The impact of protein quality on the promotion of resistance exercise-induced changes in muscle mass
© The Author(s). 2016
Received: 22 August 2016
Accepted: 21 September 2016
Published: 29 September 2016
Protein supplementation during resistance exercise training augments hypertrophic gains. Protein ingestion and the resultant hyperaminoacidemia provides the building blocks (indispensable amino acids – IAA) for, and also triggers an increase in, muscle protein synthesis (MPS), suppression of muscle protein breakdown (MPB), and net positive protein balance (i.e., MPS > MPB). The key amino acid triggering the rise in MPS is leucine, which stimulates the mechanistic target of rapamycin complex-1, a key signalling protein, and triggers a rise in MPS. As such, ingested proteins with a high leucine content would be advantageous in triggering a rise in MPS. Thus, protein quality (reflected in IAA content and protein digestibility) has an impact on changes in MPS and could ultimately affect skeletal muscle mass. Protein quality has been measured by the protein digestibility-corrected amino acid score (PDCAAS); however, the digestible indispensable amino acid score (DIAAS) has been recommended as a better method for protein quality scoring. Under DIAAS there is the recognition that amino acids are individual nutrients and that protein quality is contingent on IAA content and ileal (as opposed to fecal) digestibility. Differences in protein quality may have important ramifications for exercise-induced changes in muscle mass gains made with resistance exercise as well as muscle remodelling. Thus, the purpose of this review is a critical appraisal of studies examining the effects of protein quality in supplementation on changes in muscle mass and strength as well as body composition during resistance training.
KeywordsLeucine Hypertrophy DIAAS
Performing resistance exercise results in a fundamentally anabolic stimulus for skeletal muscle. When performed often enough resistance training can result in varying degrees of muscular hypertrophy . The degree of hypertrophy seen with resistance exercise training is, however, highly variable [2–7] and likely dependent on a number of variables including a persons’ prior training status, sex, and age; however, the purpose of this review is not to interrogate these variables and the interested reader is directed to the following reviews [8–10]. A number of lines of evidence show that ingestion of supplemental protein during a program of resistance training can augment the hypertrophic and strength responses . Research has been undertaken to try and define how protein can augment resistance training-induced training responses and relevant variables have been examined including protein quantity (dose) and protein timing (relative to exercise). While beyond the scope of this review, recent reviews looking at the issues of protein dose  and protein timing  are also excellent adjuncts to the topic covered here. The impact of protein quality, using PDCAAS estimates, on skeletal muscle anabolic responses, at rest, have recently been comprehensively reviewed ; however, there has been less attention paid to the impact of protein quality as a variable and its importance in driving resistance training-induced hypertrophy. This is despite several instances showing that protein quality can affect the acute post-exercise muscle protein synthetic response  and muscle hypertrophy with resistance training [5, 15, 16]. The focus of this review is solely on muscular hypertrophy as a result of resistance training and protein supplementation and not on strength. Recognizing that strength gains as a result of resistance training, which while dependent on gains in muscle mass/cross-sectional area, are likely equally as dependent (or possibly even more so) on gains in neuromuscular factors. The aim of this review is to examine how lower versus higher quality proteins impact the adaptations to resistance exercise training with a focus on skeletal muscle hypertrophy.
The role of supplemental protein in promoting muscle hypertrophy
Muscle hypertrophy following resistance training is the result of several processes  that include changes in satellite cell content and activity (for review see ), as well as protein turnover (for review see ). It is clear from a number of studies that resistance exercise ‘sensitizes’ the muscle to hyperaminoacidemia . Thus, resistance exercise has the effect of acting in a synergistic manner with the normal rise in muscle protein synthesis (MPS) that occurs with protein feeding (see the following reviews [8, 20, 21] for more detail). Ultimately, resistance exercise results in periods of extended positive muscle protein balance, greater than those with feeding alone. The effect of these extended periods of positive protein balance is that the muscle fiber undergoes addition of contractile protein mass and increases the fiber size . Supplementation (i.e., consumption of protein over and above a habitual protein intake) of a persons’ normal dietary intake with various protein sources has been shown to augment the hypertrophic response with resistance training in both younger and older participants [11, 22]. A meta-analysis shows that protein timing (i.e., rapid consumption within a certain time period pre-, during, or post-exercise) is not as important in determining strength or hypertrophic gains . Nonetheless, a pragmatic recommendation for athletes and resistance trainees would still be to begin recovery from exercise as soon as possible. Thus, post-exercise protein consumption (as well as hydration and carbohydrate provision) has been shown to be effective at stimulating MPS (reviewed here and elsewhere [8, 21]) and thus is recommended over pre-exercise [23–25] or during-exercise provision of protein , which would have a more variable effect on MPS and possibly resistance training-induced hypertrophy.
