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Journal of Nutrition, doi:10.3945/jn.108.086462
Vol. 138, No. 11, 2212-2216, November 2008
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© 2008 American Society for Nutrition J. Nutr. 138:2212-2216, November 2008

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Whey Protein Ingestion Enhances Postprandial Anabolism during Short-Term Bed Rest in Young Men1–3,

Raffaella Antonione4, Elena Caliandro4, Francesca Zorat4, Gianfranco Guarnieri4, Martina Heer5 and Gianni Biolo4,*

4 Department of Clinical, Technological and Morphological Sciences, Division of Internal Medicine, University of Trieste, I-34149 Trieste, Italy and 5 German Space Agency-Institute of Aerospace Medicine, D-51147 Cologne, Germany

* To whom correspondence should be addressed. E-mail: biolo{at}units.it.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Methods
 Results
 Discussion
 LITERATURE CITED
 
We tested the relative ability of rapidly digested whey and slowly digested casein to stimulate net whole-body protein synthesis during prolonged physical inactivity. We studied 8 young male volunteers after they consumed isonitrogenous casein or whey mixed meals on d 12 or d 14 of experimental bed rest. Rates of phenylalanine hydroxylation were measured by primed-constant oral administration of L[2-2H2]tyrosine and L[ring-2H5]phenylalanine for 3 h in the postabsorptive state and 6 h after an isonitrogenous bolus meal containing sucrose (0.27 g/kg) and casein or whey (0.40 g/kg). Net protein synthesis in the fed state was calculated during the first 6 h postmeal as the difference between phenylalanine hydroxylation and phenylalanine content in the ingested casein or whey. In the fed state, the integrated changes in phenylalanine hydroxylation were lower (P < 0.05) after whey (–2 ± 8 µmol·kg–1·6 h–1) than after casein ingestion (34 ± 7 µmol·kg–1·6 h–1). During bed rest, net postprandial protein synthesis was greater (P < 0.05) after whey (96 ± 8 µmol phenylalanine·kg–1·6 h–1) than after casein ingestion (82 ± 7 µmol phenylalanine·kg–1·6 h–1). The rapidly digested whey protein was more efficient than the slowly digested casein in increasing postprandial net protein synthesis during short-term bed rest.


   Introduction
TOP
 ABSTRACT
 Introduction
Methods
 Results
 Discussion
 LITERATURE CITED
 
Rates of body protein synthesis are acutely stimulated by provision of dietary proteins or amino acids (1). However, this process appears to be time dependent and becomes limited despite continued availability of amino acids (1). Bohé et al. (1) infused free amino acids for 6 h to increase their plasma concentrations by 70%. The rate of muscle protein synthesis increased from 30 min to 2 h, then fell rapidly to basal values despite continued amino acid availability. This evidence supports the concept that a pulse-feeding pattern or a rapidly digested protein could induce a greater stimulation of body protein synthesis than a spread-feeding pattern or a slowly digested protein. The milk proteins, whey and casein, are taken as paradigms for quickly and slowly digested proteins, respectively. After whey ingestion, plasma appearance of dietary amino acids is fast, high, and transient, whereas after casein it is slow, low, and prolonged (2,3). However, despite these theoretical considerations, whey ingestion was better than casein at promoting protein anabolism only in old men with lean body mass atrophy (4); in physically active, healthy, young men at rest (5) or after resistance exercise (6), it was not superior to casein. Physical activity has a great impact on the interaction between nutrient ingestion and regulation of body protein kinetics. Synthesis rate of skeletal muscle protein is upregulated for several hours following exercise (7,8), leading to enhanced anabolic efficiency of dietary proteins (9,10). In contrast, anabolic efficiency of hyperaminoacidemia is impaired during inactivity (11). We speculate that physical activity, besides enhancing protein synthesis at any given amino acid level, could prolong the ability of constant hyperaminoacidemia to stimulate protein synthesis. Consequently, the relative ability of whey and casein ingestion to stimulate body protein synthesis would be dependent on physical activity level. To directly assess the influence of reduced physical activity on the ability of whey and casein to promote postprandial anabolism, we studied healthy young volunteers at the end of 12–14 d of experimental bed rest. We used constant oral intake of phenylalanine and tyrosine stable isotopes to determine net whole body protein synthesis during the absorption of isonitrogenous mixed meals based on whey or casein protein (12–14).


