Update on maximal anabolic response to dietary protein

doi:10.1016/j.clnu.2017.05.029

Clinical Nutrition

Volume 37, Issue 2, April 2018, Pages 411-418

https://doi.org/10.1016/j.clnu.2017.05.029 Get rights and content

Summary

The anabolic response to dietary protein can be defined as the difference between protein synthesis and breakdown, or the net protein balance, in response to ingestion of protein alone or a mixed meal containing protein. Others have concluded that a maximal anabolic response can be achieved with ingestion of 20–35 g of a high quality protein, leading to the formulation of a popular concept that the maximal anabolic response can be achieved by distributing the total protein intake evenly throughout the day, rather than eating a majority of dietary protein with dinner. However, this concept was based entirely on the measurement of muscle protein synthesis and thus ignored the potential contributions of suppression of protein breakdown to the anabolic response, as well as the possibility that tissues and organs other than muscle may also play a role in the anabolic response. In this review we discuss the factors comprising the total anabolic response, discuss relevant methodological issues, derive a theoretical maximal anabolic response based on current literature values, and interpret recent papers addressing the issue of maximal anabolic response as well as meal distribution of dietary protein. We conclude that it is not likely that there is a practical limit to the maximal anabolic response to a single meal, and the most efficient way in which to maximize the total anabolic response over a 24-h period is to increase dietary protein at breakfast and lunch without reducing protein intake with dinner.

Introduction

Dietary protein intake serves many physiological roles, but the most prominent is the maintenance or gain of body protein stores. This is accomplished by stimulation of protein synthesis, the inhibition of protein breakdown, or a combination thereof. A net gain in protein balance (i.e., synthesis minus breakdown) is called an anabolic response, as opposed to a catabolic response caused by the rate of protein breakdown exceeding the rate of protein synthesis. An anabolic response usually refers to gain of muscle protein, but can involve the entire body. Optimal protein nutrition in an individual meal could be defined as the minimal amount of protein intake that results in the maximal anabolic response, as that will be the most likely approach to maintaining or increasing lean body mass (LBM) over time. Consumption of dietary protein in excess of the amount needed to elicit the maximal anabolic response could be considered excessive, since no further stimulation of the net gain of body protein can occur. Consequently, determining the amount of dietary protein needed to elicit the maximal anabolic response is directly relevant to defining the “optimal” amount of dietary protein in a meal. Determining the optimal amount of dietary protein in a meal involves quantification of the rates of protein synthesis, breakdown, and the balance between synthesis and breakdown in response to dietary protein in the context of a complete mixed meal. There is presumably a limit to the extent to which protein synthesis can be stimulated by dietary protein intake, and protein breakdown cannot be suppressed to less than zero. Therefore, there must be some level of protein intake beyond which no further gains in net balance can occur, which we will define as the maximal anabolic response.

It has been postulated that the maximal anabolic response can be elicited with intake of 20–35 g of high quality protein solely based on the stimulation of muscle protein synthesis (MPS) [1]. If true, this would mean that the typical, uneven distribution of dietary protein intake in the American diet results in considerable excessive protein consumption in the dinner meal, as the average protein intake at dinner may be as much as 40 g or more [2]. As a consequence, it has been proposed that the anabolic response to protein intake would be improved if the traditional pattern of the American diet in which approximately half of dietary protein is consumed at dinner were altered so that daily intake of protein is more evenly distributed throughout breakfast, lunch and dinner. In this paper we will examine the validity of this perspective within the practical range of protein intake (i.e., the Acceptable Macronutrient Distribution Range or AMDR, 10–35% of daily calorie intake). In that context we will discuss if the maximal anabolic response to dietary protein is important physiologically, the physiological determinants of the net anabolic response, and the methodologies that have been used to evaluate the “even distribution” hypothesis. We will discuss relevant experimental data from studies performed in human subjects, including consideration of the difference between the responses to pure protein intake as opposed to intake of a protein-containing mixed meal. Finally, we will conclude that, based on currently-available data, there is no practical limit to the anabolic response to dietary protein intake at least within the range of AMDR in a single meal. Further, we conclude that the total amount of dietary protein over the day is more relevant to the total anabolic response to dietary protein than the distribution of intake over the course of the day. From a practical standpoint this conclusion can most readily be incorporated into daily nutritional pattern by increasing the amount of dietary protein as part of breakfast and lunch without diminishing the amount of dietary protein eaten at dinner.

