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Unité Mixte de Recherche Institut National de la Recherche Agronomique-Institut National Agronomique Paris-Grignon, Physiologie de la Nutrition et du Comportement Alimentaire, Paris, France
2To whom correspondence should be addressed. E-mail: tome{at}inapg.inra.fr.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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KEY WORDS: • Nutrition • protein metabolism • isotope tracer • compartmental model • dietary proteins
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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). During the postprandial phase, the synergistic effects of nutrients and secreted hormones constitute important parameters influencing protein synthesis, breakdown and amino acid oxidation. The rates of these complex processes and the overall final state of equilibrium depend on both the nutritional/physiological status and specific meal composition (2
,3
).
The investigation of protein metabolism in various nutritional and physiological conditions has been made possible by the use of indirect methods, principally based on tracer studies in animals or humans (4
–6
). The relative orientation of both dietary and endogenous (recycled from proteolysis) amino acids between the anabolic and catabolic pathways appears to be the key to understanding the influence of nutrient ingestion on protein kinetics. Because of limited access to the regional and tissue metabolic pools of interest in humans, these investigations have mainly been undertaken at the whole-body level. However, because changes in protein turnover may be concealed at the whole-body level by opposing regional effects, other approaches to quantifying regional metabolism have also been applied with the aim of clarifying the distribution of protein synthesis between different tissues and understanding the clinical significance of whole-body postprandial changes (3
,7
). Last, it is also important to differentiate between dietary and endogenous amino acids recycled from proteolysis in the anabolic and catabolic pathways in different tissues and organs. This paper briefly reviews the methodology, principal results and limitations of the different approaches developed over the past 30 y.
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Tracer steady-state studies of whole-body protein turnover and amino acid metabolism |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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Whole-body steady-state tracer methods |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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,9
) in either a continuous infusion or a single oral dose (10
), followed by the measurement of 15N in urine and blood urea. This method was based on several assumptions, which include the existence of a single metabolic N pool and the possibility of labeling it through the administration of an amino acid tracer; however, this statement has proven to be inaccurate (11
). Although the end-product method has been the subject of methodological criticisms and is little used today, in some situations it represents a practical noninvasive way of estimating nitrogen kinetics, e.g., in frail or sick populations.
The 15N-glycine end-product method has gradually been replaced by the 13C-leucine technique for measuring whole-body protein kinetics. The most commonly used isotopic method is the precursor method, based on the continuous infusion of L-[1-13C]-leucine (12
). The rate of appearance (Ra) of leucine is measured in terms of tracer dilution when enrichment has reached a plateau. Achievement of the plateau is accelerated by the infusion of a primed dose of the tracer. A better estimate of intracellular leucine enrichment is obtained when its 
-ketoacid (ketoisocaproate (KIC)) is considered. The leucine flux from endogenous protein breakdown is calculated from the difference between Ra and intake, whereas the synthesis flux is indirectly assessed from the difference between the rate of disappearance (Ra in the steady state) and oxidative losses of leucine. Leucine oxidation is measured by monitoring 13CO2 excretion. A variant of the latter method is to use L-[ring 2H5]-phenylalanine as a tracer by continuous infusion, and to assess the rate of oxidation by enrichment at the plateau of the product of phenylalanine hydroxylation and its subsequent loss, i.e., L-[2H4]-tyrosine (13
,14
). The total production of tyrosine can concomitantly be monitored by an infusion of L-[2H2]-tyrosine (15
). This technique is analytically easier to perform than the 13C-leucine method.
When investigating the responses of protein metabolism to dietary modulations, these isotopic methods can be applied in either the fasting or the fed state. In the latter case, the constancy of the free amino acid pool required to validate flux calculations means that investigators are forced to feed subjects via either a constant nasogastric infusion of nutrients or the ingestion of small, frequent meals throughout the study period. The possible bias introduced by this constraint will be discussed later. Another approach has been developed to study the specific effects of dietary components on the feeding response, based on an alternate protocol designed by Millward and colleagues (16
,17
). The method involves a three-period, whole-body, steady-state infusion protocol, during which subjects receive a continuous 13C-leucine infusion, first in the fasting state, then while being fed with small meals providing a low protein (LP, 2%) intake for 3 h, and finally receiving an isoenergetic, normal protein intake (NP, 12%) for the last 3 h. The postprandial protein gain is derived from the whole-body turnover, calculated on the basis of leucine kinetics. The transition between the postabsorptive period and the LP period is expected to represent the effect of energy and insulin-mediated processes, whereas the transition from LP to NP is more specifically representative of the effect of protein ingestion.