   Methods
TOP
 ABSTRACT
 Introduction
 Methods
Results
 Discussion
 LITERATURE CITED
 
    Experimental design. Eight healthy men [aged 26 ± 2 (SEM) y; BMI, 23 ± 2 kg/m2] voluntarily consented to participate in the study at the Clinical Research Center of the German Aerospace Institute, Cologne, Germany. The experimental protocol was approved by the Ethical Committee of the Ärztekammer Nordrhein, Düsseldorf, Germany. Each subject was studied twice at d 12 or d 14 of a 2-wk bed rest period in the postabsorptive state and during the absorption of test meals containing 0.4 g/kg of whey or casein protein and 0.27 g/kg of sucrose. Whey and casein were provided by Nestec. The amino acid compositions of whey and casein were determined by HPLC after hydrolysis (Supplemental Table 1). Whey and casein had similar phenylalanine and tyrosine contents, whereas the leucine content was ~50% greater in whey than in casein. The 14-d bed rest period was preceded by 6 d of adaptation in the DLR-Clinical Research Center. Energy requirements were calculated for each individual according to the FAO/WHO equations (11). Dietary energy content was reduced during the immobilization and the hypocaloric periods. Participants received a specifically prepared diet containing 1.4 or 1.1 times their basal metabolic rate during adaptation and bed rest periods, respectively (11). Ten percent of total energy was added to account for dietary-induced thermogenesis. Subjects received 1 g protein/(kg body weight·d). Dietary fat content was planned to be ~30% of energy. Daily intakes of water, sodium, calcium, and vitamin D were also predefined daily at fixed levels and monitored during the 2 periods. No caffeine, methylxanthine, or alcohol were allowed. Six meals were provided daily, i.e. 3 main meals (breakfast, lunch, and dinner) and 3 snacks. All foods were weighed exactly for each participant, who was asked to consume the complete meal.

On d 12 and 14 of the bed rest periods, 9-h stable isotope tracer studies were carried out in each subject in the postabsorptive state from 0800 to 1700. A polyethylene catheter in a wrist vein was heated to obtain arterialized venous blood. Blood samples were taken before the beginning of isotope administration to determine baseline natural enrichments of L[ring-2H5] phenylalanine, L[ring-2H4]tyrosine, and L[3,3-2H2]tyrosine. Thereafter, oral priming doses of L[ring-2H5] phenylalanine (5 µmol/kg), L[ring-2H4]tyrosine (0.71 µmol/kg), and L[3,3-2H2]tyrosine (1.5 µmol/kg) were administered, followed by hourly oral doses of L[ring-2H5] phenylalanine (5 µmol·kg–1·h–1) and L[3,3-2H2]tyrosine (1.5 µmol·kg–1·h–1). All tracers were obtained from Cambridge Isotopes Laboratory. Oral tracers were dissolved in distilled water. After 3 h, at 1100, a test meal containing 0.27 g/kg of sucrose and 0.4 g/kg of either whey or casein was administered and volunteers were asked to consume it within 10 min. Four subjects received the whey meal on d 12 of bed rest and the casein meal on d 14 of bed rest. The other 4 subjects received the casein meal on d 12 of bed rest and the whey meal on d 14 of bed rest. Blood samples were taken every 30 min during the last 90 min of the postabsorptive period and for 6 h after ingestion of the test meals.

    Analytical methods. Phenylalanine and leucine concentrations in plasma were determined by GC-MS (Agilent HP5973 Mass Spectrometer) using L[1-13C] phenylalanine and L[1-13C] leucine as internal standards (15). Isotopic enrichment of L[ring-2H5] phenylalanine, L[ring-2H4]tyrosine, and L[3,3-2H2]tyrosine in plasma were determined by GC-MS as t-butyldimethylsilyl derivatives (15). GC-MS analyses were performed using electron impact ionization and monitoring mass-to-charge ratio at 234, 239, 336, and 337 for phenylalanine and 466, 468, and 430 for tyrosine. Calculations of tracer:tracee ratios included corrections for background enrichments (within each tracer infusion) and isotopomer contributions (16).

