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The metabolic and temporal basis of muscle

hypertrophy in response to resistance exercise
a a a a
Matthew S. Brook , Daniel J. Wilkinson , Kenneth Smith & Philip J. Atherton
a
MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic
and Molecular Physiology, University of Nottingham, UK
Published online: 20 Aug 2015.

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 European Journal of Sport Science, 2015
http://dx.doi.org/10.1080/17461391.2015.1073362

REVIEW ARTICLE

The metabolic and temporal basis of muscle hypertrophy in response to

resistance exercise

MATTHEW S. BROOK, DANIEL J. WILKINSON, KENNETH SMITH, & PHILIP

J. ATHERTON

MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical, Metabolic and Molecular Physiology,
Downloaded by [Ecole Hautes Etudes Commer-Montreal] at 05:53 22 August 2015

University of Nottingham, UK

Abstract
Constituting ∼40% of body mass, skeletal muscle has essential locomotory and metabolic functions. As such, an insight into
the control of muscle mass is of great importance for maintaining health and quality-of-life into older age, under conditions of
cachectic disease and with rehabilitation. In healthy weight-bearing individuals, muscle mass is maintained by the equilibrium
between muscle protein synthesis (MPS) and muscle protein breakdown; when this balance tips in favour of MPS
hypertrophy occurs. Despite considerable research into pharmacological/nutraceutical interventions, resistance exercise
training (RE-T) remains the most potent stimulator of MPS and hypertrophy (in the majority of individuals). However,
the mechanism(s) and time course of hypertrophic responses to RE-T remain poorly understood. We would suggest that
available data are very much in favour of the notion that the majority of hypertrophy occurs in the early phases of RE-T
(though still controversial to some) and that, for the most part, continued gains are hard to come by. Whilst the
mechanisms of muscle hypertrophy represent the culmination of mechanical, auto/paracrine and endocrine events, the
measurement of MPS remains a cornerstone for understanding the control of hypertrophy – mainly because it is the
underlying driving force behind skeletal muscle hypertrophy. Development of sophisticated isotopic techniques
(i.e. deuterium oxide) that lend to longer term insight into the control of hypertrophy by sustained RE-T will be
paramount in providing insights into the metabolic and temporal regulation of hypertrophy. Such technologies will have
broad application in muscle mass intervention for both athletes and for mitigating disease/age-related cachexia and
sarcopenia, alike.

Keywords: Muscle, protein turnover, hypertrophy, resistance exercise training

Introduction In addition, skeletal muscle acts as an endocrine

organ, secreting factors that can work in an auto/para-
Skeletal muscle is best recognized for the essential role
crine fashion or travel to other tissues to influence
it plays in maintaining posture and locomotion for
metabolism; possibly in a health-promoting manner
the completion of activities of daily living. Skeletal
(Pedersen, 2013).
muscles represent the largest organ of the body in
On this basis, the well-defined experimental
comprising nearly half of total body mass. Moreover,
and epidemiological links between low skeletal
it is increasingly recognized that skeletal muscles
muscle mass and function, morbidity and all-cause
play an important role in the control of whole body
mortality are perhaps unsurprising (Janssen, Heyms-
metabolism (e.g. glycemic control) and provision
field, & Ross, 2002; Jones, Doleman, Scott, Lund, &
of gluconeogenic precursors that can be liberated to
Williams, 2015; Metter, Talbot, Schrager, & Conwit,
support extra-muscular tissue needs (Felig, Owen,
2002). Crucially, skeletal muscle exhibits marked
Wahren, & Cahill, 1969; Pozefsky, Tancredi,
plasticity; that is, muscle phenotype is grossly
Moxley, Dupre, & Tobin, 1976; Shulman et al.,
subject to environmental influence – particularly in
1990; Zurlo, Larson, Bogardus, & Ravussin, 1990).
response to physical activity (Folland & Williams,

Correspondence: Matthew S. Brook, MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Division of Metabolic and
Molecular Physiology, Postgraduate Entry Medical School, Royal Derby Hospital, University of Nottingham, Uttoxeter Road, Derby
DE22 3DT, UK. E-mail: mzxmb2@nottingham.ac.uk

© 2015 European College of Sport Science

 2 M. S. Brook et al.
2007; Wernbom, Augustsson, & Thomeé, 2007) and
inactivity (Breen et al., 2013; de Boer et al., 2007).
Perhaps the best-recognized remodelling associated
with physical activity (and the focus of this YIA
award invited review) is in response to “resistance
exercise training” (RE-T), the act of forcing weights
against a fixed (isometric RE) or non-fixed
(dynamic–eccentric/ concentric RE) external load.
Yet despite considerable research efforts, the mech-
anisms and temporal basis by which muscle hypertro-
phy occurs remain poorly understood.
Skeletal muscle protein turnover and its
quantification in humans
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In addition to containing substantial stores of glucose
(as glycogen) and lipids (as triglycerides), skeletal
muscle represents the body’s largest reserve of
amino acids (AA; principally stored within proteins).
In periods in-between meals, AA are released from
muscle proteins as a result of prevailing muscle
protein breakdown (MPB) to provide gluconeogenic
substrates and building blocks for continued protein
synthesis in other tissues (Greenhaff et al., 2008;
Owen, Smalley, D’Alessio, Mozzoli, & Dawson,
1998). Crucially, these AA are replenished upon
intake of food (i.e. dietary proteins) via the stimulation
of muscle protein synthesis (MPS) (Bennet, Conna-
cher, Scrimgeour, Smith, & Rennie, 1989; Rand,
Pellett, & Young, 2003). It is the dynamic balance
between these building-breaking cycles of muscle pro-
teins that controls the stability of muscle mass in
healthy humans, causing muscle hypertrophy in
response to RE-T, postnatal and adolescent growth,
as well as atrophy in response to disuse and disease
(Atherton & Smith, 2012; Phillips, Glover, &
Rennie, 2009; Rennie, Wackerhage, Spangenburg,
& Booth, 2004). In response to activity and/or nutri-
tion, there are pronounced changes in MPS (de
Boer et al., 2007; Greenhaff et al., 2008; Phillips
et al., 1997). Whilst we acknowledge the important
role of MPB in the modulation of muscle mass,
MPB is traditionally a difficult process to study in
vivo, furthermore the main effects on MPB are pri-
marily driven through the actions of insulin (Green-
haff et al., 2008). It is believed therefore that the
modulation of MPS is predominant in driving
muscle mass changes rather than MPB and so MPS
will be primarily discussed in this review.
In the post-absorptive rested state, rates of MPS are
typically ∼0.03–0.07% h−1, increasing to ∼0.06–
0.1% h−1 following the consumption of food (Babraj
et al., 2005; Cuthbertson et al., 2005; Moore, Tang,
et al., 2009). This stimulation of MPS arises solely
from the essential amino acid (EAA) constituents
of dietary proteins (Bennet et al., 1989; Bohé, Low,
Wolfe, & Rennie, 2001), with leucine contributing
the majority to these effects (Smith, Reynolds,
Downie, Patel, & Rennie, 1998; Wilkinson et al.,
2013). The mechanism(s) by which leucine (and
other EAA’s (Smith et al., 1998)) induce increases
in MPS is via actions on anabolic signalling proteins
(i.e. the mechanistic target of rapamycin; mTORc1
(Atherton, Smith, Etheridge, Rankin, & Rennie,
2010; West et al., 2009, 2011). For example, rising
intramyocellular concentrations of AA promote gua-
nosine triphosphate (GTP) charging of Rag
GTPases, recruiting mTOR to the lysosome for coor-
dinated activation. Furthermore, in the presence of
leucine, leucyl-tRNA synthetase trans-locates to the
lysozyme where it functions as a GTPase activating
protein to activate mTORc1 (Bonfils et al., 2012;
Han et al., 2012; Sancak et al., 2008, 2011). Thus,
leucine not only acts as a substrate for MPS, but
also a signal to promote enhanced mRNA translation
(Han et al., 2012). Whilst leucine signalling is clearly
a significant driver in MPS, the mechanisms by which
EAA stimulate MPS remain unclear, with evidence
suggesting that sensing of increased extracellular
EAA is the primary signal for MPS (Bohé, Low,
Wolfe, & Rennie, 2003). Further, recent studies
have shown metabolites of leucine such as β-
Hydroxy β-methylbutyric acid and α-Ketoisocaproi-
cacid can stimulate MPS (Escobar et al., 2010; Wilk-
inson et al., 2013) and so more research is needed in
this area to unravel the mechanism/s that regulate the
stimulation of MPS.
Increases in MPS in response to dietary protein-
intake are maximized by the consumption of ∼20 g
EAA-rich protein sources. Heightened MPS is transi-
ent (lasting ∼2–3 h) and thereafter returns to basal
values, even in the face of continued plasma and intra-
myocellular aminoacidemia (Atherton, Etheridge,
et al., 2010; Bohé et al., 2001; Cuthbertson et al.,
2005). Excessive dietary protein intake therefore
does not induce skeletal muscle hypertrophy; at
least in the absence of RE. This phenomenon has
been termed “muscle-full”, being the point at which
MPS cannot be elevated further through the con-
sumption of additional AA (i.e. additional substrate
instead being diverted towards oxidation (Atherton,
Etheridge, et al., 2010; Moore, Robinson, et al.,
2009; Witard et al., 2014)). Fundamentally, suffi-
cient dietary protein intake is important for mainten-
ance of muscle mass by balancing the daily fasting/
feeding responses of MPS and MPB; yet the
amount and timing of protein intake required
throughout the day is incompletely defined.
Our understanding of the underlying processes
regulating muscle mass has developed via utility of a
range of isotopically labelled tracer techniques