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Major shortcomings of whole-body tracer steady-state approaches |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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,19
). Alternatives usually lie in measurement of the enrichment of a substrate of the tracer amino acid, more representative of the intracellular precursor pool (-ketoacid for branched-chain amino acids (BCAA)) using whole-body constant infusion techniques (20
). However, the use of KIC probably leads to an underestimation of protein synthesis and, more importantly, causes a bias that is not the same in different types of feeding status (21
). However, this approach is not accurate for other amino acid tracers such as lysine, for which -amino adipic acid constitutes an unsatisfactory surrogate for lysine when determining precursor pool enrichment (22
).
Studies in the steady state are particularly critical when exploring postprandial metabolism. Young and coworkers (23
,24
) observed a more positive fed leucine balance when subjects were given the same amount of dietary protein in three distinct meals rather than a succession of small meals. It has been observed that the artificial fed state obtained in steady-state studies does not produce the same rises in plasma amino acid and insulin levels as those measured after a bolus meal. For instance, plasma leucine or lysine concentrations rise up to 50% over their basal concentrations after a single mixed meal (our unpublished results and Refs. 25
and 26
), compared with increases in the range of 0–20% in the steady state or even a slight fall in concentrations (27
,28
). Under these circumstances, the potent effect of acute increases in the amino acid supply may be diminished or suppressed.
Another important limitation to whole-body isotopic studies lies in the discrepancy between the results obtained using different methodologies and different amino acid tracers, which may lead to differing physiological interpretations of the effects of dietary factors on protein metabolism. Although some comparative studies have shown relatively good agreement between methods and tracers (Fig. 1
) (29
), others have highlighted certain differences (4
,15
,30
). For instance, the effect of increasing the habitual dietary protein level on whole-body protein kinetics in elderly women differed depending on whether the 13C-leucine or 15N-glycine method was used (30
). Even when using same precursor method, the use of 13C-leucine or 2H5-phenylalanine as a tracer to detect the effect of feeding subjects with carbohydrate alone or carbohydrate plus protein have produced discordant results (4
). Interestingly, in this case, feeding a protein-containing meal led to an increase in protein synthesis with phenylalanine as tracer but not leucine, whereas the variations in other fluxes were equivalent between methods. This led to a much greater improvement in the protein balance in the phenylalanine experiment. In this context, the use of whole-body methods to determine the influence of nutritional adaptation on protein kinetics can usefully be associated with other measurements, notably body composition assessment, to enhance the significance of the findings (31
–33
).
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Principal findings of whole-body tracer steady-state approaches |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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End product and precursor methods have successively enabled considerable advances in our knowledge of the dietary modulation of protein turnover at the whole-body level over the past 30 y. One aspect has been the determination of changes to protein kinetics during feeding when compared with fasting. Such investigations have shown that the fast-fed transition is associated with a marked increase in amino acid oxidation and a decrease in whole-body protein breakdown, whereas the effect of feeding on the whole-body protein synthesis rate is less clear and has been shown to be either stimulating or null (for review see Refs. 1
and 34
). The effect of feeding has also been assessed by measuring postprandial protein utilization, demonstrating the differential influences of insulin and amino acids on whole-body protein kinetics (16
) and the influence of the protein source, e.g., wheat or milk protein (28
).
Another important issue that has been investigated by means of whole-body kinetics studies is the changes in protein metabolism seen with chronic low- or high-protein diets in humans. The effects of normal, marginally deficient or surfeit protein intakes on protein kinetics were first shown to be a marked modulation of the amino acid oxidation rate, notably in the fed state (35
,36
). The protein synthesis flux was only partially enhanced when dietary protein levels were sharply elevated, leading to a parallel decrease in the yield of protein utilization. Further studies confirmed these findings (37
–41
). Variations in the balance between protein breakdown and synthesis produce a whole-body increase in the amplitude of daily body protein cycling, i.e., more pronounced fasting losses and higher postprandial repletion, and only a mild effect on the whole-body protein turnover (Fig. 1)
(29
).
