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How Is Whole Body Protein Turnover Perturbed in Growth Hormone-Deficient Adults?¹

Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney; Division of Petroleum Resources, Commonwealth Scientific and Industrial Research Organization (R.P.), North Ryde; and Biomedical Mass Spectrometry Unit, University of New South Wales (M.D.), New South Wales, Australia

Address all correspondence and requests for reprints to: Dr. Ken K. Y. Ho, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria Street, Sydney, New Wouth Wales 2010, Australia.

	Abstract

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Adult patients with GH deficiency have reduced lean body mass (LBM), muscle mass, and muscle strength, suggesting an underlying abnormality of protein metabolism. As acute GH administration has previously been reported to decrease protein oxidation and increase protein synthesis in GH-deficient (GHD) adults, we investigated whether the converse might occur in untreated GH deficiency by undertaking studies of whole body protein turnover in 10 GHD and 13 normal subjects using a 3-h primed constant infusion of 1-[¹³C]leucine. Dual energy x-ray absorptiometry was used to quantify LBM and fat mass (FM).

In normal subjects, LBM was the major, independent determinant of leucine appearance (Ra; r = 0.80; P = 0.0009), leucine oxidation (r = 0.81; P = 0.0008), and leucine incorporation into protein (r = 0.75; P = 0.003). However, in an analysis of covariance, FM was also a significant independent determinant of leucine Ra (P = 0.002) and leucine incorporation into protein (P = 0.003). After correcting for LBM and FM, GHD patients had significantly reduced rates of leucine Ra (109.9 ± 4.4 vs. 125.5 ± 3.7 µmol/min, respectively; P = 0.02) and leucine incorporation into protein (87.0 ± 3.9 vs. 100.3 ± 3.3 mmol/min; P = 0.02) compared to normal subjects. There was no significant difference in the corrected rates of leucine oxidation between the two groups (22.9 ± 1.3 vs. 25.2 ± 1.0, GHD vs. normal; P = 0.20).

In summary, GHD adults have reduced rates of protein synthesis and protein breakdown, but normal rates of irreversible oxidative loss; these findings are discordant with what was predicted from the acute changes in protein metabolism observed with GH administration. We conclude that normalization of protein oxidation may be a homeostatic mechanism that operates to constrain protein loss in GHD adults.

	Introduction

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EXPANSION and contraction of the lean body mass (LBM) in the respective states of GH excess (acromegaly) (1, 2) and deficiency (3, 4) or with GH administration (5, 6) and withdrawal (7) provide persuasive evidence that GH is an important regulator of this body compartment. Although no comparison of body nitrogen between GH-deficient (GHD) adults and normal controls has been reported, it is surmised that the total protein mass is reduced in GHD, as protein constitutes the predominant solid component of muscle and lean tissue (8), nitrogen retention accompanies the GH-induced increase in LBM (5, 9), and lean tissue, skeletal muscle mass, and strength are reduced in GH deficiency (10).

The whole body protein turnover method is a powerful tool for the study of protein metabolism. An infusion of isotopically labeled leucine enables accurate estimation of the key components of whole body protein kinetics, that is rates of proteolysis, protein synthesis, and protein oxidation. Implicit in the concept is that oxidation represents the net balance between proteolysis and synthesis, because at steady state, the rate of appearance of leucine (index of proteolysis) must equal its rate of disposal through oxidation or reincorporation into protein (index of protein synthesis). Furthermore, changes in the body’s protein pool (and, hence, LBM) must result from changes in time-integrated rates of oxidation. Previous isotope tracer studies have convincingly demonstrated that short term administration of GH augments protein synthesis but has no effect on proteolysis and hence reduces protein oxidation in normal (11, 12) and GHD adults (13). Consequently, it may be predicted that GH insufficiency will be characterized by opposite changes in protein turnover, that is decreased protein synthesis and enhanced protein oxidation, without any change in proteolysis. However, if these changes in kinetics were to persist, the LBM would be expected to continuously shrink and eventually disappear. As this clearly does not occur, it may be surmised that homeostatic mechanisms occur that stabilize the LBM at a reduced level. The aim of this study was to determine what changes occur in the components of whole body protein turnover that lead to a low but stable protein mass in GHD adults.

