Effects of high versus standard essential amino acid intakes on whole-body protein turnover and mixed muscle protein synthesis during energy deficit: A randomized, crossover study

Protein intake recommendations to optimally stimulate muscle protein synthesis (MPS) are derived from dose-response studies examining the stimulatory effects of isolated intact proteins (e.g., whey, egg) on MPS in healthy individuals during energy balance. Those recommendations may not be adequate during periods of physiological stress, specifically the catabolic stress induced by energy deficit. Providing supplemental intact protein (20–25 g whey protein, 0.25–0.3 g protein/kg per meal) during strenuous military operations that elicit severe energy deficit does not stimulate MPS-associated anabolic signaling or attenuate lean mass loss. This occurs likely because a greater proportion of the dietary amino acids consumed are targeted for energy-yielding pathways, whole-body protein synthesis, and other whole-body essential amino acid (EAA)-requiring processes than the proportion targeted for MPS. Protein feeding formats that provide sufficient energy to offset whole-body energy and protein-requiring demands during energy deficit and leverage EAA content, digestion, and absorption kinetics may optimize MPS under these conditions. Understanding the effects of protein feeding format-driven alterations in EAA availability and subsequent changes in MPS and whole-body protein turnover is required to design feeding strategies that mitigate the catabolic effects of energy deficit. In this manuscript, we review the effects, advantages, disadvantages, and knowledge gaps pertaining to supplemental free-form EAA, intact protein, and protein-containing mixed meal ingestion on MPS. We discuss the fundamental role of whole-body protein balance and highlight the importance of comprehensively assessing whole-body and muscle protein kinetics when evaluating the anabolic potential of varying protein feeding formats during energy deficit.

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Essential amino acid-enriched whey enhances post-exercise whole-body protein balance during energy deficit more than iso-nitrogenous whey or a mixed-macronutrient meal: a randomized, crossover study

Journal of the International Society of Sports Nutrition ◽

10.1186/s12970-020-00401-5 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Jess A. Gwin ◽

David D. Church ◽

Adrienne Hatch-McChesney ◽

Jillian T. Allen ◽

Marques A. Wilson ◽

...

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

G Protein ◽

Essential Amino Acid ◽

Muscle Protein ◽

Energy Deficit ◽

Whole Body ◽

Free Form ◽

Protein Balance ◽

Body Protein

Abstract Background The effects of ingesting varying essential amino acid (EAA)/protein-containing food formats on protein kinetics during energy deficit are undetermined. Therefore, recommendations for EAA/protein food formats necessary to optimize both whole-body protein balance and muscle protein synthesis (MPS) during energy deficit are unknown. We measured protein kinetics after consuming iso-nitrogenous amounts of free-form essential amino acid-enriched whey (EAA + W; 34.7 g protein, 24 g EAA sourced from whey and free-form EAA), whey (WHEY; 34.7 g protein, 18.7 g EAA), or a mixed-macronutrient meal (MEAL; 34.7 g protein, 11.4 g EAA) after exercise during short-term energy deficit. Methods Ten adults (mean ± SD; 21 ± 4 y; 25.7 ± 1.7 kg/m2) completed a randomized, double-blind crossover study consisting of three, 5 d energy-deficit periods (− 30 ± 3% of total energy requirements), separated by 14 d. Whole-body protein synthesis (PS), breakdown (PB), and net balance (NET) were determined at rest and in response to combination exercise consisting of load carriage treadmill walking, deadlifts, and box step-ups at the end of each energy deficit using L-[2H5]-phenylalanine and L-[2H2]-tyrosine infusions. Treatments were ingested immediately post-exercise. Mixed-muscle protein synthesis (mixed-MPS) was measured during exercise through recovery. Results Change (Δ postabsorptive + exercise to postprandial + recovery [mean treatment difference (95%CI)]) in whole-body (g/180 min) PS was 15.8 (9.8, 21.9; P = 0.001) and 19.4 (14.8, 24.0; P = 0.001) greater for EAA + W than WHEY and MEAL, respectively, with no difference between WHEY and MEAL. ΔPB was − 6.3 (− 11.5, − 1.18; P = 0.02) greater for EAA + W than WHEY and − 7.7 (− 11.9, − 3.6; P = 0.002) greater for MEAL than WHEY, with no difference between EAA + W and MEAL. ΔNET was 22.1 (20.5, 23.8; P = 0.001) and 18.0 (16.5, 19.5; P = 0.00) greater for EAA + W than WHEY and MEAL, respectively, while ΔNET was 4.2 (2.7, 5.6; P = 0.001) greater for MEAL than WHEY. Mixed-MPS did not differ between treatments. Conclusions While mixed-MPS was similar across treatments, combining free-form EAA with whey promotes greater whole-body net protein balance during energy deficit compared to iso-nitrogenous amounts of whey or a mixed-macronutrient meal. Trial registration ClinicalTrials.gov, Identifier no. NCT04004715. Retrospectively registered 28 June 2019, first enrollment 6 June 2019

