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Articles in PresS. J Appl Physiol (September 25, 2014). doi:10.1152/japplphysiol.00609.2014
What is the relationship between acute of muscle protein synthesis response and
changes in muscle mass?
Cameron J. Mitchell1, Tyler A. Churchward-Venne2, David Cameron-Smith1, Stuart M.
Liggins Institute, University of Auckland, Auckland, New Zealand; 2Department of Human
Movement Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht
University Medical Centre, Maastricht, the Netherlands; 3Exercise Metabolism Research
Group, Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada
Professor Stuart M. Phillips
The Department of Kinesiology,
1280 Main Street West
Hamilton Ontario L8S 4L8,
P: +1-905-525-9140 x24465
Copyright © 2014 by the American Physiological Society.
Rates of synthesis of skeletal muscle protein pools (myofibrillar, mitochondrial,
sarcoplasmic) are often directly measured through determination of the fractional synthetic
rate (FSR) using stable isotope tracer labelled amino acids. This is accomplished by
measuring the incorporation of tracer amino acid into muscle protein (bound enrichment),
determining the enrichment of the precursor pool, and dividing the incorporation of amino
acid tracer over a given period of time by the precursor enrichment yielding a rate in % per
unit time (3, 22). Measures of muscle protein FSR, often referred to as muscle protein
synthesis (MPS), have been routinely employed to examine the acute effects (i.e., several
hours to 24 hours) of various exercise and nutritional stimuli. This begs the question as to
whether acute early changes in MPS, particularly following resistance exercise (RE), relate to
the magnitude of muscle hypertrophy in longer-term training studies? It has been proposed
that chronic adaptation (i.e., muscle hypertrophy) with resistance training (RT) occur as a
result of summed periods of repeated acute exercise-induced positive protein balance where
MPS exceeds muscle protein breakdown (MPB) (20). In such a scenario, one thesis is that the
clearly established heterogeneity of the hypertrophic response to resistance training (8, 14,
15) may be explained, to some degree, by divergent responses of MPS to acute exercise
stimuli; but is this the case? It is possible the variations in MPB are also important for the
regulation of muscle hypertrophy however, the measurement of MPB is hampered by
methodological limitations and thus is reported infrequently. The magnitude of regulation of
MBP is much smaller than MPS (7). Additional resistance exercise appears to regulate MPB
and MPS in a concomitant manner (21). We believe that although it would be ideal to
measure the balance between MPS and MPB that MPS is likely to have a greater relationship
with hypertrophy than MPB.
To date, only a single study has reported the within-subject association between acute
MPS rates after RE and skeletal muscle hypertrophy following prolonged RT (15). Another
study attempted to correlated MPS measured 24h after the first training session with muscle
hypertrophy (14) In neither study was a linear correlation between MPS and hypertrophy
observed (14, 15). The lack of a correlation between pre training measures of MPS and
muscle hypertrophy after prolonged training may lead one to question the value of acute
measurements of MPS to yield insight into phenotypic adaptations following RT.
Nonetheless, while acute MPS response is not always quantitatively related to muscle
hypertrophy, there are a number of examples where MPS response following an acute
intervention (nutrition and/or exercise) is aligned with changes in muscle hypertrophy in
different subject cohorts. Multiple studies from our laboratory (2, 3, 8, 16, 27, 28, 31), and
others (9, 10) have demonstrated that patterns of change in acute (i.e. over several hours) of
MPS response following a single session RE were aligned with the adaptive hypertrophic
response following repeated exposure (i.e. for several weeks) to a similar dietary/exercise
intervention. For example, the acute MPS response following post-RE consumption of milk
versus a soy beverage (31) was qualitatively aligned with changes in lean body mass obtained
following 12 weeks of RT and the same protein supplementation (8). In addition, the
response of MPS following RE employing lower load contractions (3) and RE bouts
employing greater volumes of work (three sets versus one set) (2), were congruent with the
hypertrophic response following a period of RT employing these training protocols (16).