    Calculations. We used the tracer model of phenylalanine and tyrosine metabolism first proposed by Clarke and Bier (17), with adaptations to the postprandial state (12–14). Phenylalanine hydroxylation to tyrosine was computed during the last 60 min before meal administration and after meal ingestion for 3 consecutive 120-min intervals. For each 120-min interval, the mean isotopic enrichments of phenylalanine and tyrosine in plasma were used for calculation (12–14).

Formula

where RD2–Tyr and ED2–Tyr are the L[3,3-2H2]tyrosine administration rate and tracer:tracee ratio in plasma, respectively. ED4–Tyr and ED5–Phe are L[ring-2H4]tyrosine and L[ring-2H5]phenylalanine tracer:tracee ratios in plasma, respectively. Data were presented as changes from baseline. The integrated changes from baseline of phenylalanine hydroxylation were calculated from 0 to 6 h after the meal. This figure was subtracted from phenylalanine intake to obtain phenylalanine incorporation into protein, a measure of net protein synthesis, assuming complete absorption of test meals from 0 to 6 h after the meal.

    Statistical analysis. Results are expressed as means ± SEM. Attainment of plasma isotopic steady state was evaluated in each subject by linear regression analysis. To examine the effects of whey and casein on leucine and phenylalanine concentrations at individual time points, individual curves were standardized by subtracting the mean of the baseline values (–120 to 0 min) from each individual time point. Changes from baseline were analyzed with repeated-measures ANOVA with protein meal (whey/casein) and time as the 2 factors. Post hoc analysis was performed, when appropriate, by t test with Bonferroni's adjustment. In addition, each individual curve was characterized by its zenith (Cmax) and by the area under the curve (AUC). To compare Cmax and AUC between whey and casein, we used paired Student's t tests. We examined the effects of whey and casein meals on phenylalanine hydroxylation during 3 consecutive 120-min intervals, i.e. from 0 to 6 h after a meal. Changes from baseline were analyzed with repeated-measures ANOVA with protein meal (whey/casein) and time as the 2 factors. Post hoc analysis was performed, when appropriate, by t test with Bonferroni's adjustment. Differences between postprandial and baseline values of phenylalanine hydroxylation within each study were assessed by paired t test with Bonferroni's adjustment. Differences between integrated changes from baseline of phenylalanine hydroxylation and balance were assessed by paired t tests. P-values < 0.05 were considered significantly different.


   Results
TOP
 ABSTRACT
 Introduction
 Methods
 Results
Discussion
 LITERATURE CITED
 
Following bed rest, subjects' body weights significantly decreased by ~2%. Body weights were stable on d 12 (75.7 ± 3.3 kg) and 14 (75.8 ± 3.3 kg) of the bed rest periods. During the first 3 h after meal ingestion, postprandial increases in the plasma leucine concentration were much greater after the whey than after the casein meal (Fig. 1A). During the following 3 h, plasma leucine concentrations after the 2 treatments did not differ. At Cmax, plasma leucine concentrations were 66 ± 10% greater following whey ingestion (492 ± 22 µmol/L) than after casein (300 ± 35 µmol/L). The integrated postprandial increase in the leucine concentration (AUC) was significantly greater after consumption of the whey meal (772 ± 32 µmol·L–1·6 h) than the casein meal (436 ± 30 µmol·L–1·6 h). Postprandial increases in plasma phenylalanine concentration (AUC) were much (P < 0.001) lower than those of leucine (Fig. 1B). Peak phenylalanine concentrations (Cmax) did not significantly differ following whey (97 ± 4 µmol/L) and casein ingestion (105 ± 4 µmol/L). The integrated postprandial increase in phenylalanine concentration (AUC) was significantly lower after whey (23 ± 16 µmol·L–1·6 h) than after casein intake (84 ± 10 µmol·L–1·6 h).


Figure 1
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  		FIGURE 1  Plasma leucine (A) and phenylalanine (B) concentrations in young men at d 12 or 14 of bed rest, in the postabsorptive state and after whey or casein mixed meal ingestion (time 0). Values are means ± SEM, n = 8. Changes from baseline were analyzed with repeated-measures ANOVA with protein meal (whey/casein) and time as the 2 factors. Protein meal x time interaction, leucine: P < 0.001, phenylalanine: P = 0.01. §Different from casein, P < 0.004.