(primarily “stable isotope” tracers). By introducing a
labelled AA (i.e. by replacing more common
elements of 12C, 1H or 14N with their heavier
13C, 2H or 15N isotopes) into the precursor pool
(from which muscle is synthesized) and taking sub-
sequent muscle biopsies, the rate of incorporation
of this labelled AA into tissue protein can be deter-
mined using mass spectrometric approaches, and a
measure of fractional synthetic rate (FSR i.e. MPS)
can be derived (Rennie et al., 1982). After establish-
ing “baseline” FSR, any investigative intervention
can be applied, such as exercise/nutrient combi-
nations, and resultant changes in FSR, recorded.
Despite these techniques being limited to short-
term measures (∼<24 h) and requiring specialist
clinical resources, that is, I.V infusions, blood
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samples and muscle biopsies, these techniques have
generated the majority of what we understand about
how muscle protein turnover responds acutely, for
example, to nutrition, exercise and with ageing/
disease (Atherton, Etheridge, et al., 2010; Chesley,
MacDougall, Tarnopolsky, Atkinson, & Smith,
1992; Cuthbertson et al., 2005; Kumar et al., 2009;
Williams et al., 2012).
Whilst acute measures of MPS (and signalling) have
facilitated an understanding of how RE-T and nutri-
ent interactions facilitate muscle protein accretion,
these measures only capture a small window of these
processes, that is, the response to a single bout of RE
in the absence or presence of macronutrient combi-
nations. To exemplify the limitations of this approach,
the magnitude of RE-induced increases in MPS (fol-
lowing a single bout of RE in the fed state; Mitchell
et al., 2014) are not quantitatively related to hypertro-
phy after a block of RE-T. These discrepancies may be
due to different approaches in measuring acute MPS,
with nutritional status, period of acute measurement
and time after exercise capturing varied “snapshots”
of the response. In addition, a proportion of MPS
increases will represent remodelling/reconditioning
of the muscle protein pool, as increased protein turn-
over is observed in situations that do not typically
result in increases in muscle mass (Atherton et al.,
2015; Sheffield-Moore et al., 2004). Therefore, in
order to move the field forward in the context of
understanding the metabolic basis of muscle hypertro-
phy, new methods are needed which better lend them-
selves to providing longer term insight, that is, those
reflecting the cumulative and temporal effects of RE-
T. Deuterium oxide (D2O) was one of the first
stable isotope tracers to be utilized for the study of
metabolism (Schoenheimer & Rittenberg, 1936).
Reintroduction of “heavy water” tracer techniques in
recent years has provided great advancements in
measuring not only muscle protein metabolism
(Busch et al., 2006; Gasier, Fluckey, Previs, Wiggs,
Resistance exercise and muscle hypertrophy 3
& Riechman, 2012) but a range of tissues throughout
the body (Bederman, Foy, Chandramouli, Alexander,
& Previs, 2009; Dufner et al., 2005; Neese et al.,
2002). In addition, D2O offers exciting new opportu-
nities to study longer term (days–weeks–months)
regulation of MPS in humans (Robinson, Turner,
Hellerstein, Hamilton, & Miller, 2011; Scalzo et al.,
2014) and with continued advancements in analytical
techniques enables sensitive measures of daily muscle
protein turnover and indeed individual protein turn-
over (Decaris et al., 2015; Kasumov et al., 2013; Wilk-
inson et al., 2014). However, acute AA tracers offer
their own benefit, particularly with regard to protein
breakdown and oxidation measures, and their appli-
cation will continue to provide valuable insights into
the acute regulation of muscle protein turnover. For
instance, acute AA tracers provide exceptional resol-
ution in highlighting responses to single nutrient or
RE interventions that may ultimately be averaged
out in long-term measures. The approach employed
should therefore be carefully chosen to best answer
the question asked.
Deuterium oxide is administered via oral ingestion,
enriching the body water pool and labelling myocel-
lular AA (during de novo AA synthesis and intermedi-
ary metabolism, Figure 1) permitting turnover
measures through precursor product techniques. All
AAs become enriched with deuterium (Kasumov
et al., 2013), and in particular alanine is extensively
and rapidly labelled through intracellular transamin-
ation (Yang, Matthews, Bier, Lo, & Young, 1984).
Cycling of alanine to pyruvate incorporates deuter-
ium at the α and β positions, becoming enriched ∼ 3.7
times greater than body water, representing 90% of
the total 4 hydrogen’s are accessible (MacDonald
et al., 2013; Previs et al., 2004; Wilkinson et al.,
2014). As this is an intracellular process, it is
assumed that plasma alanine will closely reflect that
of intracellular alanine and the true precursor for
protein synthesis, alanyl-tRNA. Further, alanine
closely follows the enrichment of body water
without perturbation (Dufner et al., 2005; Previs
et al., 2004) and so acts as a suitable precursor to
monitor changes in MPS, with enrichment easily
measured through samples of body water (i.e.
saliva). D2O has a long half-life in the body water
pool and so enrichment can be maintained through
regular boluses that enables longer term measure of
MPS (Robinson et al., 2011). The D2O technique
has also been expanded to measure the rate of
MPB. This can be achieved by incorporating high
levels of deuterium and monitoring the loss of
labelled bound AAs from the pool, in a similar way
to the fractional breakdown rates developed by
Wolfe and Chinkes (Zhang, Chinkes, Wolfe, &
Robert, 2002). However, this requires a lengthy
 4 M. S. Brook et al.
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Figure 1. Illustration of pathways for the incorporation of deuterium from D2O into multiple tissue pools. Intracellular cycling of alanine to
pyruvate results in deuterium incorporation from body water at the α and β hydrogen’s, with an enrichment ∼3.7x body water. This labelled
alanine will mix with the alanyl-tRNA pool and be incorporated into new muscle proteins during protein synthesis. As D2O is incorporated
into multiple pools, nucleotides and triglycerides, multiple aspects of muscle metabolism can be measured. G6P Glucose 6 Phosphate, R5P
Ribose 5 Phosphate, PRPP Phosphoribosyl Pyrophosphate, NDP Nucleotide Diphosphate, dNTP Deoxy Nucleotide Triphosphate and D2O
Deuterium Oxide

wash out period to remove D2O from the body water
pool preventing further label incorporation (Holm
et al., 2013); therefore, the practicalities of measuring
MPB using D2O may be limited. Deuterium is incor-
porated into all tissues within the body and is further
incorporated into all sub-cellular substrates, i.e.,
mitochondrial, DNA and lipids (Hellerstein, 1999;
Miller, Robinson, Bruss, Hellerstein, & Hamilton,
2012; Robinson et al., 2011). By sampling the
tissue of interest, for instance muscle, and the
ability to separate the sample into sub-fractions,
that is, myofibrillar, collagen, sarcoplasmic and mito-
chondrial, provides the opportunity to measure the
turnover of individual protein pools intimately
involved in muscle metabolism. Demonstrating the
utility of this method, it was shown that MPS was
elevated over the 24 h following a bout of RE
(Gasier et al., 2012) and more recently that MPS is
sustainably elevated even over 8 days (Wilkinson
et al., 2014). Further, Robinson et al. showed that
it was possible to quantify MPS using D2O over
6-weeks; reporting that aerobic-type exercise led to
greater longer term measures of MPS in elderly exer-
cise trained individuals compared to young sedentary
individuals (Robinson et al., 2011). Therefore, the
D2O tracer has great potential for interrogating the
true metabolic and temporal basis of hypertrophy.
The basis, and measurement of, muscle
hypertrophic responses to RE-T
Skeletal muscle hypertrophy, the result of cumulative
post-RE increases in MPS, and increased strength via
greater contractile material or neural recruitment are
the most defining physiological adaptations to RE-T
(Mccall et al., 1996; Narici et al., 1996). Muscle
hypertrophy represents an increase in muscle fibre
cross sectional area (CSA) due to the addition of
new sarcomeres, the basic contractile proteins of
muscle. This is manifested as an increase in whole
muscle size and ultimately enables greater force pro-
duction to cope with greater external loads. The
majority of muscle growth occurs through enlarge-
ment of existing muscle fibres, hypertrophy, rather
than splitting or addition of new fibres, that is, hyper-
plasia. As such, hypertrophy at the cellular level can
be detected by an increase in fibre CSA. However,