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Methods to quantify the regional protein metabolism and turnover in response to nutrient ingestion |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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). Furthermore, a refinement of the mechanisms underlying the stimulation of protein synthesis requires better targeting of the body compartment under study (7
). Consequently, numerous methods have been developed to investigate protein metabolism at the tissue and individual protein levels. |
Arteriovenous balance methods (organ-balance technique) |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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,44
) and humans (25
,45
–47
). These studies emphasized the importance of substrate supply to tissue metabolism, and the specialized roles by various organs in amino acid homeostasis, as well as the possible roles of specific amino acids in regional protein metabolism (48
). These organ-balance studies showed that, in the postabsorptive state, the skeletal muscle exhibits a net negative -amino nitrogen balance, releasing principally alanine and glutamine that are taken up by the tissues of the splanchnic bed, which has a net positive -amino nitrogen balance. After a protein meal, the splanchnic area switches from basal net amino acid uptake to net amino acid release. The splanchnic bed extracts alanine and glutamine but releases to the periphery many other amino acids, such as BCAA, which account for the majority of muscle uptake and play a key role in postprandial muscle protein repletion. With respect to skeletal muscle, the exchange of most amino acids, such as leucine, reverts from the basal net negative balance of the postabsorptive state to a net uptake after ingestion of a mixed meal, despite a continuously net release of alanine and glutamine. The primacy of alanine in the overall hepatic uptake has suggested the importance of this amino acid as the main substrate for liver gluconeogenesis, and BCAA have been indicated as the source of amino groups for alanine and glutamine synthesis by muscle catabolism. |
Methods based on the incorporation of a tracer |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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,7
,49
). The constant infusion method requires steady-state conditions and is classically particularly well suited to measuring the synthesis of proteins with slow turnover rates, such as those in the muscle (7
). This method involves the infusion of a labeled tracer amino acid at a constant rate until steady-state labeling of the precursor pool for protein synthesis is achieved. However, due to the technical difficulties of measuring enrichment in the true precursor pool, i.e., the intracellular amino acyl-tRNA pool, other alternatives have been proposed, which are largely discussed elsewhere (4
,7
). For instance, one alternative to directly measuring the labeling of aminoacyl-tRNA is to measure that of very rapid turnover proteins with an isotopic enrichment quite similar to that of the synthetic precursor pool. This approach has been applied to the mucosa by using the labeling of precursor forms of sucrase and lactase (50
), and to the liver, from the enrichment of apolipoprotein B-100 (51
,52
). Recently, a variant of this method was proposed to determine the albumin fractional synthesis rate under non-steady-state conditions by adjusting the doses of tracer infused to produce stable enrichment of the precursor pool (53
).
The flooding dose method, which involves injecting a large dose of the tracee amino acid together with the tracer amino acid, may avoid the problem of sampling the true precursor pool, because it minimizes the differences in isotopic enrichment between the extracellular, intracellular and amino acyl-tRNA pools (54
). Furthermore, the flooding dose method enables rapid measurements because it rapidly increases the labeling of the intracellular amino acid pool (7
), thus allowing the determination of tissue protein synthesis under acute, non-steady-state conditions of feeding (55
) and hormone infusion (56
). The flooding dose method is recommended for the measurement of protein synthesis in tissues with rapid turnover rates and/or high secretory contributions to their protein synthetic activity, such as proteins of the splanchnic bed (7
). However, the large dose of the tracee amino acid that needs to be injected with this method is thought to alter protein synthesis, as extensively discussed elsewhere (4
,7
,57
,58
). In humans, the synthesis of muscle proteins has been widely studied using either the constant infusion method (59
,60
) or the flooding-dose technique (61
). Despite the fact that protein synthesis rates of liver-exported plasma proteins have frequently been studied in humans using either the constant infusion method (59
) or the flooding-dose technique (62
,63
), the protein synthesis of splanchnic constitutive proteins has been the subject of little investigation, particularly in the fed state (64
,65
), because such studies require direct access to gut and liver tissues, thus raising important technical and/or theoretical difficulties and entailing potential risks (66
). The studies that have been performed revealed the broad differences between protein synthesis rates in different tissues and specific proteins, which are slower in skeletal muscle and much more rapid in the gut and liver. They also emphasized the variability in the response of the different proteins pools to the ingestion of a mixed meal (Table 1
).
