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REVIEW ARTICLE
Intramuscular Anabolic Signaling and Endocrine Response
Following Resistance Exercise: Implications for Muscle
Hypertrophy
Adam M. Gonzalez
1
•Jay R. Hoffman
2
•Jeffrey R. Stout
2
•David H. Fukuda
2
•
Darryn S. Willoughby
3
!Springer International Publishing Switzerland 2015
Abstract Maintaining skeletal muscle mass and function
is critical for disease prevention, mobility and quality of
life, and whole-body metabolism. Resistance exercise is
known to be a major regulator for promoting muscle pro-
tein synthesis and muscle mass accretion. Manipulation of
exercise intensity, volume, and rest elicit specific muscular
adaptations that can maximize the magnitude of muscle
growth. The stimulus of muscle contraction that occurs
during differing intensities of resistance exercise results in
varying biochemical responses regulating the rate of pro-
tein synthesis, known as mechanotransduction. At the
cellular level, skeletal muscle adaptation appears to be the
result of the cumulative effects of transient changes in gene
expression following acute bouts of exercise. Thus, maxi-
mizing the resistance exercise-induced anabolic response
produces the greatest potential for hypertrophic adaptation
with training. The mechanisms involved in converting
mechanical signals into the molecular events that control
muscle growth are not completely understood; however,
skeletal muscle protein synthesis appears to be regulated by
the multi-protein phosphorylation cascade, mTORC1
(mammalian/mechanistic target of rapamycin complex 1).
The purpose of this review is to examine the physiological
response to resistance exercise, with particular emphasis on
the endocrine response and intramuscular anabolic signal-
ing through mTORC1. It appears that resistance exercise
protocols that maximize muscle fiber recruitment, time-
under-tension, and metabolic stress will contribute to
maximizing intramuscular anabolic signaling; however, the
resistance exercise parameters for maximizing the anabolic
response remain unclear.
Key Points
The endocrine system and intramuscular anabolic
signaling are primary regulators of muscle growth.
Resistance exercise elicits an acute endocrine
response and up-regulation of intramuscular
signaling proteins; however, the resistance exercise
parameters for maximizing the anabolic effect
remain unclear.
1 Introduction
Maintaining skeletal muscle mass and function is critical
for disease prevention [1,2], mobility and quality of life [3,
4], and whole-body metabolism [5]. Skeletal muscle mass
is also desired by many types of athletes to enhance athletic
performance, increase body size, and improve aesthetic
appearance. The balance between synthesis and breakdown
of muscle proteins governs muscle mass accretion. If pro-
tein synthesis exceeds protein degradation, an increase in
skeletal muscle mass can occur [6]. The rate of protein
synthesis appears to be more dynamic than that of protein
&Jay R. Hoffman
jay.hoffman@ucf.edu
1
Department of Health Professions, Hofstra University,
Hempstead, NY, USA
2
Institute of Exercise Physiology and Wellness, Sport and
Exercise Science, College of Education and Human
Performance, University of Central Florida,
P.O. Box 161250, Orlando, FL 32816-1250, USA
3
Exercise and Biochemical Nutrition Laboratory, Baylor
University, Waco, TX, USA
123
Sports Med
DOI 10.1007/s40279-015-0450-4
breakdown, suggesting that growth of skeletal muscle is
primarily dictated by regulation of muscle protein synthesis
[7]. Hypertrophy is reflected by a greater muscle cross-
sectional area (CSA), which may be attributable to
increases in myofibrillar volume of individual muscle
fibers [8–10]. Increases in the number of individual myo-
fibers within a muscle, termed hyperplasia, is also a
potential mechanism contributing to muscle growth; how-
ever, documented reports are primarily in rodents [11].