	Subjects and Methods

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Subjects

Thirteen normal subjects and 10 hypopituitary GHD subjects were recruited in a cross-sectional study after obtaining informed written consent. The clinical characteristics of the GHD subjects are shown in Table 1. Efforts were made to recruit subjects of comparable age and body mass indexes. The mean age and body mass indexes of the 2 groups were not significantly different (Table 2). All patients were confirmed to be GHD as defined by a peak GH response of less than 3 ng/mL during an insulin tolerance test (14). Two patients had childhood-onset GHD, and the diagnosis was reconfirmed by an insulin tolerance test at recruitment into the present study. The duration of hypopituitarism and GHD was at least 2 yr. All hypopituitary subjects were receiving stable hormone replacement for other deficiencies, except for 1 female subject of postmenopausal age who did not receive sex steroid replacement.

The study was approved by the research ethics committee of St. Vincent’s Hospital (Sydney, Australia). All subjects underwent measurements of body composition by dual energy x-ray absorptiometry, whole body protein turnover using 1-[¹³C]leucine tracer, and measurement of serum insulin-like growth factor I (IGF-I). Four of the normal subjects underwent a second leucine turnover study 1 month later to determine the biological variability of the indexes of turnover.

Dual energy x-ray absorptiometry was performed using a total body scanner (model DPX, software version 3.1, Lunar Corp., Madison, WI) to determine LBM and fat mass (FM). At our institution, the coefficients of variation for LBM and FM are 1.5% and 2.9%, respectively (2).

Whole body protein turnover was undertaken using a primed constant infusion of 1-[¹³C]leucine. Ninety-nine percent NaH¹³CO₃ was obtained from Cambridge Isotope Laboratories (Woburn, MA), and 99% 1-[¹³C]leucine was obtained from Mass Trace (Woburn, MA). Solutions of each were prepared under sterile conditions using 0.9% saline.

Subjects were fasted overnight and took their usual hormone replacement on the morning of the study. At 0800 h, a cannula was inserted into an antecubital fossa vein for isotope infusion, and a second cannula was placed retrograde into a heated distal forearm vein for the purpose of obtaining arterialized blood. A 0.1 mg/kg priming dose of NaH¹³CO₃ was followed immediately by 1-[¹³C]leucine (prime, 0.5 mg/kg; infusion, 0.5 mg/kg·h). Blood and breath samples were collected at -10, 0, 180, 200, 220, and 240 min from commencement of the infusion. Blood was placed on ice, and plasma was separated and stored at -80 C until analysis. Breath samples were collected into 2-L aluminum bags and analyzed within 1 week. CO₂ production rates were undertaken with an open circuit, ventilated hood system (Deltatrac monitor, Datex Instrumentation Corp., Helsinki, Finland). The monitor was calibrated against standard gases before each study. Measurements were averaged over 20–40 and 160–180 min.

Calculation of whole body protein turnover

The method is based on the principle of steady state kinetics, in which the rate of appearance of substrate (Ra) equals its rate of disposal (Rd). For leucine there are two pathways of disposal: oxidation or reincorporation into protein. The fractional partitioning between these two pathways of disposal is determined from the fraction of infused isotope that appears in breath. A correction factor is applied to account for the fact that a small proportion of CO₂ released from oxidation is fixed into other metabolic pathways. We have experimentally determined in four healthy volunteers that, on the average, 71% of infused ¹³C isotope appears in breath CO₂, a finding consistent with previous reports (15, 16). The reciprocal pool model was used, in which enrichment of -ketoisocaproic acid (KIC) is used as a surrogate measure of true intracellular leucine enrichment (17). Rates of appearance of leucine, leucine incorporation into protein, and leucine oxidation were calculated as previously described (18).

The reproducibility of parameters of protein turnover were assessed by studying four normal healthy volunteers on two occasions over a period of 1 month. The average coefficients of variation for indexes of leucine turnover were 3.6% for leucine Ra, 6.3% for leucine oxidation, and 3.0% for leucine incorporation into protein.

Analytical methods

Serum IGF-I was measured by RIA after acid-ethanol extraction as previously described (19). The intraassay CVs were 9.4%, 8.3%, and 10.3% at 48, 254, and 1510 ng/mL.

KIC was extracted by the method of Nissen et al. (20). KIC enrichment was measured as the t-butyldimethylsilyl derivative by gas chromatography (model 5890, Hewlett-Packard Co., Palo Alto, CA)-mass spectrometry (MSD 5971A, Hewlett-Packard Co.), with selective monitoring of ions 302 and 303 (21). CO₂ was cryogenically purified from breath on a gas preparation line, and enrichment was analyzed on a Finnigan MAT 252 isotope ratio mass spectrometer (Bremen, Germany) operated in dual inlet mode.