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Combined methods (arteriovenous catheterization with isotopic tracer) |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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,48
,67
). It is achieved by combining repeated measurements of the tracee and tracer balances across the tissues under investigation, the first being proportional to protein synthesis whereas the second measures the difference between protein synthesis and degradation (4
,67
). Compared with the tracer incorporation method, the organ-balance tracer approach has the advantage of providing information on the relative rates of both protein synthesis and degradation in specific organs and tissues. Another advantage of the tracer balance technique is its dynamic nature, because it allows measurement of the changes in amino acid uptake and protein turnover over relatively short periods of time (67
). This is a highly significant advantage to the design of studies focusing on acute nutritional or hormonal effects (68
–70
). However, the invasive tracer balance approach shares the same problem when determining the isotopic enrichment of the protein synthetic precursor pool as the continuous infusion technique. Moreover, some technical problems have been encountered using the tracer balance approach. For instance, although the accurate measurement of blood flow is of crucial importance for determining the net balance of both the tracee and the tracer, there is no consensus in the literature as to whether plasma or whole-blood measurements are preferable. In addition, the siting of the venous catheter is particularly critical when measuring muscle protein turnover by catheterization of the forearm or leg (4
,67
). The organ-balance tracer technique (sometimes applied in conjunction with sampling of the tissue under study for direct measurements of amino acid labeling) has been applied to the study of protein turnover in the intestine and liver of animals (51
,71
,72
), and in the splanchnic bed (73
,74
) and leg muscle of humans (60
,68
,73
,74
).
Compartmental analysis of organ-balance tracer data has provided new estimates of protein and amino acid kinetics across the human muscle under steady-state conditions. Thus, a six-compartment model for the intracellular muscle kinetics of leucine and KIC in the human forearm was developed (75
) and used to evaluate muscle protein synthesis and degradation under different nutritional conditions (74
,76
). Similarly, a three-compartment model describing the leg muscle kinetics of various amino acids (77
) has been used in humans to estimate muscle protein synthesis and breakdown under various nutritional conditions (60
,70
,78
). These models have also enabled calculations of the rate of inward (from artery to muscle) and outward (from muscle to vein) amino acid transport, and have demonstrated that infused or ingested amino acids are capable of stimulating muscle protein anabolism by enhancing intracellular amino acid transport and protein synthesis. They have also been able to take account of the reutilization of amino acids derived from proteolysis for protein synthesis, thus overcoming a classical limitation to the organ-balance tracer technique (i.e., recycling of the tracer) (4
).
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Principal findings and methodological limits |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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The ingestion of a protein meal, inducing hyperaminoacidemia and hyperinsulinemia, has been shown to have an anabolic effect on muscle proteins in humans. However, controversy continues as to whether this anabolic effect is accomplished via increased protein synthesis and/or decreased protein breakdown (70
,79
–82
). In addition, the isolated and/or concomitant contribution of hormonal and substrate factors to protein anabolism still requires clarification (42
,83
,84
). Isolated hyperinsulinemia seems to reduce muscle protein breakdown, but it does not stimulate muscle protein synthesis (73
,85
), which in turn is enhanced by hyperaminoacidemia (78
) or by concomitant hyperinsulinemia and hyperaminoacidemia (86
). BCAA seem to play a special role in promoting postprandial muscle anabolism, and their anabolic effects on muscle tissues have been demonstrated in humans after the infusion of a BCAA-enriched, aromatic amino acid-deficient amino acid mixture in the concomitant presence of insulin (76
). Increasing evidence suggests that splanchnic tissue may be intimately involved in the increase in protein synthesis associated with insulin secretion (87
), because any acute hormonal effect would have an earlier impact on fast, rather than slow, turnover proteins (42
). Indeed, protein synthesis in the gut is enhanced after a mixed protein meal, and this increase has been found to be related to the postmeal insulin response (88
) and depend upon the quality of the protein ingested (72
). Similarly, albumin synthesis has been reported to be regulated by insulin and enteral amino acids (42
,83
,87
,89
). It is believed that the splanchnic anabolic processes allow the sparing of dietary nitrogen from deamination through the temporary "storage" of ingested amino acids in the labile splanchnic protein pool (52
,71
,87
,90
,91
) whereas simultaneously buffering peripheral tissues from excessive changes to free amino acid concentrations (90
,92
,93
). Recent advances in our understanding of the splanchnic interorgan transfer and metabolism of dietary amino acids in the fed state were made in animal models (51
,52
,71
,94
), indicating that mucosal metabolism may dominate overall splanchnic utilization. However, despite the nutritional and clinical implications of the quantitative importance of the intestine and liver to the splanchnic metabolism of dietary amino acids, this question remains unanswered in humans because of major technical and ethical difficulties (63
–66
).
