 15% greater in the SCD patients. Whole body protein breakdown (5.0 ± 0.3 vs. 3.8 ± 0.2 mg ⋅ kg FFM−1 ⋅ min−1; P < 0.05 vs. controls) and protein synthesis (4.4 ± 0.3 vs. 3.2 ± 0.2 mg ⋅ kg FFM−1 ⋅ min−1; P< 0.05 vs. controls) were 32 and 38% greater, respectively, in the SCD patients, but whole body amino acid oxidation was similar (0.58 ± 0.03 vs. 0.66 ± 0.03 mg ⋅ kg FFM−1 ⋅ min−1). Measures of whole body glucose and lipid metabolism were not significantly different between the groups. The additional energy required for the greater rates of whole body protein breakdown and synthesis caused by SCD contributes significantly to the observed increase in REE, suggesting that dietary energy and protein requirements are enhanced in SCD patients.

Effects of winter military training on energy balance, whole-body protein balance, muscle damage, soreness, and physical performance

2014 ◽  
Vol 39 (12) ◽  
pp. 1395-1401 ◽  
Author(s):  
Lee M. Margolis ◽  
Nancy E. Murphy ◽  
Svein Martini ◽  
Marissa G. Spitz ◽  
Ingjerd Thrane ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Muscle Damage ◽  
Energy Intake ◽  
Military Training ◽  
Whole Body ◽  
Protein Loss ◽  
Short Term ◽  
Protein Balance ◽  
Body Protein ◽  
And Performance

Physiological consequences of winter military operations are not well described. This study examined Norwegian soldiers (n = 21 males) participating in a physically demanding winter training program to evaluate whether short-term military training alters energy and whole-body protein balance, muscle damage, soreness, and performance. Energy expenditure (D218O) and intake were measured daily, and postabsorptive whole-body protein turnover ([15N]-glycine), muscle damage, soreness, and performance (vertical jump) were assessed at baseline, following a 4-day, military task training phase (MTT) and after a 3-day, 54-km ski march (SKI). Energy intake (kcal·day−1) increased (P < 0.01) from (mean ± SD (95% confidence interval)) 3098 ± 236 (2985, 3212) during MTT to 3461 ± 586 (3178, 3743) during SKI, while protein (g·kg−1·day−1) intake remained constant (MTT, 1.59 ± 0.33 (1.51, 1.66); and SKI, 1.71 ± 0.55 (1.58, 1.85)). Energy expenditure increased (P < 0.05) during SKI (6851 ± 562 (6580, 7122)) compared with MTT (5480 ± 389 (5293, 5668)) and exceeded energy intake. Protein flux, synthesis, and breakdown were all increased (P < 0.05) 24%, 18%, and 27%, respectively, during SKI compared with baseline and MTT. Whole-body protein balance was lower (P < 0.05) during SKI (–1.41 ± 1.11 (–1.98, –0.84) g·kg−1·10 h) than MTT and baseline. Muscle damage and soreness increased and performance decreased progressively (P < 0.05). The physiological consequences observed during short-term winter military training provide the basis for future studies to evaluate nutritional strategies that attenuate protein loss and sustain performance during severe energy deficits.

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.

Enhancement of tumor proteolysis by TNF-alpha: correlation of in vivo isotope estimates with growth

1991 ◽  
Vol 261 (1) ◽  
pp. R106-R116
Author(s):  
N. W. Istfan ◽  
P. R. Ling ◽  
G. L. Blackburn ◽  
B. R. Bistrian
Keyword(s):  
Protein Synthesis ◽  
Protein Metabolism ◽  
Whole Body ◽  
Independent Effect ◽  
Yoshida Sarcoma ◽  
Protein Breakdown ◽  
Body Protein ◽  
Breakdown Rates ◽  
Made In

To evaluate the accuracy of in vivo estimates of protein synthesis and breakdown, measurements of plasma and tissue leucine kinetics were made in rat tumor tissues at different conditions of growth by use of constant intravenous infusion of [14C]leucine. These measurements were made in Yoshida sarcoma tumors on days 10 and 13 after implantation, with and without tumor necrosis factor (TNF) infusion and on day 10 in Walker-256 carcinosarcoma. Expressed as micromoles of leucine per gram tissue, tumor protein breakdown increased (P less than 0.01) from 0.32 +/- 0.02 to 0.52 +/- 0.09 (SE) mumol/h, with progress of the Yoshida sarcoma tumor between days 10 and 13 after implantation. Similarly, TNF increased tumor proteolysis on day 10 (0.43 +/- 0.03 mumol.h-1.g-1, P less than 0.05 vs. day 10 control) but not on day 13 after implantation of the Yoshida tumor. Estimates of growth derived from the difference between protein synthesis and breakdown rates were not statistically different from those based on actual tumor volume changes in both tumor models. However, estimates of “whole body” protein metabolism (plasma leucine flux) were not affected either by tumor aging or by treatment with TNF. This study shows that in vivo estimates of tissue protein metabolism based on our [14C]leucine constant infusion model closely reflect the growth characteristic of that tissue. A cytotoxic perfusion-independent effect for intravenous TNF on growing tumor tissue is demonstrable as increased protein breakdown. Furthermore, the commonly used concept of whole body protein metabolism, derived solely from tracer dilution in plasma, is an oversimplification.

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