Statistics

Statistical analysis of unpaired data was performed using Student’s unpaired t test for clinical characteristics and serum IGF-I. Analysis of covariance (ANCOVA) was used to compare indexes of protein turnover between the two groups after correction for body composition, serum IGF-I levels, and GH status (normal or GHD). Statistical significance was set at an level of 0.05.

	Results

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Characteristics of the normal and GHD subjects are given in Table 2. The mean age, gender distribution, and body mass index were not significantly different between normal and GHD subjects. The percent LBM was lower and the percent FM was greater in GHD subjects, although the differences did not attain statistical significance. Serum IGF-I was significantly lower in GHD than in normal subjects (54.8 ± 9.1 vs. 125.7 ± 10.2 ng/mL; P = 0.0001).

Leucine turnover in normal subjects

In normal subjects, LBM was highly and significantly correlated to leucine Ra (r = 0.80; P = 0.0009), leucine oxidation (r = 0.81; P = 0.0008), and leucine incorporation into protein (r = 0.75; P = 0.003; Fig. 1). To determine whether FM also contributes to rates of protein turnover, ANCOVA was performed with LBM and FM as the two independent variables. LBM was the major, independent determinant of the three indexes of protein turnover, accounting for 64.6% of the variance in leucine Ra, 65.6% of the variance in leucine oxidation, and 56.4% of the variance in leucine incorporation into protein (Table 3). However, FM was also a significantly independent determinant of leucine Ra (23.1% of variance) and leucine incorporation into protein (28% of variance). FM did not significantly contribute to the variance in leucine oxidation. The independent effect of FM is further illustrated in Fig. 2, in which residual indexes of leucine turnover (actual value - predicted value from LBM-determined regression line) are plotted against FM. There were highly significant relationships for leucine Ra (r = 0.76; P = 0.002) and leucine incorporation into protein (r = 0.75; P = 0.003). The association was not significant for leucine oxidation. Age, gender, and serum IGF-I levels did not significantly contribute to the residual rates of leucine Ra, leucine oxidation, or leucine incorporation into protein (data not shown).

View larger version (16K): [in this window] [in a new window]   Figure 1. Relationship between lean body mass and rate of leucine appearance (Leucine Ra, panel A), leucine oxidation (panel B), and leucine incorporation into protein (panel C) in 13 normal subjects.

View larger version (15K): [in this window] [in a new window]   Figure 2. Relationship between fat mass and residual rates of leucine appearance (residual leucine Ra, panel A) and residual leucine incorporation into protein (panel B) in normal subjects.

As in normal subjects, LBM in GHD patients was a major determinant of leucine Ra (r = 0.83; P = 0.0003), leucine oxidation (r = 0.83; P = 0.003), and leucine incorporation into protein (r = 0.88; P = 0.0007; Fig. 3). LBM accounted for 82.9% of the variance in leucine Ra, 69.0% of the variance in leucine oxidation, and 78.0% of the variance in leucine incorporation into protein (Table 3). FM did not significantly contribute to the variance in any of the three indexes of protein turnover in the GHD patients. Indexes of protein turnover were compared between the GHD and normal groups after adjusting for the effects of body composition. Adjusted values (mean ± SD) were calculated from the ANCOVA model, in which age, sex, lean body mass, and fat mass were treated as covariates. After adjusting for the influence of these covariates, GHD patients had significantly reduced rates of leucine Ra (109.9 ± 4.4 vs. 125.5 ± 3.7 µmol/min, respectively; P = 0.02) and leucine incorporation into protein (87.0 ± 3.9 vs. 100.3 ± 3.3 mmol/min; P = 0.02) compared to control subjects (Fig. 4). There was no significant difference in the rate of leucine oxidation between the two groups (22.9 ± 1.3 vs. 25.2 ± 1.0, GHD vs. normal; P = 0.20).

View larger version (16K): [in this window] [in a new window]   Figure 3. Relationship between lean body mass and rates of leucine appearance (Leucine Ra, panel A), leucine oxidation (panel B), and leucine incorporation into protein (panel C) in 10 GH deficient subjects.