It has been shown that only the indispensable amino acids (IAA) are required for the stimulation of MPS [27–29] (here the term indispensable amino acid, as opposed to essential amino acid is used in keeping with recommended usage [30, 31]). Of the IAA a position of prominence belongs to leucine as an amino acid that acts as a signaling molecule to stimulate MPS, as well as being a building block for protein [32–35]. The mediation of MPS by leucine is through the mechanistic target of rapamycin complex-1 (mTORC1; for reviews see [36–38]). It has recently been shown that a protein named Sestrin2 is the leucine-binding sensor for mTORC1 [39, 40]. Upon leucine binding with Sestrin2 there is dissociation of Sestrin2 and GATOR2 (a GTPase-activating protein) and activation of mTORC1 to allow it to phosphorylate/de-phosphorylate downstream proteins and activate MPS. Thus, when leucine binds to Sestrin2 this would stimulate MPS. The result, as hypothesized [41–43], is that leucinemia (and subsequently intracellular leucine concentration) following protein ingestion is a more likely determinant of muscle protein accretion than total protein alone. With these new understandings of how leucine is a stimulator of MPS, it is noteworthy that commonly consumed sources of supplemental proteins vary greatly in their leucine content. A brief discussion of protein quality is important at this stage to understand the potential for how not only protein quantity, but protein quality can impact changes in MPS and potentially muscle mass with resistance training.
Protein quality: PDCAAS and DIAAS
PDCAAS and DIAAS scores, the limiting amino acid assessed by the amino acid reference ratio for selected proteins. Values from 
Soy PI A
Met + Cys
Soy PI B
Met + Cys
Met + Cys
DIAAS = (mg of digestible dietary IAA in dietary test protein)/(mg of the same IAA in the reference protein)
Importantly, the reference protein in this equation is not egg (as it was for PDCAAS) but a theoretical protein that covers all of the known requirements for the IAA. However, as with protein and the RDA, the requirement levels of IAA that form the DIAAS score reflect the minimum levels of intake of each amino acid. Thus, there is no attempt to define ‘optimal’ and potentially unique roles of amino acids such as leucine, as a stimulator of MPS, as well as its role as a substrate for the same process.
In relation to the leucine trigger thesis (Fig. 1), it appears that the elderly have a greater leucine threshold and thus require greater levels of protein/leucine to stimulate MPS both at rest [42, 51] and following resistance exercise [52, 53]. Thus, in an effort to produce greater gains in muscle mass in the elderly, both with protein supplementation in the absence of exercise , and with performance of resistance training larger doses of protein (leucine)  would have to be consumed. The higher protein/leucine needed to stimulate MPS in the elderly would be obtained at lower protein doses with higher quality proteins such as whey (Fig. 2, Table 1), which may be advantageous from both an energy intake and potential appetite suppression standpoint.
Whey protein supplementation and hypertrophy with resistance training
A recent systematic review and meta-analysis of studies involving the high leucine-containing protein whey has been performed . In this review the authors found that of 14 studies included in the analysis 5 were whey protein replacement studies (i.e., the whey protein was not supplemental) and 9 were supplementation studies . The authors found, “…a statistically significant increase in LBM [lean body mass] (WGMD [weighted group mean difference]: 2.24 kg, 95 % CI, 0.66, 3.81) among studies that included a resistance exercise component along with WP provision.” The same authors  concluded, “…[the findings] support the use of WP [whey protein], either as a supplement combined with resistance exercise or as part of a weight loss or weight maintenance diet, to improve body composition parameters.” It needs to be emphasized that in this same review  the authors pointed out that, “…the effects of WP [whey protein] were more favorable when compared with carbohydrates than protein sources other than whey, although findings did not reach statistical significance.” This is to be expected since carbohydrates provide only energy, not amino acids, and results only in hyperinsulinemia and thus cannot stimulate a net positive protein balance [55, 56]. Nonetheless, when considered together the studies in which whey was compared to other proteins [57–62] did not show marked differences. When compared to soy, a lower quality protein (Table 1), whey protein did not show a greater effect [57, 58]. However, in only one study was resistance exercise included , but this study had a very small sample size. Thus, the data are limited and a firm conclusion is hard to form regarding an advantage to supplementation with whey protein over other protein sources. Since the publication of this meta-analysis  there have been studies published in which whey protein has been compared to soy protein , pea protein , and rice protein .
