Download Regulation of muscle protein synthesis in humans

REVIEW
URRENT
C
OPINION
Regulation of muscle protein synthesis in humans
Bethan E. Phillips, Derek S. Hill, and Philip J. Atherton
Purpose of review
Investigations into the regulation of muscle protein synthesis (MPS) are a cornerstone of understanding the
control of muscle mass. Rates of MPS are finely tuned according to levels of activity, nutrient availability
and health status. For instance, rates of MPS are positively regulated by exercise and nutrition, and
negatively regulated by inactivity (e.g. disuse), ageing (i.e. sarcopenia) and in muscle-wasting related
diseases (e.g. cancer).
Recent findings
Skeletal muscles display a high degree of intrinsic regulation. Increases in MPS after exercise occur
independently of the systemic milieu for example growth hormone/testosterone concentrations. In the
absence of exercise, increases in MPS after feeding are of finite duration despite enduring precursor
availability; that is muscles can sense they are ‘full’. Intriguingly, exercise delays this ‘muscle-full’ response
to allow for building and repair. In contrast, muscle-wasting conditions exhibit a premature ‘muscle-full’
response to nutrition and exercise (i.e. anabolic resistance), which may cause atrophy. Observations of
‘dissociations’ between MPS and anabolic signalling pathways have cast doubt on how much we
understand of the molecular regulation of human MPS.
Summary
Anabolic and anticatabolic interventions in health and disease should be aimed at manipulating the
‘muscle-full’ set point to maximize muscle maintenance/hypertrophy.
Keywords
anabolic resistance, mTOR signalling, protein synthesis, skeletal muscle
INTRODUCTION
Muscle mass is maintained by a dynamic equilibrium in protein turnover in which net efflux of
amino acids during fasting periods is offset by net
influx (and incorporation into protein) during fed
periods. Exercise, ageing and diseases associated
with muscle wasting may modulate the capacity
for muscles to incorporate available amino acids
into protein which we propose represents the key
aspect regulating hypertrophy and atrophy.
REGULATION OF MUSCLE PROTEIN
SYNTHESIS BY NUTRIENTS: NEW
FINDINGS
The anabolic effects of feeding are driven through
two principal mechanisms: first, fractional synthesis
rates of muscle proteins increase approximately
300% [1 ] and second, muscle protein breakdown
(MPB) rates are depressed approximately 50% [2]. As
the magnitude of change in muscle protein synthesis (MPS) is greater than those of MPB, increases
in MPS are the main driver of anabolic responses to
feeding. Work over the past 20 years has established
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that the anabolic effects of feeding could not occur
without ingestion of foodstuffs sufficient in essential amino acids (EAA; [3]) and more recently
that additional macronutrients have no additive
anabolic effects; that is addition of carbohydrate to
protein neither enhances MPS nor attenuates MPB
[4 ]. Of course, teleologically, the anabolic effects of
EAA must be short-lived otherwise one could
achieve hypertrophy through overfeeding (forsaking
adaptive increases in MPB). Indeed, recent
work by Atherton et al. [1 ] has confirmed this
premise: young men provided an oral bolus of
48 g whey protein demonstrated 300% increases in
MPS between 45–90 min which rapidly returned
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Division of Clinical Physiology, School of Graduate Entry Medicine and
Health, University of Nottingham, Derby, UK
Correspondence to Dr Philip J. Atherton, Division of Clinical Physiology,
School of Graduate Entry Medicine and Health, University of Nottingham,
Derby Royal Hospital, Uttoxeter Road, Derby DE22 3DT, UK. Tel: +44 0
1332 724725; fax: +44 0 1332 724611; e-mail: philip.atherton@not
tingham.ac.uk
Curr Opin Clin Nutr Metab Care 2012, 15:58–63
DOI:10.1097/MCO.0b013e32834d19bc
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Regulation of muscle protein synthesis in humans Phillips et al.
KEY POINTS
Muscle protein synthesis is driven by activity and
nutrient status.