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Muscle wasting in emphysema

Clinical Science ◽

10.1042/cs0750415 ◽

1988 ◽

Vol 75 (4) ◽

pp. 415-420 ◽

Cited By ~ 73

Author(s):

W. L. Morrison ◽

J. N. A. Gibson ◽

C. Scrimgeour ◽

M. J. Rennie

Keyword(s):

Protein Synthesis ◽

Protein Turnover ◽

Muscle Wasting ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Myofibrillar Protein ◽

Whole Body ◽

Protein Breakdown ◽

Body Protein ◽

Net Protein

1. We have investigated arteriovenous exchanges of tyrosine and 3-methylhistidine across leg tissue in the postabsorptive state as specific indicators of net protein balance and myofibrillar protein breakdown, respectively, in eight patients with emphysema and in 11 healthy controls. Whole-body protein turnover was measured using l-[1-13C]leucine. 2. Leg efflux of tyrosine was increased by 47% in emphysematous patients compared with normal control subjects, but 3-methylhistidine efflux was not significantly altered. 3. In emphysema, whole-body leucine flux was normal, whole-body leucine oxidation was increased, and whole-body protein synthesis was depressed. 4. These results indicate that the predominant mechanism of muscle wasting in emphysema is a fall in muscle protein synthesis, which is accompanied by an overall fall in whole-body protein turnover.

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Assessing the whole-body protein synthetic response to feeding in vivo in human subjects

Proceedings of The Nutrition Society ◽

10.1017/s0029665120008009 ◽

2021 ◽

pp. 1-9

Author(s):

Jorn Trommelen ◽

Luc J. C. van Loon

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Amino Acid ◽

Protein Intake ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Human Subjects ◽

Whole Body ◽

Body Protein ◽

Breakdown Rates

All tissues are in a constant state of turnover, with a tightly controlled regulation of protein synthesis and breakdown rates. Due to the relative ease of sampling skeletal muscle tissue, basal muscle protein synthesis rates and the protein synthetic responses to various anabolic stimuli have been well defined in human subjects. In contrast, only limited data are available on tissue protein synthesis rates in other organs. Several organs such as the brain, liver and pancreas, show substantially higher (basal) protein synthesis rates when compared to skeletal muscle tissue. Such data suggest that these tissues may also possess a high level of plasticity. It remains to be determined whether protein synthesis rates in these tissues can be modulated by external stimuli. Whole-body protein synthesis rates are highly responsive to protein intake. As the contribution of muscle protein synthesis rates to whole-body protein synthesis rates is relatively small considering the large amount of muscle mass, this suggests that other organ tissues may also be responsive to (protein) feeding. Whole-body protein synthesis rates in the fasted or fed state can be quantified by measuring plasma amino acid kinetics, although this requires the production of intrinsically labelled protein. Protein intake requirements to maximise whole-body protein synthesis may also be determined by the indicator amino acid oxidation technique, but the technique does not allow the assessment of actual protein synthesis and breakdown rates. Both approaches have several other methodological and inferential limitations that will be discussed in detail in this paper.

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Increase in anterior tibialis muscle protein synthesis in healthy man during mixed amino acid infusion: studies of incorporation of [1−13C]leucine

Clinical Science ◽

10.1042/cs0760447 ◽

1989 ◽

Vol 76 (4) ◽

pp. 447-454 ◽

Cited By ~ 158

Author(s):

