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DOI 10.1007/s00726-017-2390-9
Amino Acids
REVIEW ARTICLE
Dietary proteins and amino acids in the control of the muscle
mass during immobilization and aging: role of the MPS response
Jason M. Cholewa1 · Dominique Dardevet4 · Fernanda Lima‑Soares2,3 · Kassiana de Araújo Pessôa2,3 ·
Paulo Henrique Oliveira2,3 · João Ricardo dos Santos Pinho2,3 · Humberto Nicastro3 · Zhi Xia5,6 ·
Christian Emmanuel Torres Cabido2,3 · Nelo Eidy Zanchi2,3
Received: 1 October 2016 / Accepted: 28 January 2017
© Springer-Verlag Wien 2017
intake via the consumption of an overall increase in dietary
protein appears to be the most effective dietary intervention
toward increasing or attenuating lean mass during aging;
however, more research investigating the optimal dose and
timing of protein ingestion is necessary. Several studies
have demonstrated that decreases in postprandial MPS as
a result of increased circulating oxidative and inflamma-
tory are more responsible than muscle protein breakdown
for the decreases in muscle mass during disuse and health
aging. Therefore, nutritional interventions that reduce oxi-
dation or inflammation in conjunction with higher protein
intakes that overcome the anabolic resistance may enhance
the MPS response to feeding and either increase muscle
mass or attenuate loss. In preliminary studies, antioxidant
vitamins and amino acids with antioxidant or anti-inflam-
matory properties show potential to restore the anabolic
response associated with protein ingestion. More research,
however, is required to investigate if these nutrients trans-
late to increases in MPS and, ultimately, increased lean
mass in aging humans. The purpose of the present review is
to discuss the role of protein/EAA intake to enhance post-
prandial MPS during conditions associated with muscle
loss, and bring new perspectives and challenges associated
nutritional interventions aimed to optimize the anabolic
effects of dietary protein/EAAs ingestion.
Keywords Proteins · Betaine · Amino acids · Essential
amino acids · Leucine · Glycine · Postprandial muscle
protein synthesis · Atrophy · Hypertrophy
Introduction
Proteins and essential amino acids (EAAs) are of the most
popularly supplemented nutrients worldwide, especially
Abstract Dietary proteins/essential amino acids (EAAs)
are nutrients with anabolic properties that may increase
muscle mass or attenuate muscle loss during immobiliza-
tion and aging via the stimulation of muscle protein syn-
thesis (MPS). An EAA’s anabolic threshold, capable to
maximize the stimulation of MPS has been hypothesized,
but during certain conditions associated with muscle loss,
this anabolic threshold seems to increase which reduces the
efficacy of dietary EAAs to stimulate MPS. Preliminary
studies have demonstrated that acute ingestion of dietary
proteins/EAA (with a sufficient amount of leucine) was
capable to restore the postprandial MPS during bed rest,
immobilization or aging; however, whether these improve-
ments translate into chronic increases (or attenuates loss)
of muscle mass is equivocal. For example, although free
leucine supplementation acutely increases MPS and muscle
mass in some chronic studies, other studies have reported
no increases in muscle mass following chronic leucine sup-
plementation. In contrast, chronically increasing leucine
* Nelo Eidy Zanchi
neloz@ig.com.br
1 Department of Kinesiology, Coastal Carolina University,
Conway, SC 29528, USA
2 Federal University of Maranhão (UFMA), Department
of Physical Education, São Luis, Maranhão, Brazil
3 Laboratory of Cellular and Molecular Biology of Skeletal
Muscle (LABCEMME), São Luis, Maranhão, Brazil
4 INRA, UMR 1019, UNH, CRNH Auvergne,
63000 Clermont-Ferrand, France
5 Exercise Physiology and Biochemistry Laboratory, College
of Physical Education, Jinggangshan University, Ji’an, China
6 Department of Sports Medicine, Chengdu Sport Institute,
Chengdu, China
J. M. Cholewa et al.
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among individuals who seek to increase muscle mass.
