1 Department of Biochemistry, Aged rats are more sensitive to injury, possibly
through an impairment of nitrogen and glutamine (Gln) metabolisms
mediated by glucocorticoids. We studied the metabolic kinetic response of adult and old rats during glucocorticoid treatment. The male Sprague-Dawley rats were 24 or 3 mo old. Both adult and old rats were
divided into 7 groups. Groups labeled G3, G5, and G7 received, by
intraperitoneal injection, 1.50 mg/kg of dexamethasone (Dex) for 3, 5, and 7 days, respectively. Groups labeled G3PF, G5PF, and G7PF were pair
fed to the G3, G5, or G7 groups and were injected with an isovolumic
solution of NaCl. One control group comprised healthy rats fed ad
libitum. The response to aggression induced specifically by Dex (i.e.,
allowing for variations in pair-fed controls) appeared later in the
aged rats (decrease in nitrogen balance from day
1 in adults but only from day
4 in old rats). The adult rats rapidly adapted to Dex
treatment, whereas the catabolic state worsened until the end of
treatment in the old rats. Gln homeostasis was not maintained in the
aged rats; despite an early increase in muscular Gln synthetase
activity, the Gln pool was depleted. These results suggest a kinetic
impairment of both nitrogen and muscle Gln metabolisms in response to
Dex with aging.
aging; dexamethasone; duration of treatment
ELDERLY PEOPLE have a reduced capacity to recover from
a variety of stresses. Jeevanandam et al. (12) reported that, after injury, elderly patients recover their preinjury nutritional status more slowly and incompletely. Dardevet et al. (3) showed that, after
dexamethasone (Dex) withdrawal, adult rats rapidly restored their
muscle protein mass within 3 days, whereas, in old animals, this
recovery was delayed to 7 days. In the same model of
glucocorticoid-treated old rats, Savary et al. (31) described an
impairment of muscle protein synthesis during recovery. However,
although this process of recovery has been largely investigated, little
is known about the metabolic response of elderly subjects during
stress. This point deserves attention because morbidity among elderly
subjects is increased during catabolic situations.
Glutamine (Gln) is the most abundant free amino acid (AA) in the human
body and has several important metabolic roles, e.g., it is a fuel for
rapidly dividing cells (33). It is the main carrier of Glucocorticoids such as Dex are important in three ways. First, they
are a major mediator of catabolic response. They are known to induce an
augmentation of net protein catabolism (negative nitrogen balance) and
more specifically an increase in muscle myofibrillar protein catabolism
(11, 16). This muscle Dex-mediated catabolic effect is integrated in
the systemic response to stress that supplies AAs for gluconeogenesis
and for the synthesis of inflammatory proteins by the liver.
Consequently, these steroids are often used in models of stress.
Second, glucocorticoids are implicated in the alterations of the muscle
Gln pool by stimulating both GS activity (19) and muscle Gln efflux
(17). Third, these hormones are specifically important during aging,
since basal plasma concentration of corticosterone, the physiological
glucocorticoid in rodents, may be higher in old rats than in adults
(30). In addition, there are several other relevant lesions (an
aging-related adenomatous hyperplasia and a cortical metaplasia of the
periadrenal tissues). These lesions are generally regarded as
"silent" because the elevation of hormones is not sufficient to
cause overt Cushing's syndrome. Studies in humans support these
observations (34).
To understand the greater sensitivity of elderly persons to catabolic
conditions, we attempted to describe kinetic impairment of nitrogen
metabolism during prolonged stress in elderly rats by means of a
longitudinal study in adult and old glucocorticoid-treated rats. We
extended our study to muscle Gln metabolism because of its relevance to
protein metabolism. Three types of muscle have been studied that are
recognized to have different sensitivities to Dex: extensor digitorum
longus (EDL, a type II fiber-rich muscle), gastrocnemius (a mixed
muscle composed of type I and type II fibers), and soleus (a type I
fiber-rich muscle). Muscle atrophy in glucocorticoid-treated adult rats
is generally observed for both EDL and gastrocnemius (7, 15) through a
decreased concentration of RNA and a decreased protein synthesis (28).
Conversely, Dex treatment has little effect on the mass of soleus, and
protein synthesis in this muscle is not affected. The noteworthy
resistance of soleus to treatment could be due to its antigravity
function (31) or to the qualitative difference in its glucocorticoid
receptors despite their greater number (4, 16).