 
Tracer:tracee ratios of L[ring-2H5] phenylalanine, L[ring-2H4]tyrosine, and L[3,3-2H2]tyrosine were in near steady-state conditions during the last 60 min before meal consumption and after meal ingestion during 3 consecutive 120-min intervals, i.e. 0–120, 120–240, and 240–360 min (Supplemental Fig. 1). Slopes of individual regression lines relative to data points collected during the last 60 min before meal administration and after meal ingestion during the 3 consecutive 120-min intervals did not significantly differ from 0.

Changes from the postabsorptive state of phenylalanine hydroxylation were computed for 3 consecutive 120-min intervals after whey or casein meal ingestion (Fig. 2). After whey ingestion, phenylalanine hydroxylation increased during the first 120-min interval and decreased below basal values during the second and third 120-min intervals. This suggests a rapid absorption of most of the whey meal during the first 2 h and a prolonged postmeal suppression of phenylalanine hydroxylation. After casein ingestion, phenylalanine hydroxylation increased during the first and second 120-min intervals and did not significantly differ from baseline during the third 120-min interval. This is in agreement with a slower absorption of the casein meal.


Figure 2
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  		FIGURE 2  Phenylalanine hydroxylation in young men at d 12 or 14 of bed rest as changes from the baseline postabsorptive state in consecutive 120-min intervals, after whey or casein meal ingestion. Values are means ± SEM, n = 8. *Different from baseline, P < 0.01. Changes from baseline were analyzed with repeated-measures ANOVA with protein meal (whey/casein) and time as the 2 factors (protein meal x time interaction: P < 0.001). §Different from casein, P < 0.01.

 
The integrated changes from the postabsorptive state of whole-body phenylalanine kinetics were computed during the first 6 h after ingestion of whey or casein meals (Table 1). We assumed complete digestion and absorption of the 2 meals. During meal absorption, changes in phenylalanine hydroxylation were significantly lower after whey than casein intake. Net protein synthesis, calculated from the difference between phenylalanine ingestion and change in hydroxylation, was significantly greater after whey than after casein intake.


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  		TABLE 1 Effects of whey and casein meals on whole-body phenylalanine kinetics in young men after 12 or 14 d of bed rest12

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Methods
 Results
 Discussion
LITERATURE CITED
 
This study was designed to assess the ability of isonitrogenous mixed meals containing either the rapidly digested whey or the slowly digested casein to promote postprandial protein anabolism in healthy, young volunteers during short-term experimental bed rest. We found that whole-body protein synthesis was more stimulated after whey than after casein meal.

We used a constant oral intake of phenylalanine and tyrosine stable isotopes to assess whole-body net protein synthesis in the postprandial states (12–14). We first calculated the rate of phenylalanine hydroxylation to tyrosine and the result was then subtracted from phenylalanine intake to obtain net protein synthesis. This kind of approach has been validated in postprandial conditions against the most-used leucine oxidation method (18). We selected the phenylalanine hydroxylation method, because whey and casein have similar, low phenylalanine contents. In contrast, leucine content in whey is much higher than that in casein (Supplemental Table 1). L[3,3-2H2]tyrosine was used to trace the appearance of L[ring-2H4]tyrosine from L[ring-2H5]phenylalanine hydroxylation. Plasma tracer:tracee ratios were nearly constant in the postprandial state (Supplemental Fig. 1) as a result of low phenylalanine and tyrosine contents in whey and casein (Supplemental Table 1) and of parallel intestinal absorption of enteral tracers and unlabeled amino acids deriving from protein digestion. We therefore applied standard tracer dilution equations to calculate tyrosine appearance from phenylalanine hydroxylation. These equations accurately assess the rate of substrate appearance even in the presence of unlabeled substrate variability, providing that tracer enrichments are nearly constant over time (19). Net protein synthesis was determined over the first 6 postprandial hours assuming complete absorption of test meals. Delayed or incomplete amino acid digestion or absorption would lead to net protein synthesis overestimation. Any delay in casein absorption related to whey would increase the observed differences between the 2 proteins. In the postprandial state, dietary phenylalanine is largely taken up at the first pass by the splanchnic organs (16) and actively hydroxylated in hepatocytes (20,21). Phenylalanine hydroxylation also occurs in the kidney (20,21). Our method does not allow the differentiation of splanchnic from peripheral phenylalanine metabolism. Evidence indicates that assessment of phenylalanine hydroxylation can be affected by the route of tracer administration. In our study, the tracers were given orally, because previous studies (14) have shown that the i.v. route of tracer administration leads to substantial underestimation of phenylalanine hydroxylation in the postprandial state. Assessment of whole-body protein turnover in the postprandial state requires the assessment of fractional splanchnic amino acid uptake (16). Fractional splanchnic uptake of whey-derived phenylalanine could differ from casein-derived phenylanine due to variability in digestion rates of the 2 proteins.