Although United States National Academy of Medicine’s
recommendation for protein intake as part of a balanced
diet expected to meet the needs of 97% of the population is
0.83 g/kg/day, dietary proteins consumed in amounts three-
fold higher than the recommended dietary allowance have
been shown to be safe (no changes in blood lipids or mark-
ers of hepatic or renal function) and effective at increas-
ing lean mass (Antonio et al. 2015). The main mechanism
associated with increases in muscle protein accretion as a
result of postprandial protein ingestion is an alteration in
the cellular balance between muscle protein synthesis
(MPS) and muscle protein breakdown (MPB), such that
MPS is favoured. Both the quantity of protein consumed
and the composition/quality of the protein source, such as
EAA and leucine content, will affect the postprandial MPS
(for review see: Guimarães-Ferreira et al. 2014). Vary-
ing physio-pathological conditions will also alter the MPS
response to protein consumption. For example, it has been
repeatedly demonstrated that postprandial MPS after a
resistance training session is enhanced via EAA ingestion
(Atherton and Smith 2012). The opposite seems to occur
during certain muscle disuse conditions in which the acute
consumption of dietary proteins fails to maximally stimu-
late postprandial MPS (Phillips et al. 2009). Since muscle
disuse (over different clinical manifestations such as bed
rest, immobilization and/or sarcopenia) leads to reduc-
tions in basal metabolic rate, glucose disposal, muscular
strength, and increases in morbidity and mortality (Kim
and Choi 2013), new strategies aiming to enhance both the
acute response and chronic adaptations to protein inges-
tion are of interest to basic scientists and practitioners.
This review discusses protein metabolism in the regulation
of muscle mass during catabolic conditions with a special
emphasis on how dietary protein and amino acid intake
impacts postprandial MPS and muscle protein accretion
during periods of bed rest, immobilization or aging. Also,
we will present how amino acid and antioxidant interven-
tions may improve the preservation of muscle mass during
catabolic states.
Muscle disuse as a general descriptor of different
clinical manifestations associated with muscle atrophy
and decreased MPS
Muscle disuse is part of a central paradigm explaining
losses in muscle mass during several common conditions
such as cast immobilization, extended bed rest or reduced
ambulation. In the literature, this is termed “simple atro-
phy” as the absence of a disease-associated state limits
the muscle atrophy process to the affected limb, rather
than systemically (Atherton et al. 2016; Bell et al. 2016).
Thus, disuse is a process intrinsic to the muscles that are
exposed to it (Atherton et al. 2016). Although episodic
periods of disuse such as limb immobilization or bed rest
clearly accelerate the loss of muscle mass and strength in
young and older adults (Kim and Choi 2013), it is difficult
to identify what components are intrinsic from muscle atro-
phy and what components are derived from disease-related
atrophy aspects. As an example, in humans, immobilization
results in the development of whole body and muscle insu-
lin resistance (MIR) within 3–5 days (Hamburg et al. 2007;
Sonne et al. 2011; Stuart et al. 1988). Also, certain models
of partial physical inactivity or “moderate muscle disuse”,
such as reduced ambulatory activity, induce MIR after just
3–14 days (Hamburg et al. 2007; Krogh-Madsen et al.
2010; Olsen et al. 2008). The impact that insulin resistance
has on muscle protein metabolism following different cata-
bolic conditions is not clear, especially in humans. In obese
subjects for example, a marked blunting in the leg glucose
disposal (under insulin clamp) is seen but this event was
not linked to lower lean tissue mass compared with their
age-matched counterparts (Atherton et al. 2016). Corrobo-
rating the absence of direct link between muscle mass and
insulin resistance, during a period of reduced ambulation,
insulin resistance develops rapidly in younger men and pre-
cedes any measurable decreases in lean mass or increases
in adipose tissue mass (Knudsen et al. 2012). In rodents,
a more direct relationship seems to occur. In this regard,
Wang et al. (2006) studied the impact of obesity and MIR
on skeletal muscle proteolysis. In muscle of insulin-resist-
ant db/db mice (a routinely used model of type 2 diabetes
in rodents), protein degradation and activities of the major
proteolytic systems were increased. Interestingly, treatment
with the hypoglycemic agent rosiglitazone improved insu-
lin resistance and decreased activities of major proteolytic
systems (namely caspase-3 and the proteasome) in mus-
cle, leading to a normalization of proteolysis. However,
there was only partial recovery of the cross-sectional area
and muscle mass. The authors suggested that the recovery
may not have been complete because rosiglitazone did not
stimulate protein synthesis. Collectively, such information
suggests that insulin resistance may increase muscle prote-
olysis and impair muscle protein synthesis but this has not
been observed in human models of disuse. The degree of
insulin resistance may be predictive of muscle losses asso-
ciated with muscle atrophy, but this hypothesis requires
further examination.