Section snippets

Is a maximal anabolic response important? Implications for health and disease

The anabolic response in the fed state affects protein mass in many tissues and organs, but prominently involves repletion of skeletal muscle proteins lost in the post-absorptive or fasting state. The issue is thus important in maintaining or increasing skeletal muscle mass. In the fasted state the net breakdown of muscle protein (i.e., protein breakdown exceeding protein synthesis) provides amino acids into the circulation. The transient increase in muscle protein breakdown (MPB) in the

The balance between protein synthesis and breakdown: the metabolic determinants of the anabolic responses

Changes in muscle protein mass are a consequence of net changes in anabolic or catabolic responses to factors including nutritional intake, hormonal milieu, physical exercise, starvation, inflammation, and more serious physiological stress such as sepsis or trauma. Changes in muscle mass are most conventionally considered the primary target of anabolic and catabolic responses, although imbalances between protein synthesis and breakdown can occur in many body tissues and organs to some extent.

Methodological considerations in determination of the anabolic response

There are various methods that estimate anabolic responses to dietary protein at the muscle and the whole body levels in response to a single meal or over the course of an entire day [5], [7]. We will discuss representative stable isotope tracer methods for exploring anabolic responses at the muscle and the whole-body levels. It has been shown that the tracer methods to quantify protein kinetics (protein synthesis, protein breakdown, and net protein balance) in response to dietary protein in

Relation of the anabolic response at the muscle level to the total whole body response

The determination of the anabolic response to dietary protein intake at the muscle level is obviously important, since muscle is a major fate of EAAs absorbed from dietary protein. However, tissues other than muscle account for more than half of the total protein turnover [21], [22]. Consequently, determination of the anabolic response at the muscle level could underestimate total anabolic response. Figure 1 illustrates schematically the potential role of protein turnover in the gut on the

Role of insulin in the anabolic response

The maximal anabolic response at the muscle level has been determined in many studies in response to the consumption of a pure protein [26], [27], [28]. The maximal anabolic response to dietary protein is complicated when considered in the context of a mixed meal, in part because of the impact of an increase in insulin concentration resulting from the meal intake. Ingestion of certain proteins and amino acids can stimulate insulin release, but the effect of carbohydrate intake on insulin

Role of intracellular EAA availability in the anabolic response

Although insulin suppresses protein breakdown, it is likely that there is an upper limit to this response. In accordance with this notion, it has been shown that no further suppression of leg muscle protein breakdown occurred at insulin concentration beyond 30 μ IU/ml [32]. However, it is likely that insulin cannot entirely explain the suppression of protein breakdown in response to a meal. We have previously shown that consumption of 70 g of dietary protein resulted in a greater reduction in

Is there a maximal anabolic response?

We previously presented data supporting the perspective that the maximal total anabolic response increases linearly in relation to the amount of amino acid or protein intake [18], [19], [33], [34], [35]. These data did not show a plateauing in the gain in the net balance between protein synthesis and breakdown as the amount of intake increased. It is reasonable to assume that there must be some upper limit to the anabolic response to the amount of dietary protein in one meal. There is some

Does meal distribution of dietary protein matter?

Consumption of dietary protein or EAA stimulates MPS in a dose-dependent manner to a point, but at higher levels of intake the extent of stimulation of MPS plateaus (e.g., Refs. [26], [27], [28]). The minimum dose of dietary protein (eaten as pure protein) that stimulates a near maximal stimulation of MPS is 20–35 g protein [41], [42] or more specifically 0.24–0.40 g/kg/meal depending on the quality of protein and individuals' age [25]. The conclusion that these values represent the maximal

Summary and conclusions

The limit of the stimulation of MPS has been studied extensively, but little attention has been given to the suppression of protein breakdown at higher rates of protein intake. It has been reported that a maximal MPS response is achieved with 20–35 g of a high quality protein [41], [42], or more specifically 0.24 g/kg/meal for young and 0.40 g/kg/meal for older adults [25]. This has been promoted as the maximal anabolic response [1]. However, this conclusion ignores the potential contribution

Author contributions

I.-Y.K. and R.R.W. drafted manuscript; I.-Y.K., N.E.D., and R.R.W. discussed, edited and approved the final manuscript.