Muscle protein synthesis and muscle mass accretion are
affected by several factors, including nutritional support,
cytokines, hormones, and growth factors, yet resistance
exercise is known to be a major regulator for promoting
hypertrophy. Resistance exercise can stimulate an increase
in muscle protein synthesis for up to 48 h post-exercise
[12–15], and repeated bouts of resistance exercise (i.e.,
training) can significantly increase muscle CSA and muscle
fiber hypertrophy [16–19]. However, the parameters of a
resistance training program for the regulation of muscle
growth remain unclear [20].
A broad range of resistance exercise intensities, volume,
and rest intervals have been demonstrated to elicit mus-
cular hypertrophy in humans [16–19]. The stimulus of
muscle contraction that occurs during resistance exercise
results in various biochemical responses regulating the rate
of protein synthesis, known as mechanotransduction [21].
At the cellular level, skeletal muscle adaptation appears to
occur from the cumulative effects of transient changes in
gene expression following acute bouts of exercise [22].
Thus, maximizing the resistance exercise-induced anabolic
response produces the greatest potential for hypertrophic
adaptation with training. The purpose of this review is to
examine the physiological response to resistance exercise,
with particular emphasis on the endocrine system and
intramuscular anabolic signaling through the mammalian/
mechanistic target of rapamycin complex 1 (mTORC1)
pathway.
2 Magnitude of Hypertrophy Following
Resistance Exercise Protocols of Different
Intensities
Controversy exists regarding a training paradigm that will
maximize hypertrophic adaptation. Long-term studies
evaluating the effects of varying exercise intensity on the
magnitude of muscle hypertrophy have yielded incon-
clusive findings. Comparisons of high-intensity versus low-
intensity resistance training programs for up to 12 weeks in
previously untrained subjects have shown no differences in
muscle CSA as measured by magnetic resonance imaging
(MRI) [23–29], computed tomography (CT) [30,31],
dual-energy x-ray absorptiometry (DEXA) [32], and
ultrasonography [32,33]. However, Holm et al. [34] found
low-intensity loads (15.5 % 1 repetition maximum [RM])
to be inferior to high-intensity loads (70 % 1 RM) for
evoking increases in quadriceps CSA assessed via MRI.
Similarly, low-intensity loads were also shown to be infe-
rior to high-intensity loads for increasing muscle fiber
hypertrophy as assessed via histochemistry from muscle
biopsies [35,36]. Other investigations, however, have
indicated that lower-intensity loads (40–80 % 1 RM) pro-
duce greater gains in muscle fiber CSA than high-intensity
loads (90 % 1 RM) [37,38].
Defining an intensity load recommendation for
enhancing muscle hypertrophy is difficult due to the
inconsistency of findings. Additionally, the contradictory
nature of these findings may be attributed to the different
assessment methods (i.e., MRI, CT, ultrasonography vs.