Another important condition associated with muscle
atrophy and reductions in physical activity is the aging
process. Aging is accompanied by a slow and inevitable
age-related decline in skeletal muscle mass referred to as
sarcopenia. Sarcopenia, in turn, contributes to increased
risk of falls and fractures in older individuals, as well to
the incidence of metabolic disorders like type 2 diabetes
mellitus. As with muscle disuse, investigators have tried
Dietary proteins and amino acids in the control of the muscle mass during immobilization and…
1 3
to categorize muscle sarcopenia to better understand this
phenomenon. For example, it has been suggested that the
term “primary sarcopenia” (or age-related) should be used
to define sarcopenia that is caused by aging itself. On the
other hand, the term “secondary sarcopenia” has been used
to describe sarcopenia that is caused by additional disuse,
disease, and/or inadequate nutrition and malabsorption
(Janssen 2011; Cruz-Jentoft et al. 2010). In our view, it can
be very difficult to separate primary sarcopenia from sec-
ondary sarcopenia in a given older person. During condi-
tions of primary sarcopenia, co-morbidities often develop
that lead to reduced physical activity and periods of bed
rest (i.e.: secondary sarcopenia), which may further the
development of an increased production of catabolic hor-
mones such as cortisol, proinflammatory molecules such
as cytokines, and increased ROS (reactive oxygen spe-
cies) formation, which may result in additional decreases
in MPS or increases in MPB (Santilli et al. 2014; Brocca
et al. 2012). Since not all aged persons are sarcopenic, the
term “healthy” elderly individuals or non-sarcopenic older
adults are also widely used in the literature to describe sub-
jects without significant muscle loss or disuse-associated
diseases. Therefore, this paper will only classify between
non-sarcopenic and sarcopenic older adults, referred to as
“healthy” and “sarcopenic”, respectively.
Basal protein turnover in the regulation of muscle mass
The term “proteostasis” (the fusion of the words protein
and homeostasis), was first coined to designate the bal-
ance between synthetic (biogenesis, folding, trafficking
and export) and proteolytic (degradation of proteins pre-
sent within and outside the cell) pathways integrating the
protein metabolism in a cell (Powers et al. 2009). At the
macroscopic level, the term proteostasis strictly relates to
protein metabolism and can be interpreted as the balance
between the rates of MPS and MPB, the main determinants
of skeletal muscle turnover. Although imbalances in the
basal (postabsorptive) rates of protein metabolism in favour
of increased MPB are responsible for decreases in muscle
mass during several disuse-induced atrophies (sepsis, can-
cer, heart failure, glucocorticoid treatment), it is becom-
ing clear that during conditions such as immobilization,
extended bed-rest or sarcopenia, a basal increase in MPB
may not be observed (Dardevet et al. 2000; Phillips et al.
2009).
In this regard, markers of basal MPS do not seem to
be affected by 24 days of bed rest (Brocca et al. 2012) or
14 days of step-reduction (Breen et al. 2013). On the other
hand, a more prolonged immobilization period seems to
reduce basal MPS in the immobilized leg, compared to the
control leg (Gibson et al. 1987; Glover et al. 2009). This
suggests that basal MPS may or may not be reduced during
disuse inducing muscle atrophy, likely depending on if
muscle disuse is induced for a short or long term. Another
recurrent finding from disuse studies is a reduction in the
fed-state gains in muscle protein synthesis in response to
amino acid infusion (Glover et al. 2009) or following the
ingestion of protein (Wall et al. 2013), a condition termed
“anabolic resistance”. Considering that the two main deter-
minants of MPS (postabsorptive and postprandial), are
reduced under different muscle disuse conditions, is cor-
rect to consider that a chronic daily reduction in MPS is
the major determinant of skeletal muscle atrophy during
disuse. In this regard, it has been estimated (based on acute
measurements) that reductions to the magnitude of 40–50%
are expected to occur both in early (10 days or less) and
later (beyond 10 days) disuse (Crossland et al. 2010).