Control of MPS/muscles mass is under intrinsic control.
represents the foremost intervention in offsetting
declines in muscle mass in ageing and other musclewasting conditions. In terms of understanding the
mechanisms of muscle hypertrophy an emerging
theme is the intrinsic capacity of muscle to adapt
to exercise. For example, in an elegantly designed
study, West et al. [9 ] manipulated endogenous
concentrations of ‘anabolic hormones’ [growth
hormone (GH) and testosterone] through varying
muscle recruitment volume thereby creating a
‘high’ hormone and ‘low’ hormone environment.
Intriguingly, systemic concentrations of GH and
testosterone did not impact either acute responses
to exercise in terms of MPS or adaptive responses to
resistance exercise training in terms of muscle
hypertrophy [10 ]. In agreement with a questionable role for these hormones on human MPS,
14-day recombinant GH administration which
increased serum GH, insulin-like growth factor
(IGF-1) and IGF-1 mRNA expression in muscle did
not affect MPS [11 ]. Thus, contrary to widespread
belief, ostensibly anabolic hormones do not drive
(i.e. are permissive at best) MPS or loading-induced
adaptation in humans, which must instead be controlled by intrinsic autocrine/paracrine factors and
mechanotransduction processes.
Not only must muscle cells have an intrinsic
signal to increase MPS, but also selectivity over
which proteins are to be synthesized, that is resistance training increases myofiber size, whereas
endurance training enhances fatigue resistance.
Measuring MPS in distinct muscle fractions (sarcoplasmic, collagen, myofibrillar, mitochondria)
could prove valuable in predicting such chronic
alterations in muscle phenotype. For example,
Wilkinson et al. [12] reported that, whereas endurance trained individuals specifically upregulated
mitochondrial protein synthesis after exercise,
those resistance trained upregulated myofibrillar
protein synthesis. In addition, Moore et al. [13]
reported that resistance type exercise induced sustained increases in myofibrillar but not sarcoplasmic
MPS. Together, these results support the concept
that myofibrillar protein accretion is quantitatively
more important for muscle hypertrophy [12]. Nonetheless, we know nothing of the intracellular
signals regulating these fraction-specific adaptations which were found to be similar irrespective
of fraction-specific regulation of MPS; more work is
needed to address this [12].
How can we maximize anabolic responses to
exercise? Optimizing patterns of loading and nutrition represent a major area of study. For example,
recent findings have cast new light on the role that
the intensity of exercise has in determining MPS
responses to exercise. For instance, work from
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Modulating muscles sensitivity to activity and nutrients
underlies atrophy/hypertrophy.
to baseline thereafter. Curiously, declines in MPS
occurred despite sustained plasma and muscle amino
acids availability suggesting an innate ‘muscle-full’
set point rather than MPS being driven by plasma/
intracellular amino acids bioavailability per se.
What about the mechanism of increased MPS in
response to EAA? Confirmation of a role for mammalian target of rapamycin complex 1 (mTORc1)
signalling was recently provided in a study in which
administration of rapamycin (a specific inhibitor of
mTORc1) blocked increases in MPS and mTORc1
signalling after oral EAA in humans [5 ]. In agreement with this, Atherton et al. [1 ] reported that after
feeding 48 g whey protein, rising MPS rates were
matched closely with mTORc1 substrate phosphorylation. It would then seem a straightforward assertion
that mTORc1 signalling controls the anabolic effects
of EAA, albeit with a caveat. In the latter study, the
authors found that declines in MPS to baseline
90 min after feeding (‘muscle-full’) occurred despite
continued upregulation of mTORc1 signalling, thus
revealing a ‘dissociation’ between mTORc1 and MPS
[6]. Nonetheless, whether this is a true dissociation
or an artefact of using single phosphorylation sites
as a proxy for kinase activity remains to be defined.