However, the magnitude of the acute response of MPS and the subsequent hypertrophy with
the same stimuli in RT is highly variable between individuals. The source of such
hypertrophic variability is likely due to an individual’s inherited genetic predisposition,
epigenetic influence, and transcriptional plasticity, all of which are likely further impacted by
factors such as age, habitual physical activity, and training status. For example, multiple set
training has been demonstrated to elicit a greater acute response of MPS (2) and training
mediated muscle hypertrophy (12, 16) than single set training, however a ‘hypertrophic
responder’ to resistance exercise may demonstrate a greater response both acutely (i.e. MPS),
and in response to RT (i.e. muscle hypertrophy), following single set training, than a ‘non-
responder’ to multi-set RT. We propose that the response heterogeneity to RT (8, 14) is often
overlooked but it is inherently hard to modify and highlights the importance of adequate
sample size to detect differences in the hypertrophic response to various exercise/nutritional
In comparison to younger persons older persons have a lower MPS rates in response
to protein feeding and exercise (5, 13, 17), a condition termed ‘anabolic resistance’ (5).
Reductions in loading/physical activity very quickly lead to reductions in anabolic sensitivity
to feeding (1, 6, 26). Conversely, even relatively short-duration moderate intensity aerobic
exercise performed 15 hours earlier improves the MPS response to meal feeding (25). We
hypothesize that physical activity in the hours, possibly days, before measurement of MPS, as
well as habitual levels of physical activity and training status, can have a significant impact
on magnitude of the MPS response to feeding (25) and possibly exercise. To date, only a few
studies have measured MPS in both the trained and untrained state within the same
individuals (11, 24, 29). These studies have shown that RT generally reduces the duration of
the acute MPS response to a session of RE preformed at the same relative intensity (11, 24);
however, we do not know when in a RT program this change occurs. It is known, however,
that the transcriptional response following the first exercise session is reflective of muscle
damage and differs substantially from a second RE bout performed 48 h later (18). In
addition, integrated daily MPS rates were shown to be lower after only two workouts during
an 8 day resistance training period (29). Thus, it appears that very little ‘training’ is required
to modify the acute transcriptional (18) and protein synthetic (11, 24, 29) responses to a bout
of RE, at least of the same relative intensity. These observations (11, 18, 24, 29) suggest that
acute measurement of the response of MPS to RE is not going to be useful in predicting
longer-term capacity for adaption to RT within individuals because it does not represent a
‘typical’ response over a RT program comprised of multiple training sessions (3-4 per week).
Indeed, we reported that following the first training session the acute MPS response is not
correlated with muscle hypertrophy after RT in the same individuals (15). There are multiple
factors that might explain this observation (15): the short duration of the FSR measurement,
subtle differences in proteolysis (7), or inherent variation in the measurement (23); however,
we theorize that the most likely explanation for the discordance is that the magnitude and
duration of the MPS response to acute RE is highly variable between individuals and can
change considerably (11, 24, 29, 30) as RT progresses.
It is important to point out that in addition the physiological variability
methodological variability and test retest reliability could obscure any relationship between
acute MPS and hypertrophy. Muscle hypertrophy can be measured in a number of different
ways including fibre area from histological section, lean mass from DXA and cross sectional
area of volume from MRI or CT scans. In our previous study (15) hypertrophy was measured
by MRI derived muscle because in our experience and that of others (19) variability is ~1%.