In addition, it seems that MPB is slightly elevated in the
early disuse, but in late periods, MPB seems to be adap-
tively reduced, which explains why muscle atrophy is less
in chronic observations compared to acute models of dis-
use (Baehr et al. 2016). Thus, considering that MPB is not
robustly affected during periods of muscle disuse, the loss
of lean tissue due to reduced activity appears to be primar-
ily driven by both a reduced basal MPS and a blunting of
MPS response to the ingestion of dietary protein. Corrobo-
rating such information, in a recent study, Wall et al. (2013)
have reported that during reduced ambulation, fed-state
gains in muscle protein are reduced and that fasted losses
remain the same (or are slightly increased transiently), with
a large part of the muscle atrophy being due to a reduc-
tion in the fed-state MPS response. A similar phenomenon
seems to occur during healthy aging. Compared to healthy
young adults, decrements in the postabsorptive MPS are
barely detectable in the healthy elderly (Breen et al. 2012).
In contrast, MPS becomes partially insensitive to the
stimulating effect of a normal protein meal, thus partially
explaining why the muscle mass is eroded over time during
the aging process (Dardevet et al. 2012).
Role of decreased postprandial MPS in the regulation
of the muscle mass during aging and muscle disuse
The switch from a fasted to a fed state results in changes in
MPS that are 10–20-fold greater than any measured change
in MPB (Tang and Phillips 2009). In catabolic conditions
where the postabsorptive rates of MPB are not increased,
this specific but robust regulation carries the potential to
be a major target for the metabolic control of muscle mass.
Since the human organism is under the influence of food
intake for 40% of the day, it is predictable that the quan-
titative and qualitative characteristics of the food intake
will strongly condition the maintenance of muscle mass.
In healthy conditions, a standard dose of proteins (20–25 g
composed by 8–9 g of EAA with 2.5–3.5 g of leucine)
J. M. Cholewa et al.
1 3
is sufficient to maximally increase MPS in young men
(Moore et al. 2015. In states of muscle atrophy, however,
this stereotypic response has been shown to be altered. With
a quadriceps immobilization, for example, a “resistance” of
MPS to amino acids has been demonstrated, which appears
to explain one half of the muscle loss (Glover et al. 2008).
The intrinsic reasons why the skeletal muscle presents
anabolic resistance in some physio-pathological condi-
tions are still unclear. In nature, not all animals exposed to
a prolonged physical inactivity present increased muscle
atrophy associated to muscle disuse. In bears, for example,
hibernating periods are linked to a diminishment in the adi-
pose tissue reservoir with no major muscle loss, even under
extreme starvation (Harlow et al. 2001; Fuster et al. 2007).
In rodents, on the other hand, in models mimicking human-
based immobilization, a marked increase in MPB is seen
(together with decreased MPS rates) (Krawiec et al. 2005).
Thus, across species, a general mechanism explaining how
muscle disuse induces muscle atrophy does not seem to
exist. In humans, however, as previously described, reduc-
tions in MPS seem to contribute to the majority of muscle
loss during disuse.
The dampened MPS response to feeding occurs dur-
ing aging in humans, although the causative mechanisms
are still unknown. Two possible factors linked to anabolic
resistance in the aging muscle are a gradual decline in
physical activity or an age-related increase in inflamma-
tion, especially low-grade inflammation. In this regard,
Balage et al. (2010) demonstrated in old rats that the pres-
ence of low-grade inflammation did not change postab-
sorptive MPS but robustly blunted the postprandial MPS.
In humans, Toth et al. (2005) demonstrated, in elderly sub-
jects, increased circulating concentrations of several mark-
ers of immune activation which were related to reduced
MPS rates. The reason why decreased MPS, and not
increased MPB, is the major determinant of muscle mass
loss during disuse and the aging process requires further
investigation. One possible explanation is that there are sig-
nificantly less circulating stimulants of muscle proteolysis
(hypercortisolemia, inflammation, ROS) in healthy older
adults compared to what has been observed during diseases
like cancer cachexia, sepsis, infections, chronic heart fail-
ure, or uncontrolled diabetes (Fuster et al. 2007; Crossland
et al. 2008; Crossland et al. 2010).