It is remarkable that no consensus has been reached concerning the "true" values of protein synthesis and protein degradation in the different protein pools during the postabsorptive state and in response to nutrition, despite the vast amount of literature and the different techniques that have been applied to their study (67
). The discrepancies in values in the literature concerning protein turnover in response to nutrition may result to some extent from the variety of nutritional conditions studied and the different methods and tracers used (95
). Reasons for these discrepancies can also be found in theoretical limitations to the interpretation of tracer balance data as indices of protein synthesis and breakdown (84
). This lack of consensus thus mainly reflects the fact that protein dynamics have been measured indirectly using a variety of isotopic approaches, because these processes occur in inaccessible compartments that are metabolically and kinetically compartmentalized in some tissues (67
). Indeed, splanchnic tissues receive amino acids and other nutrients from two extracellular sources (the intestinal lumen and mesenteric artery for the mucosa; the portal vein and hepatic artery for the liver), and the preferential use of dietary amino acids for splanchnic anabolism has been demonstrated in both animals (51
,52
,96
) and humans (97
,98
).
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Methods enabling a differentiation between dietary and recycled amino acid metabolism |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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Multiple-tracer studies to quantify the splanchnic extraction of dietary amino acids |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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) and fed states under steady-state conditions, i.e., either after the constant intragastric (38
,100
) or intraduodenal (101
) administration of a meal or after repetitive small boluses (70
,102
–104
). These studies indicated the important first-pass splanchnic uptake and metabolism of dietary amino acids. The degree of splanchnic metabolism varies for different dietary amino acids, with values ranging from 20% (leucine) to >50% (phenylalanine) of amino acid intake. |
Studies to assess the metabolic utilization of recycled and dietary amino acids |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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). This model was adapted from the non-steady-state equations developed by Steele, initially used to assess glucose kinetics (106
). To summarize, this method is based on the administration of a single protein meal containing 2H3-leucine, together with the intravenous infusion of 13C-leucine and the subsequent measurement of total and dietary leucine Ra and the calculation of endogenous leucine Ra (reflecting protein breakdown). As during whole-body steady-state studies, leucine oxidation is calculated from 13CO2 production and protein synthesis is derived from leucine nonoxidative disposal. The main advantage of this approach is that it accounts for time-dependent changes in the plasma leucine pool and monitors the postprandial evolution of protein synthesis and breakdown, estimating the postprandial leucine balance in a much more physiological context. The results obtained so far have allowed a distinction between different protein "behaviors": slow (casein) or fast (whey protein), associated with different protein postprandial gains (107
). Another investigation proved that the discrepancy between these two protein sources was attributable to their different digestion rates rather than their amino acid composition, emphasizing the importance of the postprandial kinetic aspects of protein metabolism (108
). However, this point should also be assessed in the situation of a mixed meal, where the impact of protein type on the digestion rate may be less pronounced. These data also provide results that conflict with those of steady-state studies, insofar as they show that a bolus meal tends to stimulate protein synthesis with little effect on protein breakdown when compared with the same protein intake given in small hourly meals (108
).
To better understand the in vivo metabolism of dietary proteins and their interactions with both other components of a meal and the nutritional status of subjects, another method has been applied which measures the whole-body retention of dietary nitrogen under normal conditions of feeding, i.e., after the ingestion of a single meal (109
). The protocol involves an 8-h study period with blood sampling and urine collection after subjects have ingested a standard meal containing uniformly and intrinsically 15N-labeled protein. The bioavailability of dietary protein is also monitored by the insertion of an ileal tube that enables calculation of that part of ingested protein that is not digested. Total and dietary nitrogen deamination is calculated from the cumulative urinary nitrogen excretion and variations in the body urea pool size. This approach made it possible to demonstrate differences in postprandial nitrogen retention according to the protein source (109
), the protein fraction (110
) and the nature of other nutrients in the meal (111
–113
) (Table 2
). These data underline the poor predictive value of amino acid scoring patterns to the prediction of dietary protein utilization in vivo. In other respects, a recent series of studies performed in our laboratory has addressed the question of the influence of habitual dietary protein levels on dietary nitrogen metabolism in humans. The results indicated that high-protein diets probably produce a greater enhancement of dietary protein retention than total feeding protein gain. We therefore hypothesized that dietary amino acids made a greater contribution to synthesis pathways when the protein intake is chronically increased (C. Morens, G. Bos, C. Gaudichon, D. Tome, unpublished results). In other words, if the protein intake rises, there may be changes to the participation of recycled endogenous amino acid in protein turnover, with possible adjustment of the dietary amino acid pattern required to sustain amino acid maintenance needs in high protein diets.