In old men with lean body mass atrophy, previous evidence has shown that whey ingestion was better than casein at promoting protein anabolism (4). In contrast, whey was not superior to casein in physically active, healthy, young men either at rest (5) or after resistance exercise (6). Taken together, previous evidence and our data suggest that the relative ability of whey and casein to stimulate net whole-body protein synthesis is dependent on physical activity level. In addition to the fact that physical inactivity and sedentary lifestyle are closely related to the ageing process, our results suggest that whey ingestion could be beneficial in all conditions of compulsory reduction of physical activity, as observed in many physiological and pathological states. In many orthopedic and neurological diseases, mobility is often seriously impaired or completely abolished. Physical activity is also reduced to a variable extent in many chronic systemic diseases such as coronary artery disease, kidney failure, chronic obstructive pulmonary disease, cancer, depression, arthritis, etc. Human subjects dwelling in a microgravity environment are characterized by muscle unloading rapidly leading to muscle atrophy. Human studies clearly indicate that decreased protein synthesis is the main protein catabolic mechanism associated with muscle inactivity during experimental bed rest (22) and space flight (23). Whey's ability to stimulate whole-body and muscle protein synthesis could represent an effective countermeasure to prevent muscle atrophy associated with physical inactivity and muscle unloading, both in acute and chronic disease states and during space flight and ageing. Further studies examining the long-term effects of whey ingestion on body composition are needed.

Molecular mechanisms responsible for a greater efficiency of whey and/or a lower utilization of casein during experimental bed rest are unclear. The method adopted in our study did not allow accurate quantification of the absolute rates of protein synthesis and degradation. Whey ingestion is associated with sharp increases in plasma leucine concentrations due to fast whey protein digestion and absorption and to a greater leucine content than casein. Leucine has proven direct action on protein synthesis by cooperation with insulin pathway. The crosslink between leucine and insulin pathways occurs at mammalian target of rapamycin and of inhibitor of eukaryotic initiation factor 4e levels (24). Through these mechanisms, leucine may enhance insulin action on either protein synthesis or glucose utilization (24). Resistance to anabolic effects of leucine and amino acids has been previously observed in aging (25,26). This alteration may also involve unloading of skeletal muscle. Amino acid supplements are able to prevent bed rest-induced muscle atrophy (27). Indeed, stimulation of protein synthesis by amino acid administration was blunted in bed-ridden subjects (11). This suggests that amino acid availability becomes critical during bed rest. It is possible therefore that slow-rate delivery of amino acids from casein may be rate-limiting for protein synthesis during inactivity, whereas a higher and more transient elevation of aminoacidemia after whey ingestion could normalize bed rest-induced impairment in protein kinetics.


   ACKNOWLEDGMENTS
 
We thank Mariella Sturma and Anna De Santis for excellent technical assistance.


   FOOTNOTES
 
1 Supported by grants from the German Space Agency, Italian Space Agency, and Nestec Ltd., Research Centre, Lausanne, Switzerland. G. Biolo received research support for this study from Nestec Ltd., Research Centre, Lausanne, Switzerland. Back

2 Author disclosures: R. Antonione, E. Caliandro, F. Zorat, G. Guarnieri, M. Heer, and G. Biolo, no conflicts of interest. Back

3 Supplemental Table 1 and Supplemental Figure 1 are available with the online posting of this paper at jn.nutrition.org. Back

Manuscript received 15 January 2008. Initial review completed 1 March 2008. Revision accepted 29 August 2008.


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 Introduction
 Methods
 Results
 Discussion
 LITERATURE CITED
 

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