Role of dietary proteins and leucine on postprandial
MPS
Considering that the stimulation of MPS is dependent on
both the dose and quality of dietary proteins/EAAs and the
muscle sensitivity to amino acid changes, it is interesting
to consider how to deal with such a variety of factors to
maximize postprandial MPS. In the case of both muscle
disuse and aging, it has been postulated that increasing the
amount of dietary proteins (or specific amino acids) in each
meal would be enough to overcome the anabolic resistance
in skeletal muscle. In this respect, it has been observed that
the difference in the MPS response to food intake between
adult and old rats was explained by the dose–response
curves of leucine action in incubated epitrochlearis mus-
cles (Dardevet et al. 2000). Specifically, MPS in vitro still
responded to leucine in old rats but at leucine concentra-
tions two- to threefold greater than in healthy adult rats. In
elderly subjects, a similar phenomenon has been observed
with an EAA supplementation mimicking a whey protein
dosage of 15 g, which increased postprandial MPS but to
a lesser extent when compared to young adults (Katsanos
et al. 2006). During bed-rest immobilization in elderly sub-
jects, Ferrando et al. (2010) reported the maintenance of the
24-h FSR (fractional synthetic rate, an index of MPS) with
a supplementation of EAAs (15 g, 3× per day), whereas
a significant decrease in FSR occurred in the non-supple-
mented control group (Ferrando et al. 2010). This evidence
demonstrates that, at least acutely, protein doses must be
doubled during the aging process to achieve a substantial
MPS response.
The beneficial effect of such protein/EAA supplemen-
tation on muscle mass in the long term is less clear since
there is a lack of consistent evidence in humans. In aged
animals, an increased leucine intake for several days under
free leucine supplementation or whey proteins (Rieu et al.
2003, 2007) was capable to restore MPS chronically; how-
ever, there were no changes in muscle mass (Rieu et al.
2007). Similar observations have been made by Verhoeven
et al. (2009) with long-term leucine supplementation which
did not increase muscle mass or strength in healthy elderly
men. During bed-rest conditions, a leucine-supplemented
diet (0.06 g/kg/meal) has also been shown to protect
against muscle loss after 7 days, but not after 14 days in
middle-aged subjects (English et al. 2016). However, sev-
eral reports related that muscle atrophy during short-term
(28 days) and long-term bed rest (60 days) (Trappe et al.
2007a, b, 2008) failed to be impacted by daily AA sup-
plementation or by a daily leucine-enriched whey protein
supplement, respectively. On the other hand, several recent
investigations have demonstrated positive effects of pro-
tein/AA supplementation not only on MPS but also on lean
mass tissue. In a recent investigation, Murphy et al. (2016)
observed in healthy old subjects that leucine supplementa-
tion increased the integrated MPS response. However, this
effect was observed only in the group who consumed low
amounts of dietary proteins. In a recent study, the relation-
ship between dietary protein and leucine consumption and
lean mass was assessed over 6 years among younger and
older adult Danes (aged 35–65 years). In this study, adults
over 65 years of age consumed less protein and leucine
Dietary proteins and amino acids in the control of the muscle mass during immobilization and…
1 3
than those of 35–55 years of age. Moreover, protein and
leucine intake was associated with positive LBM change
in those older than 65 years, with no effect seen in those
younger than 55 years. Older participants in the highest
leucine intake (7 × 1 g/day) experienced LBM mainte-
nance, whereas lower intakes were associated with LBM
loss over 6 years (McDonald et al. 2016).
It is not clear why chronic leucine supplementation,
despite its powerful effects on acute MPS, sometimes
translates and sometimes does not translate into increased
muscle mass when chronically evaluated. Several possible
mechanisms have been postulated, including a “desyn-
chronization effect” of leucine (Dardevet et al. 2012). It
seems that leucine excess can stimulate key enzymes in
BCAA catabolism (BCAA aminotransferase and BCKA
dehydrogenase), thus increasing the oxidation of serum
leucine. Excess leucine intake can also decrease the
plasma concentration of the other EAAs such as valine and
isoleucine, an effect called antagonism of BCAAs (May
et al. 1991). More research is currently needed to confirm
the “desynchronization effect” hypothesis. Collectively,
however, these results in addition to the results of Mur-
phy et al. (2016) discussed above suggest that the efficacy
of leucine (in the isolated form) to increase muscle mass
mainly occurs when a low-protein diet is present, and con-
suming more leucine through additional dietary protein is
likely the most effective dietary intervention to increase
lean mass.