muscle histochemistry), experimental designs (i.e.,
within- vs. between-subject designs), activated muscula-
ture (i.e., single- vs. multi-joint movements), rest intervals
utilized, and protocol parameters (i.e., equated vs. non-
equated volume). A number of researchers equate volume
to account for the potentially greater dose response
associated with hypertrophic adaptation [39]. Further-
more, these studies are collectively limited as observa-
tions of early-phase hypertrophic adaptations among
untrained subjects. Greater training experience has been
shown to attenuate post-exercise anabolic responses,
including muscle protein synthesis rates [40–42]and
intracellular anabolic signaling [42–45]. Therefore, these
findings cannot be generalized to a well-trained popula-
tion. Schoenfeld et al. [46]recentlyassessedthemagni-
tude of hypertrophy following 8 weeks of a hypertrophy-
style resistance training program versus a volume-equated
strength-style program in resistance-trained men and
found no significant differences in muscle thickness of the
biceps brachii assessed via ultrasonography. In a subse-
quent study by the same research team, muscle thickness
of the elbow flexors, elbow extensors, and quadriceps
femoris assessed via ultrasonography was not signifi-
cantly different following 8 weeks of low-load
(25–35 RM) versus high- load resistance training
(8–12 RM) in resistance-trained men [47]. In conjunction
with training intensity, factors including muscle fiber
recruitment [48], time-under-tension [49], and metabolic
stress [50] have all been suggested to influence intra-
muscular anabolic signaling. Furthermore, muscular
adaptation following regimented resistance training is
highly variable between individuals [51–54]. Several
factors appear to influence muscle remodeling and the
magnitude of hypertrophy, including nutritional support,
muscle fiber-type distribution, and genetic predisposition
[20,55]. An additional concern when examining diver-
gent resistance exercise protocols in trained individuals is
A. M. Gonzalez et al.
123
the novelty of the stimulus, as muscle adaptations may be
enhanced when unaccustomed program variables are uti-
lized [56].
The intensity of training necessary to stimulate muscle
growth has been suggested to be greater than 60 % of an
individual’s 1 RM [57,58], while others have suggested that
maximal growth occurs at training intensities between 80
and 95 % of 1 RM [59]. However, recent research has
shown that training intensities as low as 30 % of 1 RM can
be equally as effective at stimulating muscle protein syn-
thesis and muscle hypertrophy when performed to volitional
fatigue in previously untrained men [24,25,60]. Moreover,
a majority of the scientific evidence supporting a greater
anabolic response following a high-volume, moderate-in-
tensity training protocol (i.e., designed to elicit muscle
hypertrophy) has emerged from acute investigations indi-
cating a superior endocrine response compared to other
training paradigms [61–67]. However, the mechanisms of
exercise-mediated muscle hypertrophy have been suggested
to be solely an intrinsic process, which is not influenced by
transient changes in circulating hormones [54,68–70]. Thus,
the acute activation of intrinsically located signaling proteins
and the acute elevation of muscle protein synthesis may be
more reflective of the potential to increase muscle mass with
resistance training [69]. Whether a high-volume, moderate-
intensity training protocol activates intramuscular anabolic
signaling to a greater degree than other training paradigms
remains to be determined.
3 Role of Mammalian/Mechanistic Target
of Rapamycin Complex 1 (mTORC1) in Skeletal
Muscle Adaptation to Resistance Exercise
One of the most widely recognized mechanisms for regu-
lating muscle mass involves mechanical tension [71].
Resistance exercise initiates a multifaceted series of events
converting the stimulus of muscle contraction into bio-
chemical responses regulating the rate of protein synthesis,
known as mechanotransduction [21]. The mechanisms
involved in converting mechanical signals into the molecu-
lar events that control muscle growth are not completely
understood; however, phosphorylation of intramuscular
signaling molecules appears to play an important role in
skeletal muscle adaptation to resistance exercise [21]. Pro-
tein phosphorylation is a reversible post-translational mod-
ification causing conformational changes in protein structure
accompanied by an increase or decrease in enzymatic
activity [72]. Skeletal muscle protein synthesis appears to be
regulated by the multi-protein phosphorylation cascade,
mTORC1 [73–75]. Upon activation, phosphorylation of
upstream (i.e., insulin receptor substrate 1 [IRS1], protein
kinase B [Akt], tumor sclerosis complex 2 [TSC2]) and
downstream (i.e., mammalian/mechanistic target of rapa-
mycin [mTOR], ribosomal S6 kinase 1 [p70S6k], RPS6
[ribosomal protein S6]) effectors of mTORC1 signal to
promote anabolic and inhibit catabolic cellular functions,
providing a biochemical mechanism for controlling pro-
cesses related to cell differentiation and muscle remodeling
(Fig. 1)[75]. The protein kinase mTOR serves as a critical
protein that confers signaling to p70S6k and several other
downstream signaling molecules that regulate protein syn-
thesis and skeletal muscle mass [21,75].