Recent work has also provided new evidence that
amino acids transporters might serve as more sophisticated import mechanisms than first thought. For
instance, it was shown that the anabolic effects
of leucine require glutamine efflux via sodiumcoupled neutral amino-acid transporter member
2 (SNAT2) so the system-L amino acid transporter
1 (LAT1) heteroexchange system can import leucine
[7]. Importantly, these transporters have been
demonstrated to be acutely regulated by oral EAA
in humans, with Rasmussen’s group reporting
increases in mRNA and protein for LAT1 and
SNAT2 [8 ]. These findings suggest that EAA
are downstream as well as upstream of amino acids
transporters.
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REGULATION OF MUSCLE PROTEIN
SYNTHESIS BY EXERCISE: NEW FINDINGS
Increasing muscle mass is the aim of bodybuilders
and recreational weightlifters alike, but also
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Protein, amino acid metabolism and therapy
Kumar et al. [14] has shown a sigmoidal dose
response to resistance exercise such that MPS is
greatest at exercise intensities greater than 60%
1 repetition maximum (1-RM); even wherein repetition number is increased at lower intensities (20–
40%) to balance workloads. These findings support
the notion that exercising above 60% 1-RM
represents an anabolic ‘ceiling’. Interestingly, the
intensity of exercise to elicit a robust increase in MPS
can be reduced drastically (20% 1-RM) when combined with blood flow restriction (i.e. vascular
occlusion [15 ]) suggesting that high-intensity exercise is not a prerequisite for exercise-induced
increases in MPS. Indeed, increasing the volume
of work at a low intensity (30% to failure) was
shown to be more effective than low-volume,
high-intensity exercise (90% to failure) [16 ] in
terms of amplitude/duration of MPS after exercise.
Although the work done was much greater in the
30% group, these findings are important as they
suggest that high-intensity exercise per se is not a
prerequisite for maximizing MPS after exercise and
factors such as fibre recruitment or muscle perfusion
may also be important. Nonetheless, how manipulating these parameters would translate into training adaptation remains to be fully defined.
It is well established that nutrient sufficiency
represents a necessary component of muscle remodelling and hypertrophy [17] and that EAA potentiates acute anabolic responses to exercise. However,
recent work has provided new information surrounding the synergistic anabolic effects of exercise
and nutrients: Moore et al. [18 ] reported that the
phosphorylation of mTORc1 and mitogen-activated
protein kinase related proteins were shown to be
greater with the combination of exercise and feeding than feeding alone which may explain additive
effects on MPS. Although the question over optimal
timing of nutrient intake has been a hotly
researched topic, recent observations of Burd et al.
[19 ] have highlighted good reason to question the
importance of timing. This is because even 24 h after
a single bout of unilateral resistance exercise, provision of EAA caused a much greater increase in MPS
in the exercised than rest leg which suggests that the
additive effects of exercise on MPS response to EAA
are long-lived (i.e. there is a delaying of the ‘musclefull’ signal; see Fig. 1). Therefore, it is speculated that
consuming adequate dietary EAA intake is likely to
be more important than timing per se.
Nonetheless, recent work has highlighted that
even the most optimal of feeding and exercise strategies may not elicit substantial effects in all individuals. In a recent study by Davidsen et al. [20 ], a
fully supervised resistance exercise training program
to younger adults elicited strikingly heterogeneous
Muscle protein
synthesis
Catabolic
Anabolic
Anabolic
Catabolic
Time
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FIGURE 1. Schematic showing muscle protein synthesis
responses in normal (− ), catabolic ( ) and anabolic ()
states. Arrows indicate the ‘muscle-full’ set point, which can
be modulated in terms of amplitude and/or duration of MPS.
