The Journal of Nutrition
Editorial
Efficiency of Free Amino Acids in Supporting
Muscle Protein Synthesis
Daniel Tome
UMR PNCA, INRAe, AgroParisTech, Université Paris-Saclay, Paris, France
Amino acids (AAs) are essential nutrients involved in various
cellular and body activities and functions. The 20 proteinogenic
AAs are the precursors of body protein synthesis and include 9
indispensable amino acids (IAAs) that are not synthesized in the
body and must be provided by the diet (1). Proteinogenic AAs
stimulate body, and more particularly, muscle protein synthesis
as substrates, and some AAs (i.e., leucine, isoleucine, valine,
arginine, glutamine) act as nutritional signaling molecules able
to activate mRNA translation and protein synthesis (2). In
the usual human diet, dietary AAs are mostly, or even totally,
supplied in the form of intact proteins subjected to the digestion
process, which releases AAs, which are then absorbed. However,
crystalline free AAs are also used for food protein fortification
(3) or in some specific situations, such as supplements post
exercise (4, 5). The efficiency of crystalline free AAs to support
protein synthesis remains to be established.
Following ingestion of a meal, dietary proteins are digested
and the released dietary protein–derived AAs are transferred
to the body and provide nitrogen and the 9 IAAs required to
achieve nitrogen balance and support body and muscle (1). The
efficiency of the anabolic effects of dietary AAs on body and
muscle protein depends on the quantity and bioavailability of
the AAs, and on the pattern of IAAs, which should closely
correspond to the pattern required by the tissues. IAA content
is the main criterion for assessing protein quality, and the
currently accepted method for assessing protein quality is a
chemical scoring that relates the IAA content, corrected by their
bioavailability in individual foodstuffs or diets, to reference IAA
profiles (1, 6). In addition to AA bioavailability and IAA profiles,
the kinetics of the delivery of AAs to muscle tissues also appears
to be an important factor in modulating the anabolic efficiency
of dietary AAs in muscle protein synthesis (7). It is assumed
that the postprandial rise in circulating AAs represents a main
driver of the muscle protein synthetic response to feeding. A
high rate of protein digestion, AA absorption, and blood AA
delivery has been previously observed with soluble proteins such
as whey protein or with different hydrolyzed proteins with a
high rate of digestion and AA delivery (7, 8). It was observed
that these more rapidly digested and absorbed AA sources (i.e.,
whey or hydrolyzed protein) lead to a lower extraction of
dietary protein–derived AAs by the splanchnic tissues, a greater
The author reported no funding received for this study.
Author disclosures: The author reports no conflicts of interest.
DT is an Associate Editor of the Journal of Nutrition and played no role in the
Journal’s evaluation of the manuscript.
Address correspondence to DT (e-mail: tome.daniel@orange.fr).

C The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition. All rights reserved. For permissions, please e-mail:
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First published online November 23, 2021; doi: https://doi.org/10.1093/jn/nxab370.
See corresponding article on page 59.
release of protein-derived AAs to peripheral tissues, and a
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greater supply of AAs to muscle for supporting protein synthesis
(7, 8).
In this issue of the Journal, Weijzen et al. (9) hypothesize
that a mixture of free AAs mimicking the AA composition
of an intact milk protein would exhibit more rapid intestinal
absorption than the same dietary AAs provided after intact milk
protein digestion, and should lead to reduced splanchnic AA
retention, greater release of AAs in the circulation, and greater
delivery to muscle for protein synthesis. To test this hypothesis,
they provided to young healthy volunteers 30 g milk protein or
an equivalent mixture of free AAs, in an elegant experimental
design using stable isotope–labeled AAs for measuring AA
delivery and muscle protein synthesis. This article provides
interesting new data on the impact of free AAs on the kinetics
of AA absorption, blood AA transfer, muscle AA supply, and
muscle protein synthesis. Following ingestion, the free AA mix-
ture compared with intact milk protein, produced as expected
a greater increase in postprandial plasma AA concentrations,
and also a greater positive net protein balance and significantly
higher dietary phenylalanine incorporation into mixed muscle
protein, strongly suggesting a greater postprandial tissue protein
accretion. No differences were observed between treatments in
postprandial muscle protein synthesis, likely due to achieving
a plateau with the high quantity of 30 g ingested protein or
AAs that maximizes muscle protein synthesis in these healthy
young subjects. However, these results are very promising, and
suggest that the AA mixture, compared with intact milk protein,
should induce greater postprandial plasma AA concentrations
and muscle protein synthesis at intakes <30 g, although this
remains to be tested.
The important study of Weijzen et al. (9) confirms that,
in addition to AA digestibility and IAA profile, the rate of
protein digestion and AA absorption and delivery to the blood
controls postprandial plasma AA concentrations and represents
an additional criterion for assessing dietary protein. It has
been shown that more rapid AA absorption leads to greater
postprandial plasma AA concentrations and subsequent greater
stimulation of muscle protein synthesis (7, 8, 10). This is the case
for some specific proteins that remain soluble in the stomach
or with hydrolyzed protein preparations, both being rapidly
delivered to the small intestine where AAs are rapidly released
and absorbed. In addition, free crystalline AAs, which are also
rapidly absorbed, appear at least as efficient and might be
even more efficient than intact protein to increase postprandial
plasma AA concentrations and muscle protein synthesis. As
discussed by the authors, free crystalline AA mixtures can
3
provide some benefit and could be used in specific situations
requiring a fast increase of the availability of systemic AAs to
support protein and AA homeostasis, to limit loss of lean and
muscle tissue, or to restore and maintain body functions. Thus,
supplementation with free crystalline AAs to limit sarcopenia
in older subjects or in patients with syndromes characterized
by protein and AA metabolism derangements is an attractive
option and merits further study.
The efficient utilization of free AAs for muscle protein
synthesis also contributes to the debate on AA fortification
to improve the quality of dietary protein by addition of
the limiting AAs in free crystalline form. This procedure is
primarily of interest in relation to the improvement of plant
protein, and primarily lysine fortification of cereals, and sulphur
AA fortification of legumes and oilseeds, although, where
appropriate, other IAAs or derivatives can be considered (3, 11,
12). Interest in IAA fortification of plant protein–based infant
formula is well documented and well accepted. The benefits
of similar fortification for human adults are unresolved (13–
15), and the article by Weijzen et al. (9) showing that free
AAs efficiently support muscle protein synthesis is an interesting
contribution to this debate. However, AA fortification of intact
protein (especially those with low digestibility such as plant
proteins) might not deliver AAs to the periphery in the same
profile as a free AA mixture, due to differences in timing of
digestion and/or absorption.
Conflict of interest: The author declares no conflict of
interest.
Acknowledgment
The sole author was responsible for all aspects of this
manuscript.
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