|
,115
). A dynamic picture of the postmeal transfers of dietary nitrogen to splanchnic tissues, individual amino acids and peripheral tissues was drawn. These studies have also enabled considerable progress in our understanding of the regulation of protein metabolism in cases of elevated protein intakes. Indeed, adaptive changes in the postprandial metabolism of dietary nitrogen almost exclusively concern the splanchnic zone, which seems to be the main compartment responsible for the higher postprandial protein gain seen in situations of higher protein intakes (Fig. 2
).
|
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Compartmental modeling of regional dietary N distribution and metabolism in the postprandial non-steady state in humans |
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|
TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
|---|
). It consists of a linear, 11-compartment model that was developed on the basis of experimental data concerning 15N kinetics in the ileum, blood and urine in healthy adults fed a single 15N-labeled milk protein meal (Fig. 3
). This modeling tool provides insight into the dynamics of dietary nitrogen absorption, elimination and distribution throughout the body in the postprandial non-steady state. In particular, it enables dynamic simulation of the partitioning of dietary nitrogen in metabolic pools that had not previously been experimentally monitored. This model therefore provides data relevant to our understanding of dietary nitrogen metabolism that are not dependent upon interpreting the results of animal studies. It has helped to clarify how the energy content of a meal and the type of protein ingested can modulate the regional metabolic fate of dietary nitrogen and its postprandial partitioning between splanchnic and peripheral organs, governed by amino acid absorption kinetics and the insulin response (117
,118
). This was achieved through compartmental analysis of various experimental data obtained after the ingestion of a single meal composed of milk protein with fat, milk protein with sucrose or soy protein with sucrose (Table 3
). The addition of sucrose to a pure milk protein meal, which induced acute hyperinsulinemia, was predicted to enhance the splanchnic extraction and incorporation into splanchnic proteins of dietary nitrogen, thus causing a reduction in peripheral dietary amino acid availability and use for anabolic purposes (117
). In contrast, the addition of fat to a pure milk protein meal was predicted to enhance the splanchnic dietary nitrogen anabolism in only a transient fashion, without significantly affecting the global kinetics of splanchnic retention and peripheral uptake (117
). Moreover, the model made it possible to determine that the lower whole-body retention of dietary nitrogen observed experimentally with the mixed soy rather than the mixed milk protein meal was associated with i) the more rapid intestinal transit and absorption of dietary nitrogen from soy protein, ii) its increased transfer to urea concurrently with its similar sequestration in the splanchnic bed and iii) its subsequent reduced uptake by the peripheral area (118
). In addition, the protein synthesis efficiency of dietary nitrogen (i.e., its rate of incorporation into protein divided by its Ra in the precursor free amino acid pool) was stimulated in the splanchnic bed and reduced in the peripheral area after soy protein. This suggested that the region-specific anabolic response may be sensitive to the kinetics of dietary nitrogen absorption and appearance in free amino acid pools and/or the amino acid composition of dietary protein (118
). Such a model thus enables description of the processes involved in the differential metabolic utilization of dietary proteins and constitutes a valuable tool to further define the notion of protein quality during the period of protein gain.
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Conclusion |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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). Methodologically speaking, the techniques used at present need to be improved to address directly the still unresolved questions. Organ-balance studies allow determination of the net organ balance of amino acids, without discriminating between dietary and endogenous amino acid metabolism, whereas multiple tracer methods address the splanchnic extraction of dietary amino acid without making a distinction between that part used for protein synthesis and the remaining deaminated part of the splanchnic uptake (92
,102
). The difficulties encountered in establishing the underlying mechanisms of sarcopenia well illustrate the limitations of the current approaches in the context of understanding regional protein metabolism. The measurement of fluxes at the whole-body, organ or protein levels is probably insufficiently specific to accurately detect any chronic slight dysfunction in the normal pattern of daily protein depletion-repletion cycling. In particular, the widespread use of leucine in whole-body studies to quantify protein kinetics in response to dietary modulations might be called into question in view of the limited metabolism of this amino acid in the splanchnic zone, which is of crucial importance to postprandial protein accretion.
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FOOTNOTES |
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3 Abbreviations used: BCAA, branched-chain amino acid; KIC, ketoisocaproate; LP, low protein; Ra, rate of appearance; tRNA, transfer RNA.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONTracer steady-state studies of...Whole-body steady-state tracer...Major shortcomings of whole-body...Principal findings of whole-body...Methods to quantify the...Arteriovenous balance methods...Methods based on the...Combined methods (arteriovenous...Principal findings and...Methods enabling a...Multiple-tracer studies to...Studies to assess the...Compartmental modeling of...ConclusionLITERATURE CITED |
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