The mTORC1 complex plays an important regulatory
role during the process of skeletal muscle hypertrophy
[76]. mTORC1 is involved in many cell processes,
including the regulation of cell size, mRNA translation,
biogenesis of mitochondria and ribosomes, and autophagy
[77]. At the cellular level, mTORC1 functions as a critical
regulator of translation initiation, the rate-limiting step in
protein synthesis [72,75]. It appears that the phosphory-
lation of signaling molecules in response to resistance
exercise is a prerequisite for increasing translation initi-
ation and muscle protein synthesis. The inhibition of
mTOR via rapamycin treatment has been consistently
demonstrated to blunt increases in muscle protein syn-
thesis [78–80] and prevent skeletal muscle hypertrophy,
which normally occurs following prolonged resistance
training [76,81]. In humans, rapamycin treatment has
been shown to block the acute exercise-induced increase
in muscle protein synthesis in addition to blunting several
downstream components of the mTORC1 signaling
pathway, including p70S6k [73,80]. Further, the magni-
tude of p70S6k phosphorylation has been shown to be a
proxy marker of myofibrillar protein synthesis rates [82,
83], and also corresponds with resistance training-induced
muscle hypertrophy [54,84–86]. Collectively, these
observations suggest that mTOR acts as the primary
regulator of intracellular anabolic signaling via phos-
phorylation of p70S6k and several other downstream
signaling molecules that regulate protein synthesis and
skeletal muscle mass [73–75,87]. Although the exact
mechanism underlying increased mTORC1 activation
following resistance exercise remains relatively elusive,
mechanical loading has been suggested to promote
mTORC1 activation by increasing the activity of Rheb
(Ras homolog enriched in brain) and increasing the
abundance of phosphatidic acid (PA) [88].
mTORC1 activity is regulated by the modulation of
tumor suppressor tuberous sclerosis complex 1/2 (TSC 1/2)
activity [77]. TSC 1/2 negatively regulates mTORC1
activity by converting Rheb into its inactive guanosine
diphosphate (GDP)-bound state [89]. Tumor sclerosis
complex 2 (TSC2) acts as the guanosine triphosphatase
(GTPase)-activating enzyme that keeps Rheb in the GDP-
bound state [90]. TSC2 phosphorylation inactivates the
Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise
123
GTPase-activating enzyme activity of TSC2, repressing the
hydrolysis of Rheb–GTP (guanosine triphosphate) [91].
When Rheb is in its active GTP-bound state, it translocates
to the lysosome, allowing mTORC1 activity to continue
[91,92]. Jacobs et al. [93] showed that TSC2 localizes with
Rheb at rest; however, following resistance exercise, TSC2
phosphorylation corresponds with the movement of TSC2
away from Rheb. In summary, resistance exercise-induced
activation of mTORC1 requires the TSC2 complex (a
negative regulator of Rheb) to be sequestered away from
Rheb (Fig. 2). However, it remains unclear what mediates
TSC2 phosphorylation following resistance exercise [88].
While insulin and growth factors phosphorylate TSC2
through Akt, resistance exercise-induced activation of
mTORC1 appears to be Akt-independent [94]. Several
studies have shown that Akt phosphorylation either does
not change [43,45,49] or decreases [95,96] following
resistance exercise, despite downstream activation of
mTORC1.
An additional mTORC1 activator associated with
resistance exercise-induced muscle hypertrophy involves
the lipid second messenger known as PA [97]. Exogenous
administration of PA, or an over-expression of enzymes
that produce PA, results in an increase in mTORC1 acti-
vation [98–100]. Similarly, limiting PA production atten-
uates mTORC1 activity [97]. It has been suggested that PA
mediates mTORC1 activation by competing with the
FKBP12 (FK506 binding protein 12)–rapamycin complex
for binding to the FKBP12–rapamycin-binding (FRB)
domain of mTOR [101,102]. PA may also promote
mTORC1 activation as a primary effector of Rheb [103].
GTP-bound Rheb has been shown to activate phospholi-
pase D (PLD), an enzyme that generates PA from phos-
phatidylcholine [103]. PA can be synthesized by various
classes of enzymes, such as PLD, diacylglycerol kinase f
(DGKf), and lysophosphatidic acid acyltransferases
(LPAAT) [74,98,104,105]. Joy et al. [106] found that
stimulating myoblast cells with PA in vitro increased
Fig. 1 Simplistic overview of
the influence of muscle
contraction and growth factors
on mTORC1 signaling and the
regulation of muscle growth.