muscle hypertrophy involves a multitude of architec-
tural adaptations which fibre CSA cannot solely
account for (D’Antona et al., 2006). Indeed,
changes in fibre CSA in response to training have
been reported to be greater or less than changes in
whole muscle CSA (Aagaard et al., 2001; Narici
et al., 1996). These differences maybe a result of
variability in fibre (and fibre-type) hypertrophy and
reproducibility of fibre CSA estimates (Viitasalo,
Saukkonen, & Komi, 1980). Further, myofibrillar
packing in parallel can increase physiological CSA
(CSA area perpendicular to muscle fibres) greater
than anatomical CSA, whilst muscle hypertrophy is
non-uniform along the muscle belly, and influenced
by contraction type (Aagaard et al., 2001; Franchi
et al., 2014; Narici et al., 1996). Finally, the point
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at which the addition of new contractile protein pro-
duces a detectable increase in CSA of a single fibre is
unclear and will likely involve significant rearrange-
ment of the surrounding extracellular matrix (Miller
et al., 2005). At the whole muscle level, MRI and
CT scans are considered the gold standard for pro-
viding accurate muscle measures (Mitsiopoulos
et al., 1998). However, repeated measures using
these techniques are costly, potentially limiting fre-
quent practice. Although initial costs for all these
instruments are expensive, dual-energy X-ray absorp-
tiometry (DXA) provides measures of muscle mass at
relatively low running costs and minimal radiation
exposure (Heymsfield et al., 1990). When compared
to MRI and CT, DXA may overestimate muscle
mass (Maden-Wilkinson, Degens, Jones, &
McPhee, 2013) although shows good agreement in
representing training induced changes in body com-
position (Nindl et al., 2000). The use of ultrasound
techniques to quantify hypertrophy, that is, as
muscle thickness – is gaining popularity primarily as
it offers a cheap and minimally invasive technique
that also provides information about architectural
adaptations (i.e. fascicle length and pennation
angle; Franchi et al., 2014). The choice of method
depends on the endpoint of the study, for example,
whether regional or whole body measures of mass,
volume or architectural adaptations are required.
Nonetheless, it is important to highlight that data in
the literature on “changes” in muscle mass in
response to RE-T depend heavily upon the method
chosen to detect muscle growth (Heymsfield,
Wang, Baumgartner, & Ross, 1997).
MPS and signalling responses to
unaccustomed and accustomed RE
Mechanical loading of skeletal muscle via RE is a
powerful stimulator of MPS with a single bout of
Resistance exercise and muscle hypertrophy 5
RE increasing MPS ∼3 fold (depending upon the
duration of measurement). In the absence of nutri-
tion, myofibrillar protein synthesis returns to baseline
approx. 4 h later (Kumar et al., 2009), whilst mixed
MPS remains elevated for up to 48 h (Phillips et al.,
1997). Indeed, as with intake of dietary proteins
(Cuthbertson et al., 2005), RE-induced increases in
MPS exhibit an upper limit and follow a sigmoidal
dose response relationship being near maximal
between ∼60% and 90% of one-repetition
maximum (1-RM) (Kumar et al., 2009). Nonethe-
less, higher mechanical loads are not a pre-requisite
for the stimulation of MPS. For example, RE at
30% 1-RM to failure increases MPS equal to that at
90% 1-RM (Burd et al., 2010). Despite large
increases in MPS, RE performed in the fasted state
is in fact catabolic. Without AA substrate to support
the stimulation of MPS, the duration of the increase
in MPS is limited, and when combined with
elevations in MPB that occur to replace damaged
tissue or promote tissue remodelling, this results in
negative protein balance (Biolo, Maggi, Williams,
Tipton, & Wolfe, 1995; Phillips et al., 1997). Positive
net balance (i.e. net gain of muscle) is only achieved
where RE is combined with AA or dietary protein
intake due to potentiating effects on MPS versus
dietary protein intake or RE alone (Biolo, Tipton,
Klein, & Wolfe, 1997; Chesley et al., 1992; Louis &
Poortmans, 2003; Witard et al., 2014). This is
achieved by RE effectively delaying the onset of
“muscle-full” allowing prolonged synthesis with sub-
sequent protein intake (Figure 2; Bukhari et al., 2015;
Moore, Tang, et al., 2009; Pennings et al., 2011).
This heightened sensitization may persist for as long
as 48 h (Burd et al., 2011; Cuthbertson et al., 2006;
Miller et al., 2005); at least in the untrained state.
The combination of EAA + CHO after exercise has
shown to moderately attenuate post exercise
increases in MPB, which may enhance the net ana-
bolic response driven through the inhibitory effect
of insulin on MPB. However, despite known nitro-
gen-sparing effects, CHO has no additional benefits
on promoting MPS (Glynn et al., 2010; Gorissen
et al., 2014; Staples et al., 2011), highlighting that
the modulation MPS is the primary driver in hyper-
trophy rather than adaptive effects on breakdown.
However, lack of accurate methods and studies on
MPB with RE-T prevents dismissal of adaptations
in MPB playing potential roles in hypertrophy.
The exact mechanisms by which mechanical
loading is transduced into molecular signals that
produce this rise in MPS are multifaceted (discussed
in Hornberger, 2011). Nonetheless, whatever the
initiating signals, it has been repeatedly shown that
increases in MPS are regulated by activation (i.e.
phosphorylation (Dreyer et al., 2006; Drummond,
 6 M. S. Brook et al.
Figure 2. Acute and proposed longer term changes in MPS and RE-induced changes in muscle mass. In response to an acute exercise bout
MPS is transiently increased 2–3 fold before returning to baseline ∼4 h, although this may be sustained for longer with the addition of EAA.
Repeated RE-T results in early muscle hypertrophy, ∼3–4 weeks, with any further progression relatively slow in comparison, with increases in
muscle size reported to be 5–15% by 8 weeks. Cumulative response to RE-T measured using D2O have demonstrated ∼30% increases in MPS
over 1 week, in which we propose this response becomes diminished with time and ensuing muscle hypertrophy.
Fry, et al., 2009; Kumar et al., 2009) or cellular
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re-localization (Kim & Chen, 2000; Koopman,
Zorenc, Gransier, Cameron-Smith, & van Loon,
2006)) of signalling proteins involved in “anabolic
signalling pathways” (to qualify – those linked to
the process of mRNA translation). Perhaps the
central node of this is the protein kinase mTORc1,
long known for its role in cellular growth and respon-
sive to both mechanical and nutritive stimulation. To
exemplify this, inhibition of mTORc1 (with rapamy-
cin) prevents feeding and exercise-medicated
increases in MPS (Bodine et al., 2001; Drummond,
Miyazaki, et al., 2009). These trophic effects of
mTORC1 are driven via its activation of substrates
involved in both translational initiation (e.g.
p70SK1, 4EBP1 and eIF’s) and elongation (e.g.
eEF2) (Proud, 2009) processes.
An important but often overlooked consideration is
that MPS (and for that matter hypertrophic)
responses to RE are different depending upon train-
ing status. Indeed, part of the initial elevation in
MPS to an unaccustomed bout of RE is likely to rep-
resent repair of damaged proteins and is largely deter-
mined by an individual’s previous exposure to
external loading (Constantin et al., 2013; Murton
et al., 2014), whereas later changes will more likely
reflect specific adaptive or maintenance processes.
In studies comparing how the FSRs of muscle pro-
teins change with training, it was shown that seden-
tary individuals exhibit greater MPS responses to a
bout of RE when compared with strength-trained
athletes (Phillips, Tipton, Ferrando, & Wolfe,
1999). This was further demonstrated in longitudinal
studies whereupon the completion of a unilateral RE-
T programme, reduced protein turnover was evident
in the RE-trained leg whether RE was performed at
the same absolute or relative intensity (Kim, Staron,
& Phillips, 2005; Phillips et al., 2002). Similarly,
MPS responses (0–28 h post-RE) to successive
bouts of RE are attenuated with ongoing training
(Tang, Perco, Moore, Wilkinson, & Phillips, 2008).
Furthermore, the specific pools of proteins affected
become more specific to the adaptive response; for
example, after 10-weeks of RE-T non-myofibrillar
proteins (mitochondrial) are no longer stimulated,
whereas myofibrillar proteins are, that is, to facilitate
maintenance of increased muscle mass after RE-T
(Wilkinson et al., 2008). Recently, D2O and sensitive
IRMS techniques were used to measure cumulative
short-term responses to repeated exercise bouts
over an 8-day period. Using a unilateral RET pro-
gramme and with participants in an otherwise free-
living situation, it was demonstrated that even after
only two-exercise bouts myofibrillar protein synthesis
was significantly increased over the rest leg. However
with subsequent bouts, albeit at the same intensity,
showed that increases in myofibrillar protein synthesis
were attenuated after just 4 RE bouts (Wilkinson
et al., 2014). This indicates that muscle is already
experiencing an attenuated response, highlighting
the need for “overload” regimes (or “good genes”,
given substantial natural variation in hypertrophy
responses; Phillips et al., 2013) to continue up regu-
lation of MPS, and hence hypertrophy.
The time course of muscle hypertrophy
response to RE-T
Perhaps surprisingly, the time course of muscle
hypertrophy responses to RE-T remains poorly
defined; likely due to the paucity of sufficiently
precise methods to assess early changes. Whilst it is
well established that muscle hypertrophy is the
product of cumulative post-RE increases in MPS, it
appears that muscle hypertrophy in response to a pro-
gramme of RE-T is not a linear process, that is, great-
est hypertrophy is skewed towards the early weeks of
unaccustomed RE-T (see next section; Figure 2).
This is in opposition to earlier dogma that suggested
delayed hypertrophy responses to RE-T (Moritani &
DeVries, 1979). In support of dominant early
 Resistance exercise and muscle hypertrophy 7