Animals and experimental study. One
hundred twenty-three male Sprague-Dawley rats, supplied by Iffa Credo
(L'Arbresle, France), were used. They were 24 (n = 63) or 3 mo
(n = 60) old. After their arrival in
our animal facilities, the rats were maintained on a standard diet
(17% protein, 3% fat, 59% carbohydrate, and 21% water, fibers,
vitamins, and minerals) and water ad libitum. They were kept in a
controlled environment (constant temperature 24°C and a 12:12-h
light-dark cycle). After 10 days of acclimatization in standard cages
and 5 days in individual metabolic cages, the rats were divided into 8 groups of 12 as follows: groups labeled G3, G5, G7, and G9 received, by
intraperitoneal injection, 1.50 mg/kg of Dex for 3, 5, 7, and 9 days,
respectively; groups labeled G3PF, G5PF, G7PF, and G9PF were pair fed
with the G3, G5, G7, and G9 groups and were injected with an isovolumic
solution of NaCl. There was also one healthy group of 27 rats (Al
group). Each group comprised the same number of old
(n = 6) and adult (n = 6) rats except the Al group,
which comprised 15 old and 12 adult rats. The G3, G5, G7, and G9 groups
were given Dex, as this synthetic steroid is more often used than
corticosterone because of its greater affinity for glucocorticoid
receptors (4). The dose of 1.50 mg/kg was chosen with reference to the
literature and is known to induce a severe catabolic state in adults
(19). Because treatment by glucocorticoids induces anorexia (2), the
study in parallel of pair-fed rats is mandatory. Thus the G3PF, G5PF,
G7PF, and G9PF control groups were pair fed with the G3, G5, G7, and G9
groups, respectively. They were managed as Dex-treated animals but were
injected with an isovolumic solution of 0.9% NaCl instead of Dex. The
Al group received no treatment and was fed ad libitum for the duration
of the study. For statistical analysis reasons (see Statistical
analysis) healthy rats were randomly assigned to the
following two subgroups: G0 (n = 15) and G0PF (n = 12).
Body weight, urine volume, and food intake were recorded daily from
day 0 to day
9. Rats were starved the evening before death. They
were anesthetized with ether and killed by beheading 30 h after the
last Dex or NaCl injections. Animal care and experimentation complied
with the rules of our institution, and one of us (Cynober) is
authorized by the French Ministry of Agriculture and Forestry to use
animal models of stress.
Urinary parameters. Urine was
collected in a container on a preservative (AMUKIN; Gifrer Barbezat,
Decines, France). Nitrogen was quantified by chemoluminescence using an
Antek 7000 apparatus (Antek, Houston, TX; see Ref. 8), and nitrogen
balance was calculated as the difference between nitrogen intake and
nitrogen urinary output. Limit of sensitivity and intra- and interassay coefficients of variation were 20 mg/l and 1 and 5%, respectively.
Muscle and plasma parameters. Muscles
of the hindlimbs (soleus, EDL, gastrocnemius) were rapidly removed,
weighed, and frozen in liquid nitrogen. Right muscles were used for
determination of free AA concentrations. They were ground and
deproteinized with 10% trichloroacetic acid-EDTA (10 mM). The
supernatant was stored at Blood was withdrawn in heparinized tubes to measure concentrations of
free AAs. Blood was centrifuged (4°C, 4,500 g, 10 min), and the plasma was
deproteinized with sulfosalicylic acid (50 mg/ml). The supernatant was
stored at Statistical analysis. Data are
presented as means ± SE. For parameters measured daily in live
animals, an analysis of variance (ANOVA) on repeated measurements and
with one factor (effect of treatment) was performed in either adult or
old rats for the G9 group, studied up to day
7 (most elderly rats were dead on day 8), with estimation of missing values. For parameters
measured after death, a two-way ANOVA was performed in either adult or old rats with treatment and duration of treatment as main factors. The
effects of factors (treatment or duration of treatment) were analyzed
by the Newman-Keüls test (see RESULTS and Figs.
1-6 for additional information). Because the two-way ANOVA
requires two groups of rats at each time (1 treated group and 1 control
group), healthy ad libitum-fed rats (i.e., Al group) were randomly
assigned to two subgroups: G0 and a so-called G0PF
(n = 15, including 3 rats who died
during the experiment, and n = 12, respectively). Therefore G3, G5, and G7 groups were compared with G0,
and G3PF, G5PF, and G7PF groups were compared with G0PF. There was no
difference for any parameter between G0 and G0PF. The PCSM software
(Deltasoft, Grenoble, France) was used. Values of
P < 0.05 were considered significant.