Volek et al.  conducted a long-term training study (9mo) in which a whey protein supplement was shown to significantly enhance gains in lean body mass over those seen in a soy protein-supplemented group by ~83 %. This study  is one of the longest protein supplementation with resistance exercise trial and highlighted the importance of protein quality in determining exercise-induced muscle mass gains. Given the importance of leucine in triggering MPS, the findings of a greater muscle mass gain in a whey supplemented group are consistent with the leucine trigger thesis (Fig. 1) for stimulation of MPS to promote hypertrophy. Importantly, the soy supplemented group had a muscle mass gain that was no different from the carbohydrate group, which is a finding that implies soy was no better than energy in the form of carbohydrate. While not whey protein per se, the findings of Hartman et al.  are aligned with those of Volek et al. . In this study  bovine skimmed milk was compared to a soy protein-containing beverage and it was found that the milk drinkers gained more muscle mass than did the soy beverage consumers and a control carbohydrate only consuming group.
Joy et al.  studied the influence of only 8weeks of resistance training in groups of young men consuming either 48 g/d of whey or the same quantity of rice-derived protein (Oryzatein™ rice protein, Axiom Foods; see Table 1). When compared on a weight and a digestibility basis whey protein isolate has a much greater leucine content and availability (Table 1), but the researchers overcame this difference by feeding their subjects a very large quantity of protein . In feeding their subjects 48 g of whey isolate and 48 g of rice protein concentrate they delivered doses of ~5.5 g and ~3.8 g of leucine, which would have hit the highest level of leucine (Fig. 1) and saturated the MPS response for both group . Thus, given the saturable dose-response nature of MPS [52, 65, 66], and the subsequent hypertrophy, the results from this study  are not surprising. By halving the doses that these authors used , which arguably represents a more realistic dose of protein, then the whey protein dose would still be sufficient to maximally stimulate MPS whereas the rice protein dose would not [52, 65, 66]. Thus ‘equivalency’ of protein in this study was not a function of the protein quality itself, but of the large per-dose quantities of protein (leucine) consumed. Clearly these doses of protein were sufficient to maximally stimulate MPS in the case of both the rice and the whey supplement.
Blended proteins (mixtures of different isolated protein sources) have been sparingly studied, but in all cases where MPS has been measured blends of proteins give similar responses to leucine-matched whey protein [67, 68]. A theory behind why blends of proteins might be considered to be more effective than isolated proteins would be that the delivery of amino acids could be extended or that certain amino acids are enriched in some sources ; however, as the main driver of MPS the most relevant amino acid is leucine. For example, Reidy et al. compared a blend of whey (25 % by weight), caseinate (50 % by weight), and soy (25 % by weight) to a leucine-matched quantity of whey. There were differences in the aminoacidemia obtained following ingestion of these two treatments that were accompanied by different time courses of muscle protein synthesis, however, on balance the incorporation of amino acids into muscle protein was not different between treatments. These findings are in agreement with the leucine trigger concept (Fig. 1) and highlight the importance of leucine as an amino acid that needs to be considered in comparing supplemental sources of protein. Future research on blends of protein will need to focus on comparing protein blends to other protein sources in longer-term studies with hypertrophy and/or strength as a main outcome.
Other supplemental proteins
A number of other supplemental protein sources have now become available to consumers including hemp protein and ‘insect-based’ protein, and other plant-derived proteins. While it is not possible to make specific comparisons to the proteins examined here, the leucine content and quality (due to processing and the presence of anti-nutritional compounds  unless they are removed) will be lower than most if not all more commonly available supplemental proteins (Table 1). For example, the PDCAAS (DIAAS is not available) scores were estimated by House et al.  to be 0.49–0.53 for whole hemp seed, 0.46–0.51 for hemp seed meal, 0.63–0.66 for dehulled hemp seed. Obviously, the hull of the seed contained a high quantity of antinutritional factors and its removal improved protein quality. Lysine was the first limiting amino acid in all hemp-based proteins . It is important that these proteins now be assessed and their DIAAS scores estimated so that we can make a true assessment of their quality when compared to more commonly-used isolated proteins.
Collagen has also gained in popularity as a source of protein in supplemental sources. This is intriguing given the PDCAAS score of collagen is zero due to the fact that it is lacking in tryptophan. However, protein blends containing collagen, which even with added tryptophan would have a PDCAAS score of 0.39, would add mostly dispensable amino acids (and admittedly protein content on the product label) to existing protein content and would not improve protein quality. In addition to collagen a variety of insect-derived proteins have been assessed for their protein quality and, not unsurprisingly, there are wide variation in protein digestibility . Nonetheless, insect protein tends, in general, to be lower quality and lower in IAA than comparable proteins we have examined here. Most often, in protein sources claiming to be insect protein, that are available for human consumption, they are not pure insect protein but instead blends of insect and other proteins such as a rice, hemp, and/or soy protein. Thus, the protein quality of such protein blends is a function not of the insects and unlikely to be as high as most common supplemental proteins (Table 1). As a result, to achieve a dose of leucine sufficient to stimulate MPS to an appreciable degree unless larger quantities (40–50 g per serve) of the protein are consumed; thus, these protein sources would be inferior to those proteins described in Table 1. It is important that future studies in this area emphasize that discussion of protein ‘quality’ using at least the content of IAA, PDCAAS (if available), or DIAAS (if possible) to accurately characterize proteins for use in human clinical research.