hypertrophy, marked hypertrophy has been observed
in the quadriceps, of ∼6–7%, after 5-weeks of RE-T
(Norrbrand, Pozzo, & Tesch, 2010; Seynnes, de
Boer, & Narici, 2007; Tesch, Ekberg, Lindquist, &
Trieschmann, 2004), and ∼10–15% in 4–6-weeks
in the upper body (Narici & Kayser, 1995; Ogasa-
wara, Yasuda, Ishii, & Abe, 2013). This would
suggest, if growth was linear, an increase of ∼0.2–
0.3%/d occurs (Wernbom et al., 2007; Ogasawara
et al., 2013) after which there is a marked slowing
in rates of hypertrophy. This would suggest that
there is practically no delay in hypertrophic
responses. In support of this, myofibrillar protein
content has shown to be increased after just three
training bouts (Willoughby & Taylor, 2004). Simi-
larly, early hypertrophy has also been demonstrated
Downloaded by [Ecole Hautes Etudes Commer-Montreal] at 05:53 22 August 2015
methodology (i.e. high single biopsy coefficient of
variation 10–20%; Folland & Williams, 2007) and
may not represent that of whole muscle hypertrophy
(Lexell & Taylor, 1989a, 1989b). To us, these
studies collectively clearly demonstrate that muscle
has the potential for rapid hypertrophy and beyond
this point any further increases occurs at a vastly
lower rate, despite increased intensity (Ogasawara
et al., 2013; Olsen et al., 2006). This demonstrates
early hypertrophy predominates in response to an
RE-T programme – proven by many analytical
methods, including architectural adaptations, fibre
CSA, whole CSA and DXA mass (Constantin
et al., 2013; Mayhew, Rothstein, Finucane, &
Lamb, 1995; Seynnes et al., 2007; Woolstenhulme
et al., 2006). Moreover, this notion is also supported

with increases in muscle CSA after 20 days detected by reports of dampened acute MPS responses to
using MRI (Seynnes et al., 2007), and as soon as 1- accustomed exercise (Phillips et al., 1999, 1997).
week when a greater training stimulus (i.e. 6 sets 8–
12-RM vs. 4 sets 7-RM) is used (DeFreitas, Beck,
Stock, Dillon, & Kasishke, 2011). Likewise, Abe Conclusion
et al. showed that blood flow restriction combined
Whilst we are beginning to understand the complex
with low intensity exercise yielded significant hyper-
mechanisms underlying the regulation of muscle
trophy after four days of training (Fujita, Brechue,
hypertrophy, the progression of muscle mass and phe-
Kurita, Sato, & Abe, 2008).
notypic adaptations to RE-T are unclear. The ability
Data from longer term time-course studies are
to detect changes in muscle size or mass will depend
similar. Defrietas et al. measured muscle CSA every
on the method chosen; however, there is accumulating
week using peripheral CT and showed a 7.8%
evidence using multiple techniques to suggest that
increase after 4-weeks of training with only a further
muscle remodelling/hypertrophy occurs rapidly in
increase of 1.7% over the next 4-weeks of continued
response to RE-T. Further complexity is introduced
RE-T (DeFreitas et al., 2011). Furthermore, in older
as little is known on the time course of muscle hyper-
individuals, increases in DXA-derived muscle mass
trophy between subjects, with individuals likely to
was 4.1% after the first 4-weeks and only increased
plateau at different rates due to the innate capacity to
1.3% in the next 4-weeks (Constantin et al., 2013),
build muscle (Phillips et al., 2013). Whilst traditional
whilst increases in whole body mass or fat-free mass
acute stable isotope tracer techniques can provide us
have shown to be no greater after the first 3 months
with an immediate dynamic snapshot of the responses
of training even in conditions of optimized nutritional
of muscle protein turnover to resistance exercise and/
intake (Hulmi et al., 2009; Volek et al., 2013). Once
or nutrition, the time course of muscle hypertrophy is
again matching this thesis, maximal changes after the
a cumulative process driven by chronic temporal
first 4–5 weeks of RE-T were demonstrated in both
adaptations. In order to better understand this
muscle thickness (Baroni et al., 2013) and fibre
process at a holistic level and to determine the meta-
CSA (Woolstenhulme, Conlee, Drummond, Stites,
bolic and molecular basis of predominating early
& Parcell, 2006). Similarly, Olsen showed a signifi-
hypertrophy and the inter-individual variability in
cant 13.8% increase in fibre CSA after 4-weeks,
responsiveness to stimuli, the application of D2O
without further increase after 16-weeks (Olsen
tracer approaches herald great promise. The appli-
et al., 2006), whilst a creatine supplement group
cation of this tracer technique alongside analytical
showed significantly greater fibre CSA after 4-weeks
techniques already well established (acute tracer tech-
with no further increases after 8- and 16-weeks RE-
niques, imaging and molecular biology) will provide
T (Olsen et al., 2006). In contrast, to this body of
us with unique understanding of this complex yet
data, despite a tendency for greater fibre CSA
important phenomenon.
during the initial weeks of training favouring early
hypertrophy, some authors have reported no detect-
able change until >6-weeks RE-T (Green,
Acknowledgements
Goreham, Ouyang, Ranney, & Ball-Burnett, 1999;
Staron et al., 1994); nonetheless, as mentioned D.J.W. is a Medical Research Council-Arthritis
earlier, fibre CSA can be a rather subjective Research United Kingdom (MRCARUK) Centre-
 8 M. S. Brook et al.
funded postdoctoral research fellow, and M.S.B. is
supported by a University of Nottingham Ph.D.
studentship.
Disclosure statement
No potential conflict of interest was reported by the
authors.
References
Aagaard, P., Andersen, J. L., Dyhre-Poulsen, P., Leffers, A. M.,
Wagner, A., Magnusson, S. P., … Simonsen, E. B. (2001). A
mechanism for increased contractile strength of human
pennate muscle in response to strength training: changes in
Downloaded by [Ecole Hautes Etudes Commer-Montreal] at 05:53 22 August 2015
muscle architecture. The Journal of Physiology, 534(Pt 2),
613–623.
Atherton, P. J., Etheridge, T., Watt, P. W., Wilkinson, D., Selby,
A., Rankin, D., … Rennie, M. J. (2010). Muscle full effect after
oral protein: Time-dependent concordance and discordance
between human muscle protein synthesis and mTORC1 signal-
ing. The American Journal of Clinical Nutrition, 92(5),
1080–1088. http://doi.org/10.3945/ajcn.2010.29819
Atherton, P. J., Phillips, B. E., Brook, M. S., Wilkinson, D. J.,
Smith, K., Etheridge, T. E., … Vagula, M. C. (2015).
Commentaries on Viewpoint: What is the relationship between
acute measure of muscle protein synthesis and changes in
muscle mass? Journal of Applied Physiology (Bethesda, Md. :
1985), 118(4), 498–503. http://doi.org/10.1152/japplphysiol.
01069.2014
Atherton, P. J., & Smith, K. (2012). Muscle protein synthesis in
response to nutrition and exercise. The Journal of Physiology,
590(Pt 5), 1049–1057. http://doi.org/10.1113/jphysiol.2011.
225003
Atherton, P. J., Smith, K., Etheridge, T., Rankin, D., & Rennie,
M. J. (2010). Distinct anabolic signalling responses to amino
acids in C2C12 skeletal muscle cells. Amino Acids, 38(5),
1533–1539. http://doi.org/10.1007/s00726-009-0377-x
Babraj, J. a., Cuthbertson, D. J. R., Smith, K., Langberg, H.,
Miller, B., Krogsgaard, M. R., … Rennie, M. J. (2005).
Collagen synthesis in human musculoskeletal tissues and skin.
American Journal of Physiology. Endocrinology and Metabolism,
289(5), E864–E869. http://doi.org/10.1152/ajpendo.00243.
2005
Baroni, B. M., Geremia, J. M., Rodrigues, R., De Azevedo Franke,
R., Karamanidis, K., & Vaz, M. A. (2013). Muscle architecture
adaptations to knee extensor eccentric training: Rectus femoris
vs. vastus lateralis. Muscle & Nerve, 48(4), 498–506. http://doi.
org/10.1002/mus.23785
Bederman, I. R., Foy, S., Chandramouli, V., Alexander, J. C., &
Previs, S. F. (2009). Triglyceride synthesis in epididymal
adipose tissue: Contribution of glucose and non-glucose
carbon sources. The Journal of Biological Chemistry, 284(10),
6101–6108. http://doi.org/10.1074/jbc.M808668200
Bennet, W. M., Connacher, A. A., Scrimgeour, C. M., Smith, K.,
& Rennie, M. J. (1989). Increase in anterior tibialis muscle
protein synthesis in healthy man during mixed amino acid infu-
sion: Studies of incorporation of [1-13C]leucine. Clinical Science
(London, England : 1979), 76(4), 447–454.
Biolo, G., Maggi, S. P., Williams, B. D., Tipton, K. D., & Wolfe,
R. R. (1995). Increased rates of muscle protein turnover and
amino acid transport after resistance exercise in humans I.
The American Journal of Physiology, 268(3 Pt 1), E514–E520.
Biolo, G., Tipton, K. D., Klein, S., & Wolfe, R. R. (1997). An
abundant supply of amino acids enhances the metabolic effect
of exercise on muscle protein. The American Journal of
Physiology, 273(1 Pt 1), E122–E129.
Bodine, S. C., Stitt, T. N., Gonzalez, M., Kline, W. O., Stover, G.
L., Bauerlein, R., … Yancopoulos, G. D. (2001). Akt/mTOR
pathway is a crucial regulator of skeletal muscle hypertrophy
and can prevent muscle atrophy in vivo. Nature Cell Biology, 3
(11), 1014–1019. http://doi.org/10.1038/ncb1101-1014
Bohé, J., Low, J. F., Wolfe, R. R., & Rennie, M. J. (2001). Latency
and duration of stimulation of human muscle protein synthesis
during continuous infusion of amino acids. The Journal of
Physiology, 532(Pt 2), 575–579.
Bohé, J., Low, A., Wolfe, R. R., & Rennie, M. J. (2003). Human
muscle protein synthesis is modulated by extracellular, not
intramuscular amino acid availability: A dose-response study.
The Journal of Physiology, 552(Pt 1), 315–324. http://doi.org/
10.1113/jphysiol.2003.050674
Bonfils, G., Jaquenoud, M., Bontron, S., Ostrowicz, C.,
Ungermann, C., & De Virgilio, C. (2012). Leucyl-tRNA
synthetase controls TORC1 via the EGO complex. Molecular
Cell, 46(1), 105–110. http://doi.org/10.1016/j.molcel.2012.02.
009
Breen, L., Stokes, K. a., Churchward-Venne, T. a., Moore, D. R.,
Baker, S. K., Smith, K., … Phillips, S. M. (2013). Two weeks of
reduced activity decreases leg lean mass and induces “anabolic
resistance” of myofibrillar protein synthesis in healthy elderly.
The Journal of Clinical Endocrinology and Metabolism, 98(6),
2604–2612. http://doi.org/10.1210/jc.2013-1502
Bukhari, S. S., Phillips, B. E., Wilkinson, D. J., Limb, M. C.,
Rankin, D., Mitchell, W. K., … Atherton, P. J. (2015). Intake
of low-dose leucine-rich essential amino acids stimulates muscle
anabolism equivalently to bolus whey protein in older women,
at rest and after exercise. American Journal of Physiology –
Endocrinology and Metabolism, ajpendo.00481.2014. http://doi.
org/10.1152/ajpendo.00481.2014
Burd, N. A., Holwerda, A. M., Selby, K. C., West, D. W. D.,
Staples, A. W., Cain, N. E., … Phillips, S. M. (2010).
Resistance exercise volume affects myofibrillar protein synthesis
and anabolic signalling molecule phosphorylation in young
men. The Journal of Physiology, 588(Pt 16), 3119–3130. http://
doi.org/10.1113/jphysiol.2010.192856
Burd, N. A., West, D. W. D., Moore, D. R., Atherton, P. J.,
Staples, A. W., Prior, T., … Phillips, S. M. (2011). Enhanced
amino acid sensitivity of myofibrillar protein synthesis persists
for up to 24 h after resistance exercise in young men. The
Journal of Nutrition, 141(4), 568–573. http://doi.org/10.3945/
jn.110.135038
Busch, R., Kim, Y., Neese, R. A., Schade-Serin, V., Collins, M.,
Awada, M., … Hellerstein, M. K. (2006). Measurement of
protein turnover rates by heavy water labeling of nonessential
amino acids. Biochimica et Biophysica Acta (BBA) – General
Subjects, 1760(5), 730–744. http://doi.org/10.1016/j.bbagen.
2005.12.023
Chesley, A., MacDougall, J. D., Tarnopolsky, M. A., Atkinson, S.
A., & Smith, K. (1992). Changes in human muscle protein syn-
thesis after resistance exercise. Journal of Applied Physiology
(Bethesda, Md. : 1985), 73(4), 1383–1388.
Constantin, D., Menon, M. K. M., Houchen-Wolloff, L., Morgan,
M. D., Singh, S. J., Greenhaff, P., & Steiner, M. C. (2013).
Skeletal muscle molecular responses to resistance training and
dietary supplementation in COPD. Thorax, 68(7), 625–633.
http://doi.org/10.1136/thoraxjnl-2012-202764
Cuthbertson, D., Smith, K., Babraj, J., Leese, G., Waddell, T.,
Atherton, P., … Rennie, M. J. (2005). Anabolic signaling defi-
cits underlie amino acid resistance of wasting, aging muscle.
FASEB Journal : Official Publication of the Federation of