Characteristics of animals. All of the
adult rats survived the glucocorticoid treatment. In aged rats, the
mortality rate was 14% (1 rat in G7, 5 rats in G9, and 3 rats in G0).
As most old rats in the G9 group were dead before the 9th day of
treatment, i.e., at day 8 (5/6), the
results obtained at this time point were ignored for analysis of
parameters measured at the time of killing but were considered for
parameters measured daily (i.e., food intake, body weight, and nitrogen balance).
Dex induced anorexia from day 2 in
adult and old rats. Food intake improved after day
3 in adult rats but worsened in aged animals (Fig.
1).
ABSTRACT
Top
Abstract
Introduction
MATERIALS AND METHODS
RESULTS
DISCUSSION
References
INTRODUCTION
Top
Abstract
Introduction
MATERIALS AND METHODS
RESULTS
DISCUSSION
References
-amino
nitrogen between tissues of the body and is therefore important in
interorgan traffic and acid-base homeostasis (35). Skeletal muscle is a
major site for Gln synthesis in the body via glutamine synthetase (GS)
and serves as a Gln store (29). During stress, the muscle Gln pool is
markedly decreased (2). The physiological relevance of this impairment
may be great, since Gln may promote protein synthesis (13) and inhibit
protein catabolism in muscle (32). These alterations of muscle Gln
metabolism are probably heightened during aging, as elderly subjects
already have decreased muscle protein stores (22). In addition,
hypoglutaminemia is correlated with high mortality (25). However,
although impairment of muscle Gln is largely described in injured
adults, to the best of our knowledge only one study has been performed
during aging (20).
MATERIALS AND METHODS
Top
Abstract
Introduction
MATERIALS AND METHODS
RESULTS
DISCUSSION
References
80°C until analysis of AAs by ion
exchange chromatography with an AA autoanalyzer (model 6300; Beckman,
Palo Alto, CA). For Gln, the limit of sensitivity and intra- and
interassay coefficients of variation were 5 µmol/l and 0.9 and 4.2%,
respectively. The results of our participation in the European Quality
Control Scheme (ERNDIM) indicate the accuracy of our AA determinations,
in particular for Gln. Left muscles were used to measure GS activities.
Muscles were homogenized in 10 vol of 50 mM imidazole, and GS was
measured as described by Minet et al. (21). The limit of sensitivity and intra- and interassay coefficients of variation were 2.7 nmol/min glutamyl hydroxamate formed and 1.5 and 2.6%, respectively.
80°C for no longer than 15 days before the plasma
AA analysis was performed as described for muscles.
RESULTS
Top
Abstract
Introduction
MATERIALS AND METHODS
RESULTS
DISCUSSION
References
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Fig. 1.
Food intake of adult and old dexamethasone (Dex)-treated rats. Adult
(filled bars) and old (open bars) experimental rats received 1.50 mg/kg
of Dex for 7 days by ip injection. Adult and old control animals were
pair fed during the same period (data not shown). Values are means ± SE for n = 6 rats. D0-D7,
days 0-7, respectively. Analysis
of variance on repeated measurements was performed in either adult or
old rats to discriminate among effects of dexamethasone (D), duration
of treatment (T), and their interaction (D · T). A
significant effect of T (P < 0.0001)
was observed for both ages considered. Comparison of means was carried
out with the Newman-Keuls test:
** P < 0.01 vs.
day 0.
Treatment by glucocorticoid and pair feeding induced a decrease in
whole body weight from day 1. Body
weight loss induced specifically by Dex
(P < 0.05 between Dex-treated and
pair-fed animals) occurred from day 2 in adult rats (Fig.
2A) and
from day 1 in old animals (Fig.