W. M. Bennet ◽

A. A. Connacher ◽

C. M. Scrimgeour ◽

K. Smith ◽

M. J. Rennie

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Whole Body ◽

Body Protein ◽

Anterior Tibial Muscle ◽

Acid Infusion ◽

Amino Acid Infusion ◽

Anterior Tibial

1. Anterior tibial muscle protein synthesis in seven healthy postabsorptive men was determined from increases in muscle protein bound leucine enrichment during a primed continuous infusion of l-[1−13C]leucine. Biopsies were taken 30 min after the beginning of leucine infusion (when plasma 13C enrichment was steady), 240 min later during continued fasting and again after 240 min of infusion of a mixed amino acid solution which increased plasma total amino acid concentrations by 37%. The mean enrichment of 13C in plasma α-ketoisocaproate was used as an index of the enrichment of the precursor pool for leucine metabolism. 2. Anterior tibial muscle mixed protein synthetic rate during fasting was 0.055 (sd 0.008) %/h and this increased by an average of 35% during infusion of mixed amino acid to 0.074 (sd 0.021) %/h (P < 0.05). 3. Whole-body protein breakdown (expressed as the rate of endogenous leucine appearance in plasma) was 121 (sd 8) μmol h−1 kg−1 during fasting and decreased (P < 0.01) by an average of 12% during amino acid infusion. Leucine oxidation was 18 (sd 3) μmol h−1 kg−1 during fasting and increased (P < 0.001) by 89% during amino acid infusion. Whole-body protein synthesis (non-oxidative leucine disappearance) was 104 (sd 6) μmol h−1 kg−1 during fasting and rose by 13% (P < 0.001) during mixed amino acid infusion. 4. 13C enrichment of muscle free leucine was only 61 (sd 19) % of that in plasma α-ketoisocaproate and this increased to 74 (sd 16) % (P < 0.02) during mixed amino acid infusion. 5. The results suggest that increased availability of amino acids reverses whole-body protein balance from negative to positive and a major component of this is the increase in muscle protein synthesis.

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Addition of glutamine to essential amino acids and carbohydrate does not enhance anabolism in young human males following exercise

Applied Physiology Nutrition and Metabolism ◽

10.1139/h06-028 ◽

2006 ◽

Vol 31 (5) ◽

pp. 518-529 ◽

Cited By ~ 20

Author(s):

Sarah B. Wilkinson ◽

Paul L. Kim ◽

David Armstrong ◽

Stuart M. Phillips

Keyword(s):

Protein Synthesis ◽

Muscle Glycogen ◽

Protein Turnover ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Whole Body ◽

Breakdown Rate ◽

Body Protein ◽

Post Exercise ◽

Glycogen Resynthesis

We examined the effect of a post-exercise oral carbohydrate (CHO, 1 g·kg–1·h–1) and essential amino acid (EAA, 9.25 g) solution containing glutamine (0.3 g/kg BW; GLN trial) versus an isoenergetic CHO–EAA solution without glutamine (control, CON trial) on muscle glycogen resynthesis and whole-body protein turnover following 90 min of cycling at 65% VO2 peak. Over the course of 3 h of recovery, muscle biopsies were taken to measure glycogen resynthesis and mixed muscle protein synthesis (MPS), by incorporation of [ring-2H5] phenylalanine. Infusion of [1-13C] leucine was used to measure whole-body protein turnover. Exercise resulted in a significant decrease in muscle glycogen (p < 0.05) with similar declines in each trial. Glycogen resynthesis following 3 h of recovery indicated no difference in total accumulation or rate of repletion. Leucine oxidation increased 2.5 fold (p < 0.05) during exercise, returned to resting levels immediately post-exercise,and was again elevated at 3 h post-exercise (p < 0.05). Leucine flux, an index of whole-body protein breakdown rate, was reduced during exercise, but increased to resting levels immediately post-exercise, and was further increased at 3 h post-exercise (p < 0.05), but only during the CON trial. Exercise resulted in a marked suppression of whole-body protein synthesis (50% of rest; p < 0.05), which was restored post-exercise; however, the addition of glutamine did not affect whole-body protein synthesis post-exercise. The rate of MPS was not different between trials. The addition of glutamine to a CHO + EAA beverage had no effect on post-exercise muscle glycogen resynthesis or muscle protein synthesis, but may suppress a rise in whole-body proteolysis during the later stages of recovery.

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Rapid measurement of whole body and forearm protein turnover using a [2H5]phenylalanine model

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1989.256.5.e631 ◽

1989 ◽

Vol 256 (5) ◽

pp. E631-E639 ◽

Cited By ~ 36

Author(s):

G. N. Thompson ◽

P. J. Pacy ◽

H. Merritt ◽

G. C. Ford ◽

M. A. Read ◽

...