American Societies for Experimental Biology, 19(3), 422–424.
http://doi.org/10.1096/fj.04-2640fje
Cuthbertson, D. J., Babraj, J., Smith, K., Wilkes, E., Fedele, M. J.,
Esser, K., & Rennie, M. (2006). Anabolic signaling and protein
synthesis in human skeletal muscle after dynamic shortening or
lengthening exercise. American Journal of Physiology.
Endocrinology and Metabolism, 290(4), E731–E738. http://doi.
org/10.1152/ajpendo.00415.2005
D’Antona, G., Lanfranconi, F., Pellegrino, M. A., Brocca, L.,
Adami, R., Rossi, R., … Bottinelli, R. (2006). Skeletal muscle
hypertrophy and structure and function of skeletal muscle
fibres in male body builders. The Journal of Physiology, 570
(Pt 3), 611–627. http://doi.org/10.1113/jphysiol.2005.101642
De Boer, M. D., Selby, A., Atherton, P., Smith, K., Seynnes, O.
R., Maganaris, C. N., … Rennie, M. J. (2007). The temporal
responses of protein synthesis, gene expression and cell signal-
ling in human quadriceps muscle and patellar tendon to
disuse. The Journal of Physiology, 585(Pt 1), 241–251. http://
doi.org/10.1113/jphysiol.2007.142828
Downloaded by [Ecole Hautes Etudes Commer-Montreal] at 05:53 22 August 2015
Decaris, M. L., Emson, C. L., Li, K., Gatmaitan, M., Luo, F.,
Cattin, J., … Hellerstein, M. K. (2015). Turnover Rates of
Hepatic Collagen and Circulating Collagen-Associated
Proteins in Humans with Chronic Liver Disease. PloS One, 10
(4), e0123311. http://doi.org/10.1371/journal.pone.0123311
DeFreitas, J. M., Beck, T. W., Stock, M. S., Dillon, M. a., &
Kasishke, P. R. (2011). An examination of the time course of
training-induced skeletal muscle hypertrophy. European
Journal of Applied Physiology, 111(11), 2785–2790. http://doi.
org/10.1007/s00421-011-1905-4
Dreyer, H. C., Fujita, S., Cadenas, J. G., Chinkes, D. L., Volpi, E.,
& Rasmussen, B. B. (2006). Resistance exercise increases
AMPK activity and reduces 4E-BP1 phosphorylation and
protein synthesis in human skeletal muscle. The Journal of
Physiology, 576(Pt 2), 613–624. http://doi.org/10.1113/
jphysiol.2006.113175
Drummond, M. J., Fry, C. S., Glynn, E. L., Dreyer, H. C.,
Dhanani, S., Timmerman, K. L., … Rasmussen, B. B. (2009).
Rapamycin administration in humans blocks the contraction-
induced increase in skeletal muscle protein synthesis. The
Journal of Physiology, 587(Pt 7), 1535–1546. http://doi.org/10.
1113/jphysiol.2008.163816
Drummond, M. J., Miyazaki, M., Dreyer, H. C., Pennings, B.,
Dhanani, S., Volpi, E., … Rasmussen, B. B. (2009).
Expression of growth-related genes in young and older human
skeletal muscle following an acute stimulation of protein syn-
thesis. Journal of Applied Physiology (Bethesda, Md. : 1985), 106
(4), 1403–1411. http://doi.org/10.1152/japplphysiol.90842.
2008
Dufner, D. a., Bederman, I. R., Brunengraber, D. Z., Rachdaoui, N.,
Ismail-Beigi, F., Siegfried, B. a., … Previs, S. F. (2005). Using
2H2O to study the influence of feeding on protein synthesis:
Effect of isotope equilibration in vivo vs. in cell culture.
American Journal of Physiology. Endocrinology and Metabolism, 288
(6), E1277–E1283. http://doi.org/10.1152/ajpendo.00580.2004
Escobar, J., Frank, J. W., Suryawan, A., Nguyen, H. V., Horn, C.
G., Van Hutson, S. M., & Davis, T. A. (2010). Leucine and
a-Ketoisocaproic Acid, but Not Norleucine, Stimulate Skeletal
Muscle Protein Synthesis in Neonatal Pigs 1–3. http://doi.org/10.
3945/jn.110.123042.mechanisms
Felig, P., Owen, O. E., Wahren, J., & Cahill, G. F. (1969). Amino
acid metabolism during prolonged starvation. The Journal of
Clinical Investigation, 48(3), 584–594. http://doi.org/10.1172/
JCI106017
Folland, J. P., & Williams, A. G. (2007). The adaptations to
strength training : Morphological and neurological contri-
butions to increased strength. Sports Medicine (Auckland,
N.Z.), 37(2), 145–168.
Resistance exercise and muscle hypertrophy 9
Franchi, M. V., Atherton, P. J., Reeves, N. D., Flück, M.,
Williams, J., Mitchell, W. K., … Narici, M. V. (2014).
Architectural, functional and molecular responses to concentric
and eccentric loading in human skeletal muscle. Acta
Physiologica (Oxford, England), 210(3), 642–654. http://doi.
org/10.1111/apha.12225
Fujita, T., Brechue, W. F., Kurita, K., Sato, Y., & Abe, T. (2008).
Increased muscle volume and strength following six days of low-
intensity resistance training with restricted muscle blood flow.
International Journal of KAATSU Training Research, 4(1), 1–8.
http://doi.org/10.3806/ijktr.4.1
Gasier, H. G., Fluckey, J. D., Previs, S. F., Wiggs, M. P., &
Riechman, S. E. (2012). Acute resistance exercise augments
integrative myofibrillar protein synthesis. Metabolism: Clinical
and Experimental, 61(2), 153–156. http://doi.org/10.1016/j.
metabol.2011.07.001
Glynn, E. L., Fry, C. S., Drummond, M. J., Dreyer, H. C.,
Dhanani, S., Volpi, E., … Dhanani, S. (2010). Muscle protein
breakdown has a minor role in the protein anabolic response to essen-
tial amino acid and carbohydrate intake following resistance exercise,
533–540. http://doi.org/10.1152/ajpregu.00077.2010.
Gorissen, S. H. M., Burd, N. a., Hamer, H. M., Gijsen, A. P.,
Groen, B. B., & van Loon, L. J. C. (2014). Carbohydrate coin-
gestion delays dietary protein digestion and absorption but does
not modulate postprandial muscle protein accretion. The
Journal of Clinical Endocrinology and Metabolism, 99(6),
2250–2258. http://doi.org/10.1210/jc.2013-3970
Green, H., Goreham, C., Ouyang, J., Ranney, D., & Ball-Burnett,
M. (1999). Regulation of fiber size, oxidative potential, and
capillarization in human muscle by resistance exercise. The
American Journal of Physiology, 276(Pt 2), R591–R596.
Greenhaff, P. L., Karagounis, L. G., Peirce, N., Simpson, E. J.,
Hazell, M., Layfield, R., … Rennie, M. J. (2008).
Disassociation between the effects of amino acids and insulin
on signaling, ubiquitin ligases, and protein turnover in human
muscle. American Journal of Physiology. Endocrinology and
Metabolism, 295(3), E595–E604. http://doi.org/10.1152/
ajpendo.90411.2008
Han, J. M., Jeong, S. J., Park, M. C., Kim, G., Kwon, N. H., Kim,
H. K., … Kim, S. (2012). Leucyl-tRNA synthetase is an intra-
cellular leucine sensor for the mTORC1-signaling pathway.
Cell, 149(2), 410–424. http://doi.org/10.1016/j.cell.2012.02.044
Hellerstein, M. K. (1999). De novo lipogenesis in humans:
Metabolic and regulatory aspects. European Journal of Clinical
Nutrition, 53(Suppl. 1), S53–S65.
Heymsfield, S. B., Smith, R., Aulet, M., Bensen, B., Lichtman, S.,
Wang, J., & Pierson, R. N. (1990). Appendicular skeletal
muscle mass: Measurement by dual-photon absorptiometry.
The American Journal of Clinical Nutrition, 52(2), 214–218.
Heymsfield, S. B., Wang, Z., Baumgartner, R. N., & Ross, R.
(1997). Human body composition: Advances in models and
methods. Annual Review of Nutrition, 17, 527–558. http://doi.
org/10.1146/annurev.nutr.17.1.527
Holm, L., O’Rourke, B., Ebenstein, D., Toth, M. J., Bechshoeft,
R., Holstein-Rathlou, N. H., … Matthews, D. E. (2013).
Determination of steady-state protein breakdown rate in vivo
by the disappearance of protein-bound tracer-labeled amino
acids: A method applicable in humans. American Journal of
Physiology. Endocrinology and Metabolism, 304(8), E895–E907.
http://doi.org/10.1152/ajpendo.00579.2012
Hornberger, T. a. (2011). Mechanotransduction and the regu-
lation of mTORC1 signaling in skeletal muscle. The
International Journal of Biochemistry & Cell Biology, 43(9),
1267–1276. http://doi.org/10.1016/j.biocel.2011.05.007
Hulmi, J. J., Kovanen, V., Selänne, H., Kraemer, W. J., Häkkinen,
K., & Mero, A. a. (2009). Acute and long-term effects of resist-
ance exercise with or without protein ingestion on muscle