mass and strength gains, a continuum from which
the authors categorized the top 20% ‘high’ and
bottom 20% ‘low’ responders. Profiling of miRNA
in these distinct responders yielded four miRNA
species which were associated with training responsiveness: for example in ‘low responders’ miR-378,
29a and 26a were downregulated, whereas miR-451
was upregulated. These findings suggest that these
miRNAs may have a role in determining adaptive
heterogeneity. In another study, Mayhew et al. [21 ]
determined that increased concentrations of
eukaryotic initiation factor 2B epsilon (eIF2Be)
protein after a single exercise bout was directly
associated with the degree of hypertrophy after resistance exercise training, and that in-vitro overexpression of eIF2Be lead to muscle hypertrophy; thus
upregulation of eIF2Be may partly underlie adaptive
capacity. Clearly then, using biological variability
represents a powerful approach in terms of both
bioprediction and gaining mechanistic insight in
human studies and more work is needed to link
measures such as noncoding RNA, mRNA, intracellular proteins and MPS in humans. For instance, it
could be speculated that heterogeneity in the
muscle-full set point may underlie adaptive capacity.
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REGULATION OF MUSCLE PROTEIN
SYNTHESIS IN CATABOLIC CONDITIONS:
THE CONCEPT OF ANABOLIC RESISTANCE
Causes of muscle atrophy may be broadly separated
into sarcopenia, disuse, and wasting-associated
diseases. Although it has long been known that
declines in postabsorptive MPS and/or increases in
MPB (depending upon the driving cause) are a catalyst for muscle atrophy, recent work has uncovered a
new layer of dysregulation termed anabolic resistance that seems to transcend the cause of atrophy.
In a nutshell, anabolic resistance is a deficit in the
capacity to mount anabolic responses to activity and
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Regulation of muscle protein synthesis in humans Phillips et al.
nutrients [22,23]; the key influences of muscle
maintenance. It is postulated by the authors that
anabolic resistance represents a perpetual ‘premature muscle-full state’ (see Fig. 1) that underlies
and/or exacerbates atrophy and perhaps contributes
to maladaptation to exercise (i.e. in ageing).
determining anabolic sensitivity (Note: free-EAA
would be absorbed more slowly than proteins).
Finally, research concerning overcoming anabolic
resistance may not be restricted to amino acids
composition/quantity as other novel interventions have proved efficacious. For example, 8-week
supplementation of omega-3 fish oils ameliorated
anabolic resistance in elderly men [30 ]. Thus,
although consensus on whether, and how, anabolic resistance may be overcome remains ill
defined, initial research is promising.
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ANABOLIC RESISTANCE TO FEEDING IN
AGEING MUSCLES
Although sarcopenia must involve an imbalance
between MPS and MPB, rates of MPS and MPB
during postabsorptive periods are unchanged with
age. As such, other mechanisms have been sought,
one of which being anabolic resistance. In support
of this concept, Cuthbertson et al. [24] compared
responses in MPS to oral EAA over a wide availability
(2.5–40 g) and found that above 5 g EAA, older men
exhibited smaller increases in MPS to those seen in
young people. In contrast, others have also reported
anabolic resistance but only at lower doses of EAA
[25] and Symons et al. [26] found that administration of 113 g of lean beef (30 g protein) raised
MPS by approximately 50% in both young and old
healthy patients. Similarly, Chevalier et al., [27 ]
found no blunting in the anabolic response under
hyperglycaemic, hyperinsulinaemic, hyperaminoacidaemic conditions in which blood concentrations of insulin, total amino acids and
glucose were maintained at approximately
300–400 pmol l1, 3300 mmol l1 and 8 mmol l1,
respectively. Although these findings support the
notion that overcoming anabolic resistance is
simply a matter of increasing total amino acid load
[24]; they remain at odds to reports of anabolic
resistance after consumption of 20–40 g EAA [24].
Consequently, perhaps it is the ‘quality’ (i.e.
specific amino acids content form) rather than
quantity of amino acids that is important for overcoming anabolic resistance. Pennings et al. [28 ]
used intrinsically stable isotopically labelled
proteins to compare acute anabolic responses of
older men to casein, casein hydrolysate and whey
protein. Protein synthesis rates were significantly
higher following whey ingestion (0.15% h1) than
casein (0.08% h1) or casein hydrolysate (0.10%
h1); a result which the authors explained as being
due to the faster absorption rates and a higher peak
plasma concentration of leucine. Intriguingly, the
Phillips lab recently demonstrated that a large
single bolus of protein was more effective in stimulating MPS than the sum of quantitatively equivalent small boluses in younger men [29 ].