Keyword(s):

Protein Synthesis ◽

Protein Turnover ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Rapid Assessment ◽

Whole Body ◽

Co2 Production ◽

Constant Infusion ◽

Body Protein ◽

Normal Adults

Whole body protein turnover was measured in six normal adults using a model based on a primed constant infusion of [2H5]phenylalanine and, independently, by an established method of a primed constant infusion of [1-13C]leucine. Isotopic plateau in plasma was achieved within 2 h for [2H5]phenylalanine and, in four of the subjects who received a priming dose of [2H4]tyrosine, for [2H4]tyrosine. In all subjects whole body protein turnover measured with the phenylalanine model (mean protein synthesis, 2.65 +/- (SD) 0.16 g.kg-1.24 h-1; catabolism, 3.58 +/- 0.26 g.kg-1.24 h-1) was similar to that measured using the leucine model (synthesis, 3.09 +/- 0.27 g.kg-1.24 h-1; catabolism, 3.70 +/- 0.35 g.kg-1.24 h-1). Mean forearm fractional muscle protein synthesis calculated by the phenylalanine model was 0.06 +/- 0.03%/h, which compares closely with literature values derived by other methods. The phenylalanine model allows the rapid assessment of whole body and muscle protein turnover from plasma samples alone, obviating the need for measurement of expired air CO2 production or enrichment.

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Skeletal muscle and whole-body protein turnover in cirrhosis

Clinical Science ◽

10.1042/cs0780613 ◽

1990 ◽

Vol 78 (6) ◽

pp. 613-619 ◽

Cited By ~ 71

Author(s):

W. L. Morrison ◽

I. A. D. Bouchier ◽

J. N. A. Gibson ◽

M. J. Rennie

Keyword(s):

Protein Synthesis ◽

Protein Turnover ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Whole Body ◽

Body Protein ◽

Control Subjects ◽

Healthy Control ◽

Cirrhotic Patients ◽

Net Protein

1. We investigated arteriovenous exchanges of tyrosine and 3-methylhistidine across leg tissue in the postabsorptive state as specific indices of net protein balance and myofibrillar protein breakdown, respectively, in eight patients with cirrhosis and in 11 healthy control subjects. Whole-body protein turnover was also measured using l-[1-13C]leucine. 2. Leg efflux of tyrosine was 45% greater in cirrhotic patients than in normal control subjects [−6.5(1.4 to −19.1) vs −4.2 (−2.2 to −7.7) μmol min−1 100 mg−1 of leg, median (range), P <0.025]. 3-Methylhistidine efflux was not significantly altered. 3. In cirrhosis, whole-body leucine flux was normal but whole-body leucine oxidation was elevated so that whole-body protein synthesis was depressed by 17%. 4. The results indicate the predominant mechanism of muscle wasting in cirrhosis to be a fall in muscle protein synthesis, which is accompanied by an overall fall in whole-body protein turnover.

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Comprehensive assessment of post-prandial protein handling by the application of intrinsically labelled protein in vivo in human subjects

Proceedings of The Nutrition Society ◽

10.1017/s0029665120008034 ◽

2021 ◽

pp. 1-9

Author(s):

Jorn Trommelen ◽

Andrew M. Holwerda ◽

Philippe J. M. Pinckaers ◽

Luc J. C. van Loon

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Stable Isotope ◽

Dietary Protein ◽

Protein Metabolism ◽

Muscle Protein ◽

Human Subjects ◽

Whole Body ◽

Body Protein

All human tissues are in a constant state of remodelling, regulated by the balance between tissue protein synthesis and breakdown rates. It has been well-established that protein ingestion stimulates skeletal muscle and whole-body protein synthesis. Stable isotope-labelled amino acid methodologies are commonly applied to assess the various aspects of protein metabolism in vivo in human subjects. However, to achieve a more comprehensive assessment of post-prandial protein handling in vivo in human subjects, intravenous stable isotope-labelled amino acid infusions can be combined with the ingestion of intrinsically labelled protein and the collection of blood and muscle tissue samples. The combined application of ingesting intrinsically labelled protein with continuous intravenous stable isotope-labelled amino acid infusion allows the simultaneous assessment of protein digestion and amino acid absorption kinetics (e.g. release of dietary protein-derived amino acids into the circulation), whole-body protein metabolism (whole-body protein synthesis, breakdown and oxidation rates and net protein balance) and skeletal muscle metabolism (muscle protein fractional synthesis rates and dietary protein-derived amino acid incorporation into muscle protein). The purpose of this review is to provide an overview of the various aspects of post-prandial protein handling and metabolism with a focus on insights obtained from studies that have applied intrinsically labelled protein under a variety of conditions in different populations.

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