Much less is known about reproducibility of MPS measure in the same subject and it is
conceivable variability inherent in the MPS methodology could obscure any potential
Acute measurements of MPS response can provide important insight into the
mechanistic underpinnings of divergent exercise and nutritional manipulations (3, 4, 10, 24,
31). Such measures have shown the ability to discriminate between gross differences in
muscle contraction volume (2) and relative fatigue (3, 10) as well as differences in protein
quality and amino acid composition (4, 31). Nonetheless, at an individual level a divergent
acute response in MPS may be necessary but is not sufficient to conclude that a divergent
muscle hypertrophic response will follow and similarly so for RT plus nutrition-induced
changes in hypertrophy (14, 15). It is likely that a high degree of intra-individual variation in
various factors with repeated exposure to the exercise stimulus. In conclusion, results from
acute measures of MPS should continue to be regarded important indicators of the gross-level
potential of a given exercise/nutritional intervention; however long term studies are necessary
to elucidate the capacity to which an individual will respond in terms of altered phenotype
(i.e. increased muscle mass) in response to chronic exposure to a given exercise/nutritional
Breen L, Stokes KA, Churchward-Venne TA, Moore DR, Baker SK, Smith K, Atherton PJ, and
Phillips SM. Two weeks of reduced activity decreases leg lean mass and induces "anabolic
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Burd NA, Holwerda AM, Selby KC, West DW, Staples AW, Cain NE, Cashaback JG, Potvin JR,
Baker SK, and Phillips SM. Resistance exercise volume affects myofibrillar protein synthesis and
anabolic signalling molecule phosphorylation in young men. The Journal of physiology 588: 31193130, 2010.
Burd NA, West DW, Staples AW, Atherton PJ, Baker JM, Moore DR, Holwerda AM, Parise
G, Rennie MJ, Baker SK, and Phillips SM. Low-load high volume resistance exercise stimulates
muscle protein synthesis more than high-load low volume resistance exercise in young men. PloS
one 5: e12033, 2010.
Churchward-Venne TA, Breen L, Di Donato DM, Hector AJ, Mitchell CJ, Moore DR,
Stellingwerff T, Breuille D, Offord EA, Baker SK, and Phillips SM. Leucine supplementation of a lowprotein mixed macronutrient beverage enhances myofibrillar protein synthesis in young men: a
double-blind, randomized trial. The American journal of clinical nutrition 99: 276-286, 2014.
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carbohydrate intake following resistance exercise. American journal of physiology Regulatory,
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Phillips SM. Consumption of fat-free fluid milk after resistance exercise promotes greater lean mass
accretion than does consumption of soy or carbohydrate in young, novice, male weightlifters. The
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Resistance exercise load does not determine training-mediated hypertrophic gains in young men. J
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Moore DR, Churchward-Venne TA, Witard O, Breen L, Burd NA, Tipton KD, and Phillips SM.
Protein Ingestion to Stimulate Myofibrillar Protein Synthesis Requires Greater Relative Protein
Intakes in Healthy Older Versus Younger Men. The journals of gerontology Series A, Biological
sciences and medical sciences 2014.
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Tang JE, Perco JG, Moore DR, Wilkinson SB, and Phillips SM. Resistance training alters the
response of fed state mixed muscle protein synthesis in young men. American journal of physiology
Regulatory, integrative and comparative physiology 294: R172-178, 2008.
Timmerman KL, Dhanani S, Glynn EL, Fry CS, Drummond MJ, Jennings K, Rasmussen BB,
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West DW, Burd NA, Tang JE, Moore DR, Staples AW, Holwerda AM, Baker SK, and Phillips
SM. Elevations in ostensibly anabolic hormones with resistance exercise enhance neither traininginduced muscle hypertrophy nor strength of the elbow flexors. J Appl Physiol 108: 60-67, 2009.
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Wilkinson SB, Phillips SM, Atherton PJ, Patel R, Yarasheski KE, Tarnopolsky MA, and
Rennie MJ. Differential effects of resistance and endurance exercise in the fed state on signalling
molecule phosphorylation and protein synthesis in human muscle. The Journal of physiology 586:
Wilkinson SB, Tarnopolsky MA, Macdonald MJ, Macdonald JR, Armstrong D, and Phillips
SM. Consumption of fluid skim milk promotes greater muscle protein accretion after resistance
exercise than does consumption of an isonitrogenous and isoenergetic soy-protein beverage. The
American journal of clinical nutrition 85: 1031-1040, 2007.