Together, these data support the concept that
rapid exposure of muscle to amino acids and/or
peak leucine concentration may be important in
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ANABOLIC RESISTANCE TO EXERCISE IN
AGEING MUSCLES
As is the case with feeding, there is also evidence for
anabolic resistance to exercise in ageing. For
instance, 1–2 h after exercise, Kumar et al., [14]
reported that MPS responses were blunted in the
elderly over a range of intensities of resistance exercise performed in the postabsorptive state (20–90%
1-RM). These findings were further corroborated by
Fry et al. [31 ] who showed aging impairs contraction-induced human skeletal muscle mTORc1 signalling and protein synthesis when sampling up to
24 h after exercise. Collectively, these data may
explain age-related reductions in trainability (i.e.
muscle hypertrophy) with resistance exercise training [32 ]. Moreover, the findings of anabolic resistance are not restricted to resistance type exercise:
Durham et al., [33 ] also reported age-related
declines in MPS responses to endurance type exercise (i.e. walking) in the fed state. Therefore, it is
speculated that anabolic insensitivity even to mild,
habitual activity may exacerbate the catabolic
effects of sedentarism associated with ageing. Nonetheless, as with feeding, conflicting data cast doubt
over the existence of anabolic resistance to exercise.
For example, Symons et al. [34 ] found that when a
bout of resistance exercise was combined with a
high quality protein meal there was no difference
in MPS responses between young and older individuals and Drummond et al. [35] reported that the
‘cumulative’ anabolic response to resistance exercise
and EAA is similar but the response is simply delayed
with ageing. Nonetheless, we contend that shorterduration exercise studies (unlike for feeding alone
[1 ]) cannot capture the complete long-term anabolic effects of exercise [19 ]. As such, the study by
Fry et al. [31 ] in which anabolic resistance was
confirmed over an extended recovery (3, 8 and
24 h after exercise) encompassing fasted and fed
periods, is more likely to identify small but important differences which otherwise could be masked
under short-study formats and with heterogeneity
in small sample sizes.
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Protein, amino acid metabolism and therapy
ANABOLIC RESISTANCE TO NUTRIENTS
AND EXERCISE: BEYOND AGEING?
New work is beginning to show that anabolic resistance transcends age-related muscle wasting. Disuse
atrophy is where muscles waste purely due to withdrawal of neural/mechano-input and (unlike ageing)
is associated with declines in postabsorptive MPS
rates, but also a very clear anabolic resistance to
EAA [36]. Can we assess the impact of anabolic resistance on muscle atrophy in disuse? Yes! Consider the
following: normal turnover is 0.05% h1 or 1.2% d1
in which MPS and MPB are equal and opposite. As
MPS increases approximately three-fold for 1.5 h and
approximately 5 h per day is spent in fed periods [1 ],
based on conservative assumptions from previous
findings in disuse in which MPS was suppressed
approximately 50% in both postabsorptive and fed
periods then diurnal protein accretion would be:
[0.025 19 (fasted)] þ [0.025 1.5 5 (fed)] ¼ 0.66%
0.66% day1. Thus, if MPB remained constant then
muscle would be lost at a rate of: 1.20.66 ¼ 0.54%
day1, a figure entirely consistent with that measured
(0.6% day1) over the first 30 days of immobilization [37]. Therefore, suppressions in postabsorptive
MPS coupled to anabolic resistance are sufficient to
explain muscle loss in disuse (Note: without the need
for increases in MPB). Although to date few other
muscle-wasting conditions have been investigated,
there is emerging evidence that anabolic resistance
may be a common feature. For example, Tuvdendorj
et al. [38 ] recently showed that skeletal muscles of
paediatric burn patients are unresponsive to EAA and
Deutz et al. [39 ] showed the same in cancer patients.