 10 M. S. Brook et al.
hypertrophy and gene expression. Amino Acids, 37(2), 297–308.
http://doi.org/10.1007/s00726-008-0150-6
Janssen, I., Heymsfield, S. B., & Ross, R. (2002). Low relative skel-
etal muscle mass (sarcopenia) in older persons is associated with
functional impairment and physical disability. Journal of the
American Geriatrics Society, 50(5), 889–896.
Jones, K. I., Doleman, B., Scott, S., Lund, J. N., & Williams, J. P.
(2015). Simple psoas cross-sectional area measurement is a
quick and easy method to assess sarcopenia and predicts
major surgical complications. Colorectal Disease: The Official
Journal of the Association of Coloproctology of Great Britain and
Ireland, 17(1), O20–O26. http://doi.org/10.1111/codi.12805
Kasumov, T., Dabkowski, E. R., Shekar, K. C., Li, L., Ribeiro, R.
F., Walsh, K., … Stanley, W. C. (2013). Assessment of cardiac
proteome dynamics with heavy water: Slower protein synthesis
rates in interfibrillar than subsarcolemmal mitochondria.
American Journal of Physiology. Heart and Circulatory
Physiology, 304(9), H1201–H1214. http://doi.org/10.1152/
ajpheart.00933.2012
Downloaded by [Ecole Hautes Etudes Commer-Montreal] at 05:53 22 August 2015
Kim, J. E., & Chen, J. (2000). Cytoplasmic-nuclear shuttling of
FKBP12-rapamycin-associated protein is involved in rapamy-
cin-sensitive signaling and translation initiation. Proceedings of
the National Academy of Sciences of the United States of America,
97(26), 14340–14345. http://doi.org/10.1073/pnas.011511898
Kim, P. L., Staron, R. S., & Phillips, S. M. (2005). Fasted-state
skeletal muscle protein synthesis after resistance exercise is
altered with training. The Journal of Physiology, 568(Pt1),
283–290. http://doi.org/10.1113/jphysiol.2005.093708
Koopman, R., Zorenc, A. H. G., Gransier, R. J. J., Cameron-
Smith, D., & van Loon, L. J. C. (2006). Increase in S6K1 phos-
phorylation in human skeletal muscle following resistance exer-
cise occurs mainly in type II muscle fibers. American Journal of
Physiology. Endocrinology and Metabolism, 290(6), E1245–
E1252. http://doi.org/10.1152/ajpendo.00530.2005
Kumar, V., Selby, A., Rankin, D., Patel, R., Atherton, P.,
Hildebrandt, W., … Rennie, M. J. (2009). Age-related differ-
ences in the dose-response relationship of muscle protein syn-
thesis to resistance exercise in young and old men. The
Journal of Physiology, 587(Pt 1), 211–217. http://doi.org/10.
1113/jphysiol.2008.164483
Lexell, J., & Taylor, C. C. (1989a). Variability in muscle fibre areas
in whole human quadriceps muscle: How to reduce sampling
errors in biopsy techniques. Clinical Physiology (Oxford,
England), 9(4), 333–343.
Lexell, J., & Taylor, C. C. (1989b). Variability in muscle fibre areas
in whole human quadriceps muscle. How much and why? Acta
Physiologica Scandinavica, 136(4), 561–568. http://doi.org/10.
1111/j.1748-1716.1989.tb08702.x
Louis, M., & Poortmans, J. (2003). No effect of creatine sup-
plementation on human myofibrillar and sarcoplasmic protein
synthesis after resistance exercise. American Journal of
Physiology. Endocrinology and Metabolism, 285(5), 1089–1094.
MacDonald, A. J., Small, A. C., Greig, C. A., Husi, H., Ross, J. A.,
Stephens, N. A., … Preston, T. (2013). A novel oral tracer pro-
cedure for measurement of habitual myofibrillar protein syn-
thesis. Rapid Communications in Mass Spectrometry: RCM, 27
(15), 1769–1777. http://doi.org/10.1002/rcm.6622
Maden-Wilkinson, T. M., Degens, H., Jones, D. A., & McPhee, J.
S. (2013). Comparison of MRI and DXA to measure muscle
size and age-related atrophy in thigh muscles. Journal of
Musculoskeletal & Neuronal Interactions, 13(3), 320–328.
Mayhew, T. P., Rothstein, J. M., Finucane, S. D., & Lamb, R. L.
(1995). Muscular adaptation to concentric and eccentric exer-
cise at equal power levels. Medicine and Science in Sports and
Exercise, 27(6), 868–873.
Mccall, G. E., Byrnes, W. C., Dickinson, A., Pattany, P. M., Fleck,
S. J., Mula, J., … Zentner, A. (1996). Muscle fiber hypertrophy,
hyperplasia, and capillary density in college men after resistance
training 2004–2012.
Metter, E. J., Talbot, L. a., Schrager, M., & Conwit, R. (2002).
Skeletal muscle strength as a predictor of all-cause mortality
in healthy men. The Journals of Gerontology. Series A, Biological
Sciences and Medical Sciences, 57(10), B359–B365.
Miller, B. F., Olesen, J. L., Hansen, M., Døssing, S., Crameri,
R. M., Welling, R. J., … Rennie, M. J. (2005). Coordinated col-
lagen and muscle protein synthesis in human patella tendon and
quadriceps muscle after exercise. The Journal of Physiology, 567
(Pt 3), 1021–1033. http://doi.org/10.1113/jphysiol.2005.
093690
Miller, B. F., Robinson, M. M., Bruss, M. D., Hellerstein, M., &
Hamilton, K. L. (2012). A comprehensive assessment of mito-
chondrial protein synthesis and cellular proliferation with age
and caloric restriction. Aging Cell, 11(1), 150–161. http://doi.
org/10.1111/j.1474-9726.2011.00769.x
Mitchell, C. J., Churchward-Venne, T. a., Parise, G., Bellamy, L.,
Baker, S. K., Smith, K., … Phillips, S. M. (2014). Acute post-
exercise myofibrillar protein synthesis is not correlated with
resistance training-induced muscle hypertrophy in young
men. PloS One, 9(2), e89431. http://doi.org/10.1371/journal.
pone.0089431
Mitsiopoulos, N., Baumgartner, R. N., Heymsfield, S. B., Lyons,
W., Gallagher, D., & Ross, R. (1998). Cadaver validation of
skeletal muscle measurement by magnetic resonance imaging
and computerized tomography. Journal of Applied Physiology
(Bethesda, Md. : 1985), 85(1), 115–122.
Moore, D. R., Robinson, M. J., Fry, J. L., Tang, J. E., Glover, E. I.,
Wilkinson, S. B., … Phillips, S. M. (2009). Ingested protein
dose response of muscle and albumin protein synthesis after
resistance exercise in young men. The American Journal of
Clinical Nutrition, 89(1), 161–168. http://doi.org/10.3945/ajcn.
2008.26401
Moore, D. R., Tang, J. E., Burd, N. a., Rerecich, T., Tarnopolsky,
M. a., & Phillips, S. M. (2009). Differential stimulation of myo-
fibrillar and sarcoplasmic protein synthesis with protein inges-
tion at rest and after resistance exercise. The Journal of
Physiology, 587(Pt 4), 897–904. http://doi.org/10.1113/
jphysiol.2008.164087
Moritani, T., & DeVries, H. A. (1979). Neural factors versus
hypertrophy in the time course of muscle strength gain.
American Journal of Physical Medicine, 58(3), 115–130.
Murton, a. J., Billeter, R., Stephens, F. B., Des Etages, S. G.,
Graber, F., Hill, R. J., … Greenhaff, P. L. (2014). Transient
transcriptional events in human skeletal muscle at the outset
of concentric resistance exercise training. Journal of Applied
Physiology (Bethesda, Md. : 1985), 116(1), 113–125. http://doi.
org/10.1152/japplphysiol.00426.2013
Narici, M. V., Hoppeler, H., Kayser, B., Landoni, L., Claassen,
H., Gavardi, C., … Cerretelli, P. (1996). Human quadriceps
cross-sectional area, torque and neural activation during 6
months strength training. Acta Physiologica Scandinavica, 157
(2), 175–186. http://doi.org/10.1046/j.1365-201X.1996.
483230000.x
Narici, M. V., & Kayser, B. (1995). Hypertrophic response of
human skeletal muscle to strength training in hypoxia and nor-
moxia. European Journal of Applied Physiology and Occupational
Physiology, 70(3), 213–219.
Neese, R. a., Misell, L. M., Turner, S., Chu, a., Kim, J., Cesar, D.,
… Hellerstein, M. K. (2002). Nonlinear partial differential
equations and applications: Measurement in vivo of prolifer-
ation rates of slow turnover cells by 2H2O labeling of the deox-
yribose moiety of DNA. Proceedings of the National Academy of
Sciences of the United States of America, 99(24), 15345–15350.
http://doi.org/10.1073/pnas.232551499