Conflicts of interest

Dr. Wolfe has received research grants and/or honoraria from the National Cattleman's Beef Checkoff program, Abbott Nutrition Pronutria, and PepsiCo; Dr. Deutz has received research grants and honoraria from Abbott Nutrition. Dr. Kim has no potential conflicts of interest.

Acknowledgements

This project was financially supported by Pepper Center Grant PG30-AG-028718 and Award Number UL1-TR-000039 and KL2-TR-000063 from the National Center for Advancing Translational Sciences (NCATS).

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Dose-Response of Myofibrillar Protein Synthesis To Ingested Whey Protein During Energy Restriction in Overweight Postmenopausal Women: A Randomized, Controlled Trial
2023, Journal of Nutrition
Diet-induced weight loss is associated with a decline in lean body mass, as mediated by an impaired response of muscle protein synthesis (MPS). The dose-response of MPS to ingested protein, with or without resistance exercise, is well characterized during energy balance but limited data exist under conditions of energy restriction in clinical populations.
To determine the dose-response of MPS to ingested whey protein following short-term diet-induced energy restriction in overweight, postmenopausal, women at rest and postexercise.
Forty middle-aged (58.6±0.4 y), overweight (BMI: 28.6±0.4), postmenopausal women were randomly assigned to 1 of 4 groups: Three groups underwent 5 d of energy restriction (∼800 kcal/d). On day 6, participants performed a unilateral leg resistance exercise bout before ingesting either a bolus of 15g (ERW15, n = 10), 35g (ERW35, n = 10) or 60g (ERW60, n = 10) of whey protein. The fourth group (n = 10) ingested a 35g whey protein bolus after 5 d of an energy balanced diet (EBW35, n = 10). Myofibrillar fractional synthetic rate (FSR) was calculated under basal, fed (FED) and postexercise (FED-EX) conditions by combining an L-[ring-¹³C₆] phenylalanine tracer infusion with the collection of bilateral muscle biopsies.
Myofibrillar FSR was greater in ERW35 (0.043±0.003%/h, P = 0.013) and ERW60 (0.042±0.003%/h, P = 0.026) than ERW15 (0.032 ± 0.003%/h), with no differences between ERW35 and ERW60 (P = 1.000). Myofibrillar FSR was greater in FED (0.044 ± 0.003%/h, P < 0.001) and FED-EX (0.048 ± 0.003%/h, P < 0.001) than BASAL (0.027 ± 0.003%/h), but no differences were detected between FED and FED-EX (P = 0.732) conditions. No differences in myofibrillar FSR were observed between EBW35 (0.042 ± 0.003%/h) and ERW35 (0.043 ± 0.003%/h, P = 0.744).
A 35 g dose of whey protein, ingested with or without resistance exercise, is sufficient to stimulate a maximal acute response of MPS following short-term energy restriction in overweight, postmenopausal women, and thus may provide a per serving protein recommendation to mitigate muscle loss during a weight loss program.
clinicaltrials.gov (ID: NCT03326284).
Comparison of short-term hypocaloric high-protein diets with a hypocaloric Mediterranean diet: Effect on body composition and health-related blood markers in overweight and sedentary young participants
2021, Nutrition
Citation Excerpt :
The calculation of protein intake used kilograms of FFM instead of kilograms of body mass because FFM is more metabolically active than fat tissue [25]. In addition, protein intake per meal did not exceed 20 to 30 g in either the HP or HPW group, as previously proposed [26]. Accordingly, the HP and HPW diets consisted of, respectively, 43.6% ± 2.3% and 44.1% ± 2.3% carbohydrates, 27.4% ± 0.9% and 27.2% ± 0.9% fats, 28.7% ± 1.9% and 28.9% ± 1.4% protein (no significant differences between groups, P > 0.05).
The aim of the present study was to compare the short-term effects of a hypocaloric Mediterranean diet and two high protein diets, with and without whey protein supplementation, on body composition, lipidemic profile, and inflammation and muscle-damage blood indices in overweight, sedentary, young participants.
Thirty-three young, overweight, male and female participants (mean ± SD age: 22.8 ± 4.8 y; body mass: 85.5 ± 10.2 kg; body fat percentage: 34.3% ± 8.1%) were randomly allocated to three different hypocaloric (−700 kcal/d) diets: a Mediterranean diet (MD; n = 10), a high-protein diet (HP; n = 10) diet, and a high-protein diet with whey supplementation (n = 10). The intervention lasted 6 wk. Body composition and biochemical indices were evaluated 1 wk before and after the nutritional interventions.
Body and fat mass were decreased in the MD and HP groups (−3.5% ± 1.1% and −5.9% ± 4.2% for body and fat mass respectively in MD, and −1.7% ± 1.2% and −2.0% ± 1.8% for body and fat mass respectively in HP;P < 0.05), with no significant decline of fat-free mass observed in the MD group. The MD group's diet beneficially altered the lipid profile (P < 0.05), but the HP and HPW groups’ diets did not induce significant changes. Subclinical inflammation and muscle-damage indices significantly increased in the HP and HPW groups (7.4% ± 3.5% and 66.6% ± 40.1% for neutrophils and CRP respectively in HP, and 14.3% ± 6.4% and 266.6% ± 55.1% for neutrophils and CRP respectively in HPW; P < 0.05) but decreased in the MD group (1.8% ± 1.2% and −33.3% ± 10.1% for neutrophils and CRP respectivelyc; P < 0.05). Energy intake of carbohydrates and proteins were significantly related to the changes in body composition and biochemical blood markers (r = −0.389 and −0.889; P < 0.05).