Finally, evidence is mounting that the ability to
inhibit MPB postprandially is also diminished
[2,40 ]. Thus, if present, the inability to reduce
MPB after feeding would exacerbate the wasting
due to anabolic resistance in MPS.
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CONCLUSION
Human MPS is intrinsically regulated. Growth is
achieved by delaying the ‘muscle-full’ signal
whereas approaches to minimize muscle atrophy
may be achieved by doing the same that is ameliorating anabolic resistance (Fig. 1).
Acknowledgements
None.
Conflicts of interest
P.J. Atherton is supported by a Research Councils UK
fellowship and Ajinomoto Inc. D.S. Hill has a PhD studentship supported by an NIH-NIAMS grant (AR-054342)
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and the University of Nottingham and B.E. Phillips is a
BBSRC funded research associate (BB/C516779/1).
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
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of special interest
&& of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 94–95).
1. Atherton PJ, Etheridge T, Watt PW, et al. Muscle full effect after oral protein:
time-dependent concordance and discordance between human muscle
protein synthesis and mTORC1 signalling. Am J Clin Nutr 2010;
92:1080–1088.
Demonstration of ‘muscle-full’ phenomenon.
2. Wilkes EA, Selby AL, Atherton PJ, et al. Blunting of insulin inhibition of
proteolysis in legs of older subjects may contribute to age-related sarcopenia.
Am J Clin Nutr 2009; 90:1343–1350.
3. Smith K, Barua JM, Watt PW, et al. Flooding with L-[1-13C]leucine stimulates
human muscle protein incorporation of continuously infused L-[1-13C]valine.
Am J Physiol 1992; 262:E372–E376.
4. Staples AW, Burd NA, West DW, et al. Carbohydrate does not augment
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exercise-induced protein accretion versus protein alone. Med Sci Sports
Exerc 2011; 43:1154–1161.
Highlights the solitary role of EAA in regulating protein metabolism.
5. Dickinson JM, Fry CS, Drummond MJ, et al. Mammalian target of rapamycin
&&
complex 1 activation is required for the stimulation of human skeletal muscle
protein synthesis by essential amino acids. J Nutr 2011; 141:856–862.
Demonstrates the importance of mTORc1 in regulating exercise-induced increases in MPS.
6. Greenhaff PL, Karagounis LG, Peirce N, et al. Disassociation between the
effects of amino acids and insulin on signalling, ubiquitin ligases, and protein
turnover in human muscle. Am J Physiol Endocrinol Metab 2008; 295:
E595–E604.
7. Nicklin P, Bergman P, Zhang B, et al. Bidirectional transport of amino acids
regulates mTOR and autophagy. Cell 2009; 136:521–534.
8. Drummond MJ, Glynn EL, Fry CS, et al. An increase in essential amino acid
&&
availability upregulates amino acid transporter expression in human skeletal
muscle. Am J Physiol Endocrinol Metab 2010; 298:E1011–E1018.
Amino acids transporters are acutely regulated by EAA in humans.
9. West DW, Kujbida GW, Moore DR, et al. Resistance exercise-induced
&&
increases in putative anabolic hormones do not enhance muscle protein
synthesis or intracellular signalling in young men. J Physiol 2009; 587:
5239–5247.
Systemic hormones permissive for postexercise increases in MPS.
10. West DW, Burd NA, Tang JE, et al. Elevations in ostensibly anabolic
&&
hormones with resistance exercise enhance neither training-induced muscle
hypertrophy nor strength of the elbow flexors. J Appl Physiol 2010; 108:
60–67.
Systemic hormones permissive for muscle hypertrophy after resistance exercise
training.
11. Doessing S, Heinemeier KM, Holm L, et al. Growth hormone stimulates the
&
collagen synthesis in human tendon and skeletal muscle without affecting
myofibrillar protein synthesis. J Physiol 2010; 588:341–351.