Indeed, a recent consensus statement suggests that a pro-
tein intake above the RDA may be of benefit to the pres-
ervation of lean mass in healthy older adults (Bauer et al.
2013). However, the ideal strategy of optimal distribution
of protein in meals and total daily protein consumption are
poorly defined. To address these questions, Norton et al.
(2016) provided a high-quality protein supplement (1.6 g/
kg/d in the supplemented group versus 1.2 g/kg/day in the
control group) for 24 weeks to healthy, independent-living
older adults. Supplemental protein, equivalent to 0.33 g
protein/kg per day, was consumed in two equal parts with
the lower protein-containing meals of the day (i.e., break-
fast and lunch). As a result of the intervention, protein
intakes in the protein (PRO) group increased to ~0.4 g/
kg per meal. Leucine intakes at breakfast and midday and
evening meals increased to 1.8, 1.9, and 1.5 g, respectively,
and were closer to the 3 g required to maximally stimulate
MPS in older adults (Paddon-Jones and Rasmussen 2009).
Total lean mass and appendicular lean mass increased by
0.45 and 0.28 kg, respectively, in the protein-supplemented
group but not in the control group. These results suggest
that an optimized dose and balanced distribution (in the
levels herein tested) of protein intake between meals could
be beneficial in the preservation of lean mass in the aging
population.
As previously discussed, an important mechanism
explaining losses in the muscle mass during aging or
immobilization seems to be a reduced MPS response to
protein feeding. Thus, identifying factors that lead to a
reduced efficacy of dietary amino acids to stimulate MPS
is of importance. One potential mediator of reduced MPS
and subsequent smaller increases in lean mass in response
to protein ingestion is through the large neutral amino acid
transporter 1 (LAT1) which preferentially transports leu-
cine and the other branched chain amino acids into the cell,
and, together with the system A amino acid transporter
(SNAT2/SLC38A2), has been shown to activate mTORC1
(Evans et al. 2007). LAT1 expression and activity have
been shown to decrease in the postprandial but not post-
absorptive state following a 7-day bed-rest period in older
adults (Drummond et al. 2012). Although changes in the
postabsorptive expression of the LAT1 and SNAT2 have
not been observed between young adult (30 ± 2 years) and
older (70 ± 2 years) subjects, SNAT2 expression and activ-
ity were reduced in response to post-exercise protein inges-
tion in older compared to younger subjects (Dickinson
et al. 2013). Thus, a dampening of LAT1 and SNAT2 and,
therefore, a reduced transport of amino acids into the mus-
cle cell, in response to protein ingestion could partially con-
tribute to lower postprandial MPS and reduced increases in
lean mass as a result of aging. However, further research
examining age-related differences in amino acid transporter
responses to protein ingestion in the absence of exercise is
required to substantiate this hypothesis.
Adding stimulatory co‑factors to enhance postprandial
MPS
Besides leucine, BCAA, EAA supplementation or
increased quantity of dietary protein, another possibil-
ity to increase the postprandial MPS is to re-sensitize the
protein synthetic pathways with co-factors bearing anti-
oxidant properties. The main rationale of such strategy is
that many muscle-wasting conditions, including immobi-
lization, aging, cancer cachexia, and sepsis are associated
with a proinflammatory and/or pro-oxidative environment.