Among the three hypocaloric diets, only the Mediterranean diet induced positive changes in body composition and metabolic profile in overweight, sedentary individuals.
Association between meal-specific daily protein intake and lean mass in older adults: results of the cross-sectional BASE-II study
2021, American Journal of Clinical Nutrition
Adequate total and meal-specific protein intake is considered an important prerequisite to preserve appendicular lean mass (ALM) in older adults and to prevent sarcopenia.
We analyzed the meal-specific protein intake across the main meals between participants with normal vs. low ALM to BMI ratio (ALM_BMI).
782 participants [59.6% men; median 69 (IQR: 65, 71) y] of the Berlin Aging Study II have been included in this analysis. ALM was assessed by dual X-ray absorptiometry. Low lean mass was defined as ALM_BMI using recommended sex-specific cut-offs. A 5-day nutritional protocol was used to assess total and meal-specific protein intake.
Median total protein intake was 0.89 (IQR: 0.74, 1.05) g/kg/d body weight (BW) in participants with low ALM_BMI and 1.02 (IQR: 0.86, 1.21) g/kg BW in participants with normal ALM_BMI (P < 0.001). Daily protein intake at breakfast was similar in both groups [0.23 (95% CI: 0.20, 0.26) vs. 0.24 (95% CI: 0.23, 0.26) g/kg BW; P = 0.245]. Subjects with low ALM_BMI reported a lower protein intake at lunch and dinner compared with those with normal ALM_BMI [0.29 (95% CI: 0.27, 0.32) vs. 0.35 (95% CI: 0.34, 0.36) g/kg BW; P = 0.001 and 0.32 (95% CI: 0.30, 0.35) vs. 0.36 (95% CI: 0.35, 0.37) g/kg BW; P = 0.027, respectively]. In a stepwise regression model, a higher total protein intake was positively associated with ALM_BMI [ß = 0.10 (95% CI: 0.07, 0.13) P < 0.001]. The protein intake at dinner was positively associated with ALM_BMI [ß = 0.14 (95% CI: 0.08, 0.19) P < 0.001] irrespective of protein intake at breakfast and lunch. This association disappeared after additional adjustment for total protein intake.
Our data highlight an association of total protein intake and ALM_BMI in older adults. Although current data support an association of high ALM_BMI with protein intake at dinner in particular, this was not independent from total protein intake and the findings do not allow a conclusion on causality.
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
2021, Clinical Nutrition
Citation Excerpt :
Further increases in EAA availability impart no additional MPS-specific advantage; rather the effects are directed to the improvement of NET at the whole-body level. The greater NET with the higher dose of EAA may be attributed to a reduced reliance on PB-derived precursor amino acids to support PS in non-muscle tissue [44]. These findings are also supported by evidence indicating that amino acids inhibit PB in a dose-dependent manner in the splanchnic region independent of insulin effects [47].
Consuming 0.10–0.14 g essential amino acids (EAA)/kg/dose (0.25–0.30 g protein/kg/dose) maximally stimulates muscle protein synthesis (MPS) during energy balance. Whether consuming EAA beyond that amount enhances MPS and whole-body anabolism following energy deficit is unknown. The aims of this study were to determine the effects of standard and high EAA ingestion on mixed MPS and whole-body protein turnover following energy deficit.
Nineteen males (mean ± SD; 23 ± 5 y; 25.4 ± 2.7 kg/m²) completed a randomized, double-blind crossover study consisting of two, 5-d energy deficits (−30 ± 4% of total energy requirements), separated by 14-d. Following each energy deficit, mixed MPS and whole-body protein synthesis (PS), breakdown (PB), and net balance (NET) were determined at rest and post-resistance exercise (RE) using primed, constant L-[²H₅]-phenylalanine and L-[²H₂]-tyrosine infusions. Beverages providing standard (0.1 g/kg, 7.87 ± 0.87 g) or high (0.3 g/kg, 23.5 ± 2.54 g) EAA were consumed post-RE. Circulating EAA were measured.
Postabsorptive mixed MPS (%/h) at rest was not different (P = 0.67) between treatments. Independent of EAA, postprandial mixed MPS at rest (standard EAA, 0.055 ± 0.01; high EAA, 0.061 ± 0.02) and post-RE (standard EAA, 0.055 ± 0.01; high EAA, 0.065 ± 0.02) were greater than postabsorptive mixed MPS at rest (P = 0.02 and P = 0.01, respectively). Change in (Δ postabsorptive) whole-body (g/180 min) PS and PB was greater for high than standard EAA [mean treatment difference (95% CI), 3.4 (2.3, 4.4); P = 0.001 and −15.6 (−17.8, −13.5); P = 0.001, respectively]. NET was more positive for high than standard EAA [19.0 (17.3, 20.7); P = 0.001]. EAA concentrations were greater in high than standard EAA (P = 0.001).
These data demonstrate that high compared to standard EAA ingestion enhances whole-body protein status during underfeeding. However, the effects of consuming high and standard EAA on mixed MPS are the same during energy deficit.
NCT03372928, https://clinicaltrials.gov.
Dietary protein requirements and recommendations for healthy older adults: a critical narrative review of the scientific evidence
2023, Nutrition Research Reviews
Assessing the whole-body protein synthetic response to feeding in vivo in human subjects
2021, Proceedings of the Nutrition Society