Demonstrates no effects of exogenous GH on MPS.
12. Wilkinson SB, Phillips SM, Atherton PJ, et al. Differential effects of resistance
and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle. J Physiol 2008; 586:
3701–3717.
13. Moore DR, Tang JE, Burd NA, et al. Differential stimulation of myofibrillar and
sarcoplasmic protein synthesis with protein ingestion at rest and after
resistance exercise. J Physiol 2009; 587:897–904.
14. Kumar V, Selby A, Rankin D, et al. Age-related differences in the doseresponse relationship of muscle protein synthesis to resistance exercise in
young and old men. J Physiol 2009; 587:211–217.
15. Fry CS, Glynn EL, Drummond MJ, et al. Blood flow restriction exercise
&
stimulates mTORC1 signalling and muscle protein synthesis in older men.
J Appl Physiol 2010; 108:1199–1209.
Increasing anabolic responses to low intensity exercise is possible by restricting
blood flow.
16. Burd NA, West DW, Staples AW, et al. Low-load high volume
&
resistance exercise stimulates muscle protein synthesis more than highload low volume resistance exercise in young men. PLoS One 2010;
5:e12033.
Fatiguing muscles with prolonged low intensity exercise is more effective than
brief, intense exercise for increasing MPS.
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Regulation of muscle protein synthesis in humans Phillips et al.
17. Moore DR, Robinson MJ, Fry JL, et al. Ingested protein dose response of
muscle and albumin protein synthesis after resistance exercise in young men.
Am J Clin Nutr 2009; 89:161–168.
18. Moore DR, Atherton PJ, Rennie MJ, et al. Resistance exercise enhances
&&
mTOR and MAPK signalling in human muscle over that seen at rest after bolus
protein ingestion. Acta Physiol (Oxf) 2011; 201:365–372.
Amino acids potentiate anabolic signalling responses to exercise, perhaps
explaning synergistic effects on MPS.
19. Burd NA, West DW, Moore DR, et al. Enhanced amino acid sensitivity of
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myofibrillar protein synthesis persists for up to 24 h after resistance exercise in
young men. J Nutr 2011; 141:568–573.
Highlights prolonged additive effects of exercise on anabolic responses to feeding.
20. Davidsen PK, Gallagher IJ, Hartman JW, et al. High responders to resistance
&&
exercise training demonstrate differential regulation of skeletal muscle microRNA expression. J Appl Physiol 2011; 110:309–317.
Links specific miRNAs to adaptive heterogeneity in humans.
21. Mayhew DL, Hornberger TA, Lincoln HC, Bamman MM, Eukaryotic initiation
&
factor 2B{epsilon}. (eIF2B{epsilon}) induces cap-dependent translation and
skeletal muscle hypertrophy. J Physiol 2011; 589:3023–3037.
Links intracellular protein concentrations after acute exercise to chronic training
adaptation in humans.
22. Rennie MJ, Wilkes EA. Maintenance of the musculoskeletal mass by control of
protein turnover: the concept of anabolic resistance and its relevance to the
transplant recipient. Ann Transplant 2005; 10:31–34.
23. Fry CS, Rasmussen BB, Skeletal muscle protein balance and metabolism in
the elderly. Curr Aging Sci 2011. [Epub ahead of print]
24. Cuthbertson D, Smith K, Babraj J, et al. Anabolic signalling deficits underlie
amino acid resistance of wasting, aging muscle. FASEB J 2005; 19:422–
424.
25. Volpi E, Mittendorfer B, Rasmussen BB, Wolfe RR. The response of muscle
protein anabolism to combined hyperaminoacidemia and glucose-induced
hyperinsulinemia is impaired in the elderly. J Clin Endocrinol Metab 2000;
85:4481–4490.