Recommendation and future directions
Is the protein given a supplement? A supplemental protein, by definition, is in addition to the persons’ normal dietary intake. Thus, researchers are urged to make some effort to assess normal dietary intake prior to the supplementation and exercise intervention.
Is the allocation of the protein supplements blinded and is subject compliance assessed? While blinding of the subjects and investigators to the supplementation is self-explanatory, objective measures of compliance are rarely used. As one biomarker of compliance with an increased protein intake urinary or serum urea levels could be assessed.
Is the study of sufficient duration and is adequately powered to detect differences? While the time course of muscle hypertrophy is not known exactly an 8weeks intervention would be considered the minimum as true hypertrophy (i.e., measured with muscle biopsies or by MRI and/or CT) is detectable/measurable after 6–8 weeks of resistance training [73–76]. Study power is often not mentioned, but it should be and the minimum significant effect as well as the degree of change in hypertrophy needs to be outlined. To detect hypertrophy differences in proteins of differing protein quality it appears that this should be in the range of at least 25 subjects per group [5, 15] and for a period of at least 10–12 weeks in novice lifters and possibly longer in experienced lifters.
CONSORT (http://www.consort-statement.org/) guidelines need to be followed. The CONSORT guidelines provide a minimum set of recommendations for reporting of randomized trials. Adherence to this standard allows an easy cross-comparison of one trial to the next. This aids in standardization, complete and transparent reporting, and aids in interpretation.
An appropriate placebo needs to be used. Comparisons of protein to carbohydrate (i.e., to try and make the interventions isoenergetic, but not isonitrogenous) are more likely to show an effect of supplementation. Some studies have compared protein sources based on leucine content , with the expected outcome that protein turnover is no different between the two, however, it would seem to make more sense to compare protein sources and doses that are isonitrogenous.
A further consideration in recommendations for using lower quality proteins is their potential use in populations such as the elderly for whom a requirement for protein [77, 78], and more importantly leucine [42, 79, 80], for retention of muscle mass appears to be higher than that of younger persons. For older persons lower quality protein sources would have to be rigorously tested. This sentiment would be particularly true in older persons with marginal energy intake and or lower levels of physical activity for whom high quality (and nutrient-dense) sources of protein would be recommended [54, 81, 82].
Protein quality appears to play a role in determining resistance exercise-induced muscle hypertrophy; however, the effect is more difficult to detect compared to a comparison between the protein and an isoenergetic source of carbohydrate. The leucine content of a protein is the strongest determinant of the capacity of a protein to affect MPS and likely hypertrophy. While the prior performance of exercise will lower the threshold for protein/leucine required to stimulate MPS the importance of leucine content for MPS and likely subsequent hypertrophy needs to be appreciated in the context of not only its content in a protein source but also its digestibility. While there are few studies that have actually derived the DIAAS of proteins this variable is something that needs to be considered moving forward. When comparing proteins of differing quality, larger adequately powered rigorous trials need to be run to assess the impact of protein quality in determining resistance exercise-induced hypertrophy. Future studies in this area may wish to consider the recommendations outlined here in terms of trying to improve overall study quality and, importantly, to allow for easier comparisons between trials.
Digestible indispensable amino acid score
Indispensable amino acid
Lean body mass
Muscle protein breakdown
Muscle protein synthesis
Magnetic resonance image
Mechanistic target of rapamycin complex-1
Protein digestibility-corrected amino acid score
Weighted group mean difference
The author acknowledges the support of Canadian Institutes for Health Research, the National Science and Engineering Research Council of Canada, and the Canada Research Chairs program for their support.
Availability of data and materials
All data are available by direct request of the author.
SMP conceived of wrote, edited, and bears responsibility for final content of the manuscript.
The author has received funding, honoraria for speaking, and travel expenses from the following non-government agencies: The US National Dairy Council, The US National Cattlemen’s Beef Association, and Dairy Farmers of Canada.
Ethics approval and consent to participate
As a review paper, no ethical approval was sought nor required.
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