View larger version (17K): [in this window] [in a new window]   Figure 4. Comparison of rates of leucine appearance (leucine Ra, panel A), leucine oxidation (panel B), and leucine incorporation into protein between GH deficient and normal subjects after correcting for the effects of lean body mass and fat mass.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Body composition was a major physiological determinant of protein turnover, with both LBM and FM having independent effects and together accounting for 88% of the variance in protein turnover. As the body’s protein pool resides within the LBM, it is not surprising that there was a very strong relationship between this parameter and the three indexes of protein turnover. The independent effect of FM may be unexpected, but this observation has also been made previously. Welle et al. (22) showed a significant relationship between residual leucine flux (based on whole body potassium estimates of LBM) and FM in normal subjects, with a somewhat lower correlation of r = 0.36. In the present study, the corresponding relationship between residual leucine flux and FM was even stronger, with a correlation of r = 0.76. The highly significant correlation implies that for two individuals with comparable LBM, the individual with the greater FM will have a higher rate of protein turnover.

The physiological explanation for the relationship between fat and protein turnover is unknown. Adipose tissue is an important site of leucine disposal through both oxidation and metabolic conversion to fat (23). Both of these metabolic pathways occur after decarboxylation of the 1-carbon of leucine and hence are included in the estimated rate of leucine oxidation. It may therefore be expected that FM is a determinant of leucine oxidation. However, FM was observed to be a determinant of leucine Ra, not of leucine oxidation. As insulin reduces whole body protein turnover (24), the enhanced rates of protein turnover observed in obesity suggest that insulin resistance in obesity may also affect protein metabolism (25). Weight gain arising from positive energy balance is believed to be constrained by an increase in energy expenditure exceeding that predicted from the increase in LBM (26). It may be speculated, therefore, that an adiposity-related increase in protein turnover is a mechanism for augmenting energy expenditure and constraining weight gain.

The GHD patients were found to have reduced rates of both protein breakdown and synthesis compared to normal subjects, indicating a slowing of the rate of protein turnover. In the only previously published study of protein turnover in GHD, Beyshah et al., using the leucine turnover technique, also reported reduced rates of protein breakdown and synthesis in GHD adults compared to normal controls (27). However, their findings in relation to protein oxidation were unclear, as this parameter was significantly reduced when corrected for body weight but not when corrected for LBM.

As protein oxidation is decreased with acute GH administration, it might be predicted that protein oxidation is increased, rather than normal, in GHD patients. However, it is inappropriate to contrast the protein kinetics of patients acutely treated with GH, in whom the LBM is actively expanding, with those in chronically GHD patients, who have a relatively stable LBM. Acute GH treatment reduces protein oxidative wastage, which results in a progressive rise in the body protein pool. However, this mechanism cannot remain operative over the long term because the protein mass and consequently the LBM do not expand indefinitely. The initial avid nitrogen retention (and presumed protein accretion) that occurs with initiation of GH treatment ameliorates within 1 week (28), and the LBM is known to stabilize with time (29, 30). These observations imply that the initially reduced rate of protein wastage increases progressively to normal. As a corollary, it may be hypothesized that the initial consequences of GH insufficiency are the opposite of those seen with acute GH administration: protein synthesis is reduced, whereas proteolysis remains unchanged, with a resultant net increase in protein oxidation. This situation would result in net loss of protein and lean tissue. However, clinical experience suggests that the LBM does not continue to shrink ad infinitum in GHD, but, rather, stabilizes at a reduced level. The findings from the present study suggest that metabolic adaptation occurs; there is a fall in the rate of protein breakdown that offsets the initial fall in protein synthesis, to restore the net rate of protein wastage to normal.

In summary, FM must be considered in addition to LBM as a physiological determinant of protein turnover. After correcting for both of these factors, GHD patients have reduced rates of protein synthesis. However, rates of protein breakdown are commensurately reduced, so that net protein loss is restored to normal. This mechanism may explain the development of stable, albeit reduced, protein and LBM in GHD and protects against further protein loss.

	Acknowledgments

 
We are indebted to Dr. Morey Haymond, Children’s Nutrition Research Center, Baylor College of Medicine (Houston, TX), for his generous and invaluable advice concerning the establishment of the whole body leucine turnover technique. We thank Dr. Anita Andrews for invaluable advice and Nathan Doyle for technical support.

	Footnotes

 
¹ This work was supported in part by the National Health and Medical Research Council of Australia and St. Vincent’s Clinic Research Foundation.

Received April 10, 1998.

Revised July 15, 1998.

Accepted July 31, 1998.

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