Nindl, B. C., Harman, E. A., Marx, J. O., Gotshalk, L. A.,
Frykman, P. N., Lammi, E., … Kraemer, W. J. (2000).
Regional body composition changes in women after 6 months
of periodized physical training. Journal of Applied Physiology
(Bethesda, Md. : 1985), 88(6), 2251–2259.
Norrbrand, L., Pozzo, M., & Tesch, P. a. (2010). Flywheel resist-
ance training calls for greater eccentric muscle activation than
weight training. European Journal of Applied Physiology, 110(5),
997–1005. http://doi.org/10.1007/s00421-010-1575-7
Ogasawara, R., Yasuda, T., Ishii, N., & Abe, T. (2013).
Comparison of muscle hypertrophy following 6-month of con-
tinuous and periodic strength training. European Journal of
Applied Physiology, 113(4), 975–985. http://doi.org/10.1007/
s00421-012-2511-9
Olsen, S., Aagaard, P., Kadi, F., Tufekovic, G., Verney, J., Olesen,
J. L., … Kjaer, M. (2006). Creatine supplementation augments
the increase in satellite cell and myonuclei number in human
skeletal muscle induced by strength training. The Journal of
Physiology, 573(Pt 2), 525–534. http://doi.org/10.1113/
Downloaded by [Ecole Hautes Etudes Commer-Montreal] at 05:53 22 August 2015
jphysiol.2006.107359
Owen, O. E., Smalley, K. J., D’Alessio, D. A., Mozzoli, M. A., &
Dawson, E. K. (1998). Protein, fat, and carbohydrate require-
ments during starvation: Anaplerosis and cataplerosis. The
American Journal of Clinical Nutrition, 68(1), 12–34.
Pedersen, B. K. (2013). Muscle as a secretory organ. Comprehensive
Physiology, 3(3), 1337–1362. http://doi.org/10.1002/cphy.
c120033
Pennings, B., Koopman, R., Beelen, M., Senden, J. M. G., Saris,
W. H. M., & van Loon, L. J. C. (2011). Exercising before
protein intake allows for greater use of dietary protein-derived
amino acids for de novo muscle protein synthesis in both
young and elderly men. The American Journal of Clinical
Nutrition, 93(2), 322–331. http://doi.org/10.3945/ajcn.2010.
29649
Phillips, B. E., Williams, J. P., Gustafsson, T., Bouchard, C.,
Rankinen, T., Knudsen, S., … Atherton, P. J. (2013).
Molecular networks of human muscle adaptation to exercise
and age. PLoS Genetics, 9(3), e1003389. http://doi.org/10.
1371/journal.pgen.1003389
Phillips, S. M., Glover, E. I., & Rennie, M. J. (2009). Alterations of
protein turnover underlying disuse atrophy in human skeletal
muscle. Journal of Applied Physiology (Bethesda, Md. : 1985),
107(3), 645–654. http://doi.org/10.1152/japplphysiol.00452.
2009
Phillips, S. M., Parise, G., Roy, B. D., Tipton, K. D., Wolfe, R. R.,
& Tamopolsky, M. A. (2002). Resistance-training-induced
adaptations in skeletal muscle protein turnover in the fed
state. Canadian Journal of Physiology and Pharmacology, 80
(11), 1045–1053.
Phillips, S. M., Tipton, K. D., Aarsland, A., Wolf, S. E., Wolfe, R.
R., & Wolf, E. (1997). Mixed muscle protein synthesis and
breakdown after resistance exercise in humans. The American
Journal of Physiology, 273(1 Pt 1), E99–107.
Phillips, S. M., Tipton, K. D., Ferrando, a. a., & Wolfe, R. R.
(1999). Resistance training reduces the acute exercise-induced
increase in muscle protein turnover. The American Journal of
Physiology, 276(1 Pt 1), E118–E124.
Pozefsky, T., Tancredi, R. G., Moxley, R. T., Dupre, J., & Tobin, J.
D. (1976). Effects of brief starvation on muscle amino acid
metabolism in nonobese man. The Journal of Clinical
Investigation, 57(2), 444–449. http://doi.org/10.1172/JCI108295
Previs, S. F., Fatica, R., Chandramouli, V., Alexander, J. C.,
Brunengraber, H., & Landau, B. R. (2004). Quantifying rates
of protein synthesis in humans by use of 2H2O: Application
to patients with end-stage renal disease. American Journal of
Physiology. Endocrinology and Metabolism, 286(4), E665–E672.
http://doi.org/10.1152/ajpendo.00271.2003
Resistance exercise and muscle hypertrophy 11
Proud, C. G. (2009). mTORC1 signalling and mRNA translation.
Biochemical Society Transactions, 37(Pt 1), 227–231. http://doi.
org/10.1042/BST0370227
Rand, W. M., Pellett, P. L., & Young, V. R. (2003). Meta-analysis
of nitrogen balance studies for estimating protein requirements
in healthy adults. The American Journal of Clinical Nutrition, 77
(1), 109–127.
Rennie, M. J., Edwards, R. H., Halliday, D., Matthews, D. E.,
Wolman, S. L., & Millward, D. J. (1982). Muscle protein syn-
thesis measured by stable isotope techniques in man: The effects
of feeding and fasting. Clinical Science (London, England : 1979),
63(6), 519–523.
Rennie, M. J., Wackerhage, H., Spangenburg, E. E., & Booth,
F. W. (2004). Control of the size of the human muscle mass.
Annual Review of Physiology, 66(9), 799–828. http://doi.org/10.
1146/annurev.physiol.66.052102.134444
Robinson, M. M., Turner, S. M., Hellerstein, M. K., Hamilton,
K. L., & Miller, B. F. (2011). Long-term synthesis rates of skel-
etal muscle DNA and protein are higher during aerobic training
in older humans than in sedentary young subjects but are not
altered by protein supplementation. FASEB Journal: Official
Publication of the Federation of American Societies for Experimental
Biology, 25(9), 3240–3249. http://doi.org/10.1096/fj.11-186437
Sancak, Y., Bar-peled, L., Zoncu, R., Markhard, A. L., Nada, S., &
Sabatini, D. M. (2011). NIH Public Access, 141(2), 290–303.
http://doi.org/10.1016/j.cell.2010.02.024.Ragulator-Rag
Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A.,
Thoreen, C. C., Bar-peled, L., & Sabatini, D. M. (2008).
NIH Public Access, 320(5882), 1496–1501. http://doi.org/10.
1126/science.1157535.The
Scalzo, R. L., Peltonen, G. L., Binns, S. E., Shankaran, M.,
Giordano, G. R., Hartley, D. a., … Miller, B. F. (2014).
Greater muscle protein synthesis and mitochondrial biogenesis
in males compared with females during sprint interval training.
FASEB Journal: Official Publication of the Federation of American
Societies for Experimental Biology, 28(6), 2705–2714. http://doi.
org/10.1096/fj.13-246595
Schoenheimer, R., & Rittenberg, D. (1936). Deuterium as an indi-
cator in the study of intermediary metabolism VI. Synthesis and
destruction of fatty acids in the organism. Journal of Biological
Chemistry, 114, 381–396.
Seynnes, O. R., de Boer, M., & Narici, M. V. (2007). Early skeletal
muscle hypertrophy and architectural changes in response to
high-intensity resistance training. Journal of Applied Physiology