2B).
|
Nitrogen balance. Nitrogen balance
decreased from day 1 in adult and old
treated rats (Fig. 3). This decrease was
due to the specific effect of Dex from day
1 in adult rats but only from day
4 in old rats (P < 0.01 between Dex-treated and pair-fed rats, data not shown). Nitrogen
balance remained negative until the end of the experimentation in aged
animals. In contrast, nitrogen balance increased at
day 6, becoming positive at
day 7, in adult rats.
|
Muscle mass. An atrophy of EDL and
gastrocnemius, due to the specific catabolic effect of Dex, was
observed, respectively, from day 5 and
day 3 in adult treated rats (Table
1). No similar change was noticed in
muscles from aged rats. Soleus mass was not modified during
experimentation, whatever the age of the animals.
|
Plasma Gln concentrations. Plasma Gln concentrations were decreased from day 5 only in old rats because of the specific catabolic effect of Dex [for 5 days of treatment: experimental, 580 ± 38 µmol/l vs. control pair fed, 959 ± 28 µmol/l, P < 0.01; experimental, 763 ± 112 µmol/l vs. control pair fed, 924 ± 151 µmol/l (nonsignificant) in old and adult rats, respectively].
Muscle Gln metabolism. In adult rats,
Gln concentrations decreased in both EDL (Fig.
4A) and
gastrocnemius (Fig.
5A) from 3 days of treatment by glucocorticoids. In old animals, muscle Gln
depletion occurred later: from day 5 and day 7, respectively, in EDL (Fig.
4A) and gastrocnemius (Fig.
5A).
|
|
GS activity increased from day 5 and day 3 in EDL (Fig. 4B) and gastrocnemius (Fig. 5B), respectively, in adult rats. In old animals, this rise in GS activity occurred earlier: from day 3 in both EDL (Fig. 4B) and gastrocnemius (Fig. 5B).
Whatever the age of the rats, these muscle alterations of both the Gln pool and GS activity were due to the specific catabolic effect of Dex (P < 0.01 between treated and pair-fed rats; Figs. 4 and 5). In soleus, Dex induced no modification of Gln concentrations but an increase in GS activities at day 7 in both adult and old rats (data not shown).
Relationship between muscle Gln concentrations and
muscle weights. A correlation was established between
Gln concentration in EDL and its weight (y = 45.96x 3.39;
r2 = 0.48, P < 0.0001 in adults). Similar
results were found for gastrocnemius of adult rats
(y = 2.73x
1.67; r2
=0.68, P < 0.0001; Fig.
6A). In
contrast, in old rats, weight of muscles and Gln concentrations were
not correlated (Fig. 6B).
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DISCUSSION |
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Surprisingly, none of the three types of muscles were atrophied in the old rats at any time during the glucocorticoid treatment. The hypothesis of an involution of type II fibers into type I fibers with aging (10) could explain this result. However, although such an involution has been shown in a mixed muscle, such as plantaris (10), none has been found in EDL (5).
The body weight decrease observed from day 1 in treated and pair-fed rats despite a nonsignificant decrease in food intake may result from loss of water, as indicated by the increase in their diuresis (data not shown), and from the stress of injection in experimental and control pair-fed rats, respectively.
Like weight loss, nitrogen balance decrease observed in old and adult treated rats was also more marked than in their pair-fed controls. However, this decrease in nitrogen balance was only transient in adults, unlike in old treated rats for which nitrogen balance worsened with the duration of treatment. This different kinetic response according to the age of rats may be due to the severity of anorexia, since decrease in food intake was longer in old rats than in adults. Taken as a whole, these data suggest that the metabolic response to treatment by glucocorticoids occurs in two phases: an early catabolic phase in adult rats, which is blunted in old rats, and a later phase where the response worsens only in aged rats. It is noteworthy that the first phase in old rats lags 1 or 2 days behind that of adults. These two phases have already been described in adult rats by Kayali et al. (14) and Odedra et al. (23). These authors demonstrated an early phase lasting at least 4 days, during which proteolysis increased (14) while the overall rate of protein synthesis in muscles fell gradually (23), followed by a later phase during which proteolysis decreased (14) while protein synthesis was maintained at the lower rate (23). In old rats, a decrease in protein synthesis has been described (3) after 6 days of treatment by glucocorticoids. All of these data emphasize the importance of the duration of treatment for the metabolic response. However, other works (6, 26) have focused only on the first and last days of treatment. Consequently, they failed to detect variations in a number of parameters under study. Thus one study (26) concluded wrongly that Dex was not responsible for anorexia, since food intake had been measured only at the beginning and end of treatment, i.e., when it had reverted to its basal value.
Like whole body nitrogen metabolism, Gln metabolism is not altered in the same way and for the same duration in adult and old rats.