26. Symons TB, Sheffield-Moore M, Wolfe RR, Paddon-Jones D. A moderate
serving of high-quality protein maximally stimulates skeletal muscle protein
synthesis in young and elderly subjects. J Am Diet Assoc 2009; 109:
1582–1586.
27. Chevalier S, Goulet ED, Burgos SA, et al. Protein anabolic responses to a fed
&
steady state in healthy aging. J Gerontol A Biol Sci Med Sci 2011; 66:
681–688.
Demonstrates no reduction in anabolic sensitivity to feeding in ageing.
28. Pennings B, Boirie Y, Senden JM, et al. Whey protein stimulates postprandial
&
muscle protein accretion more effectively than do casein and casein hydrolysate in older men. Am J Clin Nutr 2011; 93:997–1005.
Highlights the importance of amino acids source in mediating acute anabolic
responses to feeding in older individuals.
29. West DW, Burd NA, Coffey VG, et al. Rapid aminoacidemia enhances
myofibrillar protein synthesis and anabolic intramuscular signalling responses
after resistance exercise. Am J Clin Nutr 2011; 94:795–803.
Highlights the importance of amino acids delivery in mediating acute anabolic
responses to feeding.
30. Smith GI, Atherton P, Reeds DN, et al. Dietary omega-3 fatty acid supple&
mentation increases the rate of muscle protein synthesis in older adults: a
randomized controlled trial. Am J Clin Nutr 2011; 93:402–412.
Anabolic sensitivity to feeding can be increased using approaches other than
modulating amino acids availability/source.
31. Fry CS, Drummond MJ, Glynn EL, et al. Aging impairs contraction-induced
&&
human skeletal muscle mTORC1 signalling and protein synthesis. Skeletal
Muscle 2011; 1:11.
Definitive demonstration of anabolic resistance to exercise in ageing.
32. Bickel CS, Cross JM, Bamman MM. Exercise dosing to retain resistance
&
training adaptations in young and older adults. Med Sci Sports Exerc 2011;
43:1177–1187.
Ageing blunts adaptation to exercise.
33. Durham WJ, Casperson SL, Dillon EL, et al. Age-related anabolic resistance
&
after endurance-type exercise in healthy humans. FASEB J 2010; 24:
4117–4127.
Anabolic resistance is not restricted to resistance type-exercise.
34. Symons TB, Sheffield-Moore M, Mamerow MM, et al. The anabolic response
&
to resistance exercise and a protein-rich meal is not diminished by age. J Nutr
Health Aging 2011; 15:376–381.
Data contesting anabolic resistance to exercise in ageing.
35. Drummond MJ, Dreyer HC, Pennings B, et al. Skeletal muscle protein anabolic
response to resistance exercise and essential amino acids is delayed with
aging. J Appl Physiol 2008; 104:1452–1461.
36. Glover EI, Phillips SM, Oates BR, et al. Immobilization induces anabolic
resistance in human myofibrillar protein synthesis with low and high dose
amino acid infusion. J Physiol 2008; 586:6049–6061.
37. Phillips SM, Glover EI, Rennie MJ. Alterations of protein turnover underlying
disuse atrophy in human skeletal muscle. J Appl Physiol 2009; 107:645–654.
38. Tuvdendorj D, Chinkes DL, Zhang XJ, et al. Skeletal muscle is anabolically
&&
unresponsive to an amino acid infusion in pediatric burn patients 6 months
postinjury. Ann Surg 2011; 253:592–597.
Anabolic resistance in burns patients.
39. Deutz NE, Safar A, Schutzler S, et al. Muscle protein synthesis in cancer
&&
patients can be stimulated with a specially formulated medical food. Clin Nutr
2011. [Epub ahead of print]
Anabolic resistance in cancer.
40. Toth MJ, LeWinter MM, Ades PA, Matthews DE. Impaired muscle protein
&
anabolic response to insulin and amino acids in heart failure patients: relationship with markers of immune activation. Clin Sci (Lond) 2010; 119:467–476.
Anabolic resistance exists in heart failure patients.
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