Although the causes are specific for each catabolic state,
the overproduction of proinflammatory cytokines and ROS
is believed to play a central role in impaired muscle pro-
tein turnover (Balage et al. 2010; Ham et al. 2014; Cuth-
bertson et al. 2005) as proteins involved in the antioxidant
defence system (superoxide dismutase, carbonic anhydrase
III, peroxiredoxin 3, α,β-crystallin, heat shock protein B6,
heat shock protein B1 and heat shock protein 70) were all
downregulated following 8 and 35 days of bed rest in the
vastus lateralis (Brocca et al. 2012). Specifically, inflamma-
tion (NF-kappaB) and ROS inhibit the activity of important
enzymes involved in protein translation initiation, namely
J. M. Cholewa et al.
1 3
mTOR and p70 S6 kinase 1 (S6K1) (Frost and Lang 2011)
and enhance protein degradation through the ubiquitin pro-
teasome system (Li et al. 2003). However, since makers of
MPB and autophagy were not upregulated following bed
rest (Brocca et al. 2012), reductions in MPS due appear to
have the greatest influence on muscle atrophy during dis-
use. Therefore, consuming or supplementing with nutrients
that reduce oxidative stress and/or inflammation combined
with increased protein intake is a promising nutritional
intervention to overcome anabolic resistance and maintain
muscle mass during disuse and aging.
Since oxygen-derived free radicals are involved in sev-
eral catabolic states, a rational strategy to decrease ROS
production and increase postprandial MPS could be anti-
oxidant supplementation. To test this hypothesis, Marzani
et al. (2008) supplemented old rats for 7 weeks with a diet
containing antioxidants (a mixture containing rutin, vitamin
E, vitamin A, zinc, and selenium) and compared the MPS
response to increasing leucine concentrations. As expected,
in old rats, the ability of leucine to stimulate muscle pro-
tein synthesis was significantly decreased compared to
young adults. However, this defect was reversed when old
rats were supplemented with antioxidants. Following 8 days
of immobilization in rats, muscle mass recovery during the
next 40 days was accelerated by the antioxidant diet plus
leucine supplementation due to higher MPS rates in both
the postabsorptive and postprandial states (Savary-Auzeloux
et al. 2013). Summing up, antioxidant supplementation
seems to benefit postprandial MPS stimulation during both
immobilization and aging conditions, but more research is
required to test if this strategy will translate to humans.
Another co-factor with antioxidant properties that may
enhance the MPS response to feeding is N-acetylcysteine
(NAC). NAC comprises a cysteine with an acetyl group
attached to the nitrogen atom and is used to treat a vari-
ety of conditions marked by increased oxidative stress (Tse
and Tseng 2014). NAC appears to protect against oxidative
stress by scavenging ROS and providing cysteine for glu-
tathione synthesis (Zafarullah et al. 2003). NAC has been
shown to protect the sarcoplasmic reticulum and myofibrils
in ryr zebra fish against oxidative stress-induced swell-
ing and myofibril disruption, respectively (Dowling et al.
2012). In an acute model of muscle disuse, adult mice were
placed on a mechanical ventilator for 24 h resulting in a
state of diaphragmatic oxidative stress and proteolysis, and
treatment with 150 mg/kg NAC prevented oxidative stress
and markers of proteolysis in diaphragm muscle fibres. In
contrast, adult mice were exposed to 11 days of hind-limb
suspension and treated with a 1% NAC-enriched diet. NAC
prevented an increase in NF-kappaB but did not attenuate
muscle atrophy or functional decline (Farid et al. 2005).
The effects of NAC on MPS following feeding have yet to
be studied, and, thus, warrants further research.
In addition to antioxidants, amino acids (without ana-
bolic properties) have also been studied to improve the
postprandial MPS response. For example, the nonessen-
tial amino acid glycine (see Wang et al. 2013 for review)
is often considered biologically neutral and sometimes
used as an isonitrogenous control in supplementation stud-
ies (Ham et al. 2016). Evidence that glycine has profound
inhibitory effects on inflammatory cell activation has accu-
mulated (Zhong et al. 2003), and has been hypothesized to
enhance MPS in inflammatory conditions. In rats treated
with LPS (lipopolysaccharide), glycine supplementation
was capable to restore the postprandial MPS response to
leucine feeding. The improvement in protein metabolism
was associated with a reduction in skeletal muscle ROS
(mainly superoxide anions) but did not alter skeletal mus-
cle inflammatory signalling in vivo or in vitro (Ham et al.
2016). While glycine may be a promising nutrient in the
treatment of attenuation disuse atrophy, further investi-
gations should focus on whether these increases in MPS
translate to improvements in muscle mass.