In agreement with Parry-Billings et al. (26), the Gln plasma pool was not depleted in adult rats during the treatment, whereas it was lowered from day 5 in old rats. Consequently, either aged rats have greater requirements than adult rats and endogenous production does not supply them, or endogenous production is decreased and is not sufficient to supply the organism. The decrease in endogenous production can result either from a decrease in Gln muscle efflux or a decrease in de novo Gln synthesis by GS. This last hypothesis can be discarded since, in agreement with data from Meynial-Denis et al. (20), muscle GS activities were increased whatever the age of the rats. Consequently, Gln plasma depletion in old treated rats may result from a decrease in its muscle efflux, as previously shown by Parry-Billings et al. (27) in soleus from healthy aged rats. Irrespective of this mechanism, hypoglutaminemia seems important per se since Parry-Billings et al. (25) correlated mortality with hypoglutaminemia in burned patients. Interestingly, the mortality rate was high only in the old rat group, which suffered from marked hypoglutaminemia.
The sensitivity of muscle Gln to the duration of treatment by Dex is also different according to the age of animals. Dex induced an increase in GS activities in EDL and gastrocnemius of treated rats. As previously described by Meynial-Denis et al. (20), this augmentation was the same whatever the age of the animals but occurred earlier in old rats than in adult rats. Consequently, Gln depletion occurred later in aged animals than in adult animals and, at day 3, the muscle Gln pool was higher in the older rodents. In previous unpublished work, we showed that Dex plasma concentration kinetics were the same in adult and old rats after intraperitoneal injection of 1.50 mg/kg of this glucocorticoid. Consequently, Dex plasma concentrations cannot account for this different time response of GS activities according to the age of animals. We can speculate that GS activities in old rats are more sensitive to Dex than in adult rats. Therefore, in a recent study, we showed that intraperitoneal injection of 0.75 mg/kg of Dex for 5 days was sufficient to maximally enhance GS activity in EDL from old rats, whereas a dose of 2.50 mg/kg of Dex was required in adult rats. Induction of GS activity appears to occur at the transcriptional level, since there is an overall increase in the level of mRNA encoding the enzyme in both adult (1, 6, 19) and old rats (20). In soleus, an increase in GS activity occurred from day 7, in agreement with results of Max et al. (19) and Meynial-Denis et al. (20).
We have established a correlation between EDL or gastrocnemius weights and EDL or gastrocnemius Gln contents, respectively, only in adult rats. These results challenge the existence of an association between Gln and muscular nutritional status, as suggested by Mac Lennan (18). We can hypothesize that Gln muscle concentration and muscle weight may be the covariables of a third factor, itself the regulator of muscular nutritional status. With aging, this hypothetical regulator would rely neither on Gln concentration nor muscle weight. It has been suggested (9, 13) that insulin, thyroid hormones, or cell hydration could be the third factor. Finally, Olde Damink et al. (24) demonstrated that changes in Gln turnover and/or Gln supplementation were not related to whole body protein turnover by measuring plasma and muscle Gln concentration and whole body protein turnover in rats treated by methionine sulfoximine, an inhibitor of GS activity. Clearly, further work is needed to characterize both the exact nature of the association between muscle Gln content and muscular nutritional status and the factors that influence the concentrations of Gln in muscle, especially during aging.
In conclusion, this is the first study on the metabolic kinetic response of aged rats during treatment by glucocorticoids. This longitudinal study shows that the metabolic response of old rats to Dex is divided into two phases: an early phase where the response to Dex is blunted, followed by a later phase characterized by a worsening of nutritional status. Gln homeostasis was not maintained in the aged rats; despite an early increase in muscular GS activity, the Gln pool was depleted. Finally, it seems unlikely that nitrogen and muscle Gln metabolisms are causally related.
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ACKNOWLEDGEMENTS |
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We are indebted to P. Davot in our department and to P. Rousset (B. Beaufrère in the Laboratory of Human Nutrition) for expert technical assistance and to Dr. Meynial-Denis (INRA) for enthusiastic discussions throughout the study and during the drafting of the manuscript. We are also grateful to B. Normand (Statistics Department, Medicine School) for advice on statistical analysis.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for correspondence and reprint requests: R. Minet-Quinard, Laboratoire de Biochimie, Biologie Moléculaire et Nutrition, Faculté de Pharmacie, 28 place Henri-Dunant BP 38, 63001 Clermont-Ferrand cedex 1, France (E-mail: M.-P.Vasson{at}u-clermont1.fr).
Received 30 March 1998; accepted in final form 11 November 1998.
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