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ReviewUpdate on maximal anabolic response to dietary protein

Summary

Introduction

Section snippets

Is a maximal anabolic response important? Implications for health and disease

The balance between protein synthesis and breakdown: the metabolic determinants of the anabolic responses

Methodological considerations in determination of the anabolic response

Relation of the anabolic response at the muscle level to the total whole body response

Role of insulin in the anabolic response

Role of intracellular EAA availability in the anabolic response

Is there a maximal anabolic response?

Does meal distribution of dietary protein matter?

Summary and conclusions

Author contributions

Conflicts of interest

Acknowledgements

Clin Nutr

Am J Clin Nutr

J Nutr Am Soc Nutr

J Nutr Am Soc Nutr

Clin Nutr

Am J Clin Nutr Am Soc Nutr

Nutr Metab (Lond)

Am J Clin Nutr Am Soc Nutr

Am J Clin Nutr Am Soc Nutr

J Cyst Fibros

Clin Nutr

Ann Oncol

Am J Clin Nutr

Clin Nutr

Med Clin North Am

Am J Clin Nutr Am Soc Nutr

J Am Diet Assoc

J Nutr Am Soc Nutr

Dietary protein recommendations and the prevention of sarcopenia

Curr Opin Clin Nutr Metab Care

Energy intake: percentages of energy from protein, carbohydrate, fat, and alcohol, by gender and age, what we eat in America, NHANES 2013–2014

Isotope tracers in metabolic research

Effect of poor diabetic control and obesity on whole body protein metabolism in man

Diabetologia

Applications of stable, nonradioactive isotope tracers in in vivo human metabolic research

Exp Mol Med

Review
Update on maximal anabolic response to dietary protein