A final nutrient that merits further research as an agent
that may enhance the MPS response is trimethylated gly-
cine (betaine). Betaine is a naturally occurring compound
found in dark green leafy vegetables, beets, and whole
wheat. In humans, higher consumptions and greater con-
centrations of plasma betaine are associated with lower
markers of inflammation (Detopoulou et al. 2008) and
betaine treatment has been shown to reduce NF-kappaB
expression in mice (Lee et al. 2013). In young adults,
betaine supplementation has been shown to increase lean
mass in conjunction with resistance training (Cholewa
et al. 2013) possibly due to enhanced Akt/PKB signalling
(Apicella et al. 2012). In particular, elevated plasma homo-
cysteine and its cyclized derivative, homocysteine thiolac-
tone, directly inhibit insulin-mediated Akt/PKB and p70
S6K phosphorylation (Najib and Sánchez-Margalet 2005)
and diminish myogenic satellite cell regenerative capabili-
ties by increasing oxidative stress and p38-MAPK (Veer-
anki et al. 2015). Increasing plasma homocysteine has been
associated with the development of sarcopenia (Park and
Georgiades 2013) and betaine supplementation has been
shown to reduce homocysteine and homocysteine thiol-
actone in young and older adults (Cholewa et al. 2014).
Therefore, betaine supplementation may protect against
homocysteine-induced inhibitions in protein synthesis and
possibly attenuate sarcopenia; however, further research in
both animal models of aging and translational research in
humans is needed to test this hypothesis.
Given the partial failure of dietary amino acid admin-
istration as a strategy to overcome anabolic resistance and
attenuate muscle wasting, glycine or an antioxidant-rich diet
plus leucine/protein consumption are promising strategies to
combat muscle wasting in states where anabolic resistance
Dietary proteins and amino acids in the control of the muscle mass during immobilization and…
1 3
to amino acids is prominent. Figure 1 summarizes the cur-
rent state of the research in young adult subjects and during
muscle disuse and aging conditions in regards to the post-
prandial MPS response to protein/AA feeding alone or com-
bined with antioxidants, including the AA glycine.
Conclusion and perspectives
Postprandial MPS can be stimulated by dietary proteins/
EAAs intake such that if a threshold quantity of high-
quality protein is consumed, maximal MPS values may
be reached. However, during non-pathological conditions
associated with muscle loss such as muscle disuse (immo-
bilization) and aging, the anabolic threshold for amino
acids to stimulate MPS is increased and the anabolic poten-
tial of a stereotypical protein intake to enhance muscle
anabolism is reduced. Several years ago, pioneering stud-
ies demonstrated that increasing protein consumption or
increasing the consumption of isolated amino acids with
anabolic properties (i.e., leucine) was capable to restore
the postprandial MPS response. However, this increase
in postprandial MPS did not always translate into muscle
tissue sparing during catabolic conditions. Several recent
investigations have demonstrated positive effects of pro-
tein/AA supplementation not only on MPS but also on
lean mass tissue, which suggests that an optimized and bal-
anced distribution of protein intake between meals could
be beneficial in the preservation of lean mass in the aging
population. However, why certain studies result in a lack
of positive effects (i.e., induces a maladaptation response
of muscle protein metabolism to increased amounts of
dietary proteins) during conditions associated with muscle
loss, still remains unclear and requires further investiga-
tion. However, from a practical point of view, neutralizing
the secondary factors linked to anabolic resistance such as
increased ROS or inflammation markers may be a prom-
ising strategy. Although antioxidant excess can potentially
lead to increased ROS production or be innocuous (Abdali
et al. 2015), antioxidant-rich diets and, more recently, gly-
cine supplementation, has demonstrated a strong potential
to restore postprandial MPS during immobilization, aging
and even sepsis. More chronic studies, however, are needed
to evaluate if this renewed increase in postprandial MPS,
indeed, leads to muscle restoration, and under which spe-
cific catabolic states that it may be most beneficial. If, on
the one hand, the main dietary concern in treating atrophy
is to increase the anabolic stimuli (aminoacidemia), on the
other hand, decreasing factors related to the anabolic resist-
ance is mandatory (ROS, inflammation and others) and
warrants further investigation.
Compliance with ethical standards
Conflict of interest We have no conflict of interest to declare.
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