(Bethesda, Md. : 1985), 102(1), 368–373. http://doi.org/10.
1152/japplphysiol.00789.2006
Sheffield-Moore, M., Yeckel, C. W., Volpi, E., Wolf, S. E., Morio,
B., Chinkes, D. L., … Wolfe, R. R. (2004). Postexercise protein
metabolism in older and younger men following moderate-
intensity aerobic exercise. American Journal of Physiology.
Endocrinology and Metabolism, 287(3), E513–E522. http://doi.
org/10.1152/ajpendo.00334.2003
Shulman, G. I., Rothman, D. L., Jue, T., Stein, P., DeFronzo, R.
A., & Shulman, R. G. (1990). Quantitation of muscle glycogen
synthesis in normal subjects and subjects with non-insulin-
dependent diabetes by 13C nuclear magnetic resonance
spectroscopy. The New England Journal of Medicine, 322(4),
223–228. http://doi.org/10.1056/NEJM199001253220403
Smith, K., Reynolds, N., Downie, S., Patel, A., & Rennie, M. J.
(1998). Effects of flooding amino acids on incorporation of
labeled amino acids into human muscle protein. American
Journal of Physiology, 275, 73–78.
Staples, A. W., Burd, N. a., West, D. W. D., Currie, K. D.,
Atherton, P. J., Moore, D. R., … Phillips, S. M. (2011).
Carbohydrate does not augment exercise-induced protein
accretion versus protein alone. Medicine and Science in Sports
 12 M. S. Brook et al.
and Exercise, 43(7), 1154–1161. http://doi.org/10.1249/MSS.
0b013e31820751cb
Staron, R. S., Karapondo, D. L., Kraemer, W. J., Fry, A. C.,
Gordon, S. E., Falkel, J. E., … Hikida, R. S. (1994). Skeletal
muscle adaptations during early phase of heavy-resistance train-
ing in men and women. Journal of Applied Physiology (Bethesda,
Md. : 1985), 76(3), 1247–1255.
Tang, J. E., Perco, J. G., Moore, D. R., Wilkinson, S. B., &
Phillips, S. M. (2008). 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(1), R172–R178. http://doi.org/10.
1152/ajpregu.00636.2007
Tesch, P. A., Ekberg, A., Lindquist, D. M., & Trieschmann, J. T.
(2004). Muscle hypertrophy following 5-week resistance train-
ing using a non-gravity-dependent exercise system. Acta
Physiologica Scandinavica, 180(1), 89–98. http://doi.org/10.
1046/j.0001-6772.2003.01225.x
Viitasalo, J. T., Saukkonen, S., & Komi, P. V. (1980).
Downloaded by [Ecole Hautes Etudes Commer-Montreal] at 05:53 22 August 2015
Reproducibility of measurements of selected neuromuscular
performance variables in man. Electromyography and Clinical
Neurophysiology, 20(6), 487–501.
Volek, J. S., Volk, B. M., Gómez, A. L., Kunces, L. J., Kupchak, B.
R., Freidenreich, D. J., … Kraemer, W. J. (2013). Whey protein
supplementation during resistance training augments lean body
mass. Journal of the American College of Nutrition, 32(2),
122–135. http://doi.org/10.1080/07315724.2013.793580
Wernbom, M., Augustsson, J., & Thomeé, R. (2007). The influ-
ence of frequency, intensity, volume and mode of strength train-
ing on whole muscle cross-sectional area in humans. Sports
Medicine (Auckland, N.Z.), 37(3), 225–264.
West, D. W., Burd, N. A., Coffey, V. G., Baker, S. K., Burke,
L. M., Hawley, J. A., … Phillips, S. M. (2011). Rapid aminoa-
cidemia enhances myofibrillar protein synthesis and anabolic
intramuscular signaling responses after resistance exercise.
American Journal of Clinical Nutrition, 94, 795–803.
West, D. W. D., Kujbida, G. W., Moore, D. R., Atherton, P.,
Burd, N. a., Padzik, J. P., … Phillips, S. M. (2009).
Resistance exercise-induced increases in putative anabolic hor-
mones do not enhance muscle protein synthesis or intracellular
signalling in young men. The Journal of Physiology, 587(Pt 21),
5239–5247. http://doi.org/10.1113/jphysiol.2009.177220
Wilkinson, D. J., Franchi, M. V., Brook, M. S., Narici, M. V.,
Williams, J. P., Mitchell, W. K., … Smith, K. (2014). A vali-
dation of the application of D(2)O stable isotope tracer tech-
niques for monitoring day-to-day changes in muscle protein
subfraction synthesis in humans. American Journal of
Physiology. Endocrinology and Metabolism, 306(5), E571–E579.
http://doi.org/10.1152/ajpendo.00650.2013
Wilkinson, D. J., Hossain, T., Hill, D. S., Phillips, B. E.,
Crossland, H., Williams, J., … Atherton, P. J. (2013). Effects
of leucine and its metabolite β-hydroxy-β-methylbutyrate on
human skeletal muscle protein metabolism. The Journal of
Physiology, 591(Pt 11), 2911–2923. http://doi.org/10.1113/
jphysiol.2013.253203
Wilkinson, S. B., Phillips, S. M., Atherton, P. J., Patel, R.,
Yarasheski, K. E., Tarnopolsky, M. a., & Rennie, M. J.
(2008). 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(Pt 15), 3701–3717. http://doi.org/10.1113/jphysiol.2008.
153916
Williams, J. P., Phillips, B. E., Smith, K., Atherton, P. J., Rankin,
D., Selby, A. L., … Rennie, M. J. (2012). Effect of tumor
burden and subsequent surgical resection on skeletal muscle
mass and protein turnover in colorectal cancer patients. The
American Journal of Clinical Nutrition, 96(5), 1064–1070.
http://doi.org/10.3945/ajcn.112.045708
Willoughby, D., & Taylor, L. (2004). Effects of sequential bouts of
resistance exercise on androgen receptor expression. Medicine
and Science in Sports and Excercise, 36(9), 1499–1506. http://
doi.org/10.1249/01.MSS.0000139795.83030.DI
Witard, O. C., Jackman, S. R., Breen, L., Smith, K., Selby, A., &
Tipton, K. D. (2014). Myofibrillar muscle protein synthesis
rates subsequent to a meal in response to increasing doses of
whey protein at rest and after resistance exercise. The
American Journal of Clinical Nutrition, 99(1), 86–95. http://doi.
org/10.3945/ajcn.112.055517
Woolstenhulme, M. T., Conlee, R. K., Drummond, M. J., Stites,
A. W., & Parcell, A. C. (2006). Temporal response of desmin
and dystrophin proteins to progressive resistance exercise in
human skeletal muscle. Journal of Applied Physiology (Bethesda,
Md. : 1985), 100(6), 1876–1882. http://doi.org/10.1152/
japplphysiol.01592.2005
Yang, R. D., Matthews, D. E., Bier, D. M., Lo, C., & Young, V. R.
(1984). Alanine kinetics in humans: Influence of different isoto-
pic tracers Alanine kinetics in humans: Influence of different
isotopic tracers.
Zhang, X., Chinkes, D. L., Wolfe, R. R., & Robert, R. (2002).
Breakdown rates from a pulse tracer injection, 753–764.
Zurlo, F., Larson, K., Bogardus, C., & Ravussin, E. (1990).
Skeletal muscle metabolism is a major determinant of resting
energy expenditure. The Journal of Clinical Investigation, 86(5),
1423–1427. http://doi.org/10.1172/JCI114857