Broken arrows indicate
‘remains unclear’. Akt protein
kinase B, DAG diacylglycerol,
DGKfdiacylglycerol kinase f,
IRS1 insulin receptor
substrate 1, LPA
lysophosphatidic acid, LPAAT
lysophosphatidic acid
acyltransferases, mTOR
mammalian/mechanistic target
of rapamycin, mTORC1
mammalian/mechanistic target
of rapamycin complex 1,
p70S6k ribosomal S6 kinase 1,
PA phosphatidic acid, PC
phosphatidyl choline, PDK1
3-phosphoinositide-dependent
protein kinase-1, PI3K
phosphatidylinositol-3 kinase,
PIP2 phosphoinositol (4,5)-
bisphosphate, PIP3
phosphoinositol (3,4,5)-
trisphosphate, PLD
phospholipase D, Rheb Ras
homolog enriched in brain,
RPS6 ribosomal protein S6,
TSC1 tuberous sclerosis
complex 1, TSC2 tuberous
sclerosis complex 2
A. M. Gonzalez et al.
123
mTORC1 signaling, and trained subjects supplementing
with PA significantly improved skeletal muscle hypertro-
phy following 8 weeks of resistance training. Thus, evi-
dence suggests that PA is a direct regulator of resistance
exercise-induced mTORC1 signaling promoting muscle
hypertrophy.
4 Growth Factor Activation of mTORC1
Within the mTORC1 signaling pathway, growth factors
including insulin and insulin-like growth factor (IGF)-1
bind to their respective receptors, which promote the
inhibition of Rheb in an Akt-dependent pathway, resulting
in an increase in mTORC1 activity [91]. When insulin/
IGF-1 bind to their receptors at the muscle membrane, the
receptor autophosphorylates, creating a docking site for
IRS1 [107]. IRS1 moves to the plasma membrane, which
subsequently recruits phosphatidylinositol-3 kinase (PI3K)
[107]. PI3K phosphorylates the membrane phospholipid
phosphoinositol (4,5)-bisphosphate (PIP2), resulting in
phosphoinositol (3,4,5)-trisphosphate (PIP3) [108]. PIP3
causes the co-localization of Akt and 3-phosphoinositide-
dependent protein kinase-1 (PDK-1) to the membrane,
resulting in Akt phosphorylation [109]. Subsequently,
TSC2 is phosphorylated by Akt, resulting in relocalization
away from Rheb [91,110]. Akt also inhibits PRAS40
(proline-rich Akt substrate of 40 kDa), a negative regulator
of mTORC1 signaling [111]. In summary, similar to
resistance exercise-induced mTORC1 activation, insulin
and growth factors appear to activate mTORC1 via phos-
phorylation of TSC2. However, insulin and growth factors
appear to activate mTORC1 through Akt, while resistance
exercise induces an Akt-independent activation of
mTORC1.
5 Association Between Circulating Hormones,
mTORC1 Signaling, and Muscle Growth
The endocrine system plays an integral role in the regula-
tion of muscle mass. Hormones including testosterone,
growth hormone (GH), insulin, IGF-1 and cortisol influ-
ence muscle growth and development throughout life, and
states of hormonal excess or deficiency alter the balance
between skeletal muscle anabolism and catabolism [112,
113]. While the fundamental roles of hormones are
imperative for developmental growth and maintenance of
skeletal muscle throughout a lifetime, the impact of phys-
iological fluctuations (i.e., non-pharmacological-based
changes) in anabolic hormones has been debated [114].
Resting hormonal concentrations appear to be unaltered
Fig. 2 Simplistic overview
mTORC1 activation (curved
arrow) via phosphorylation of
TSC2. GTP guanosine
triphosphate, mTOR
mammalian/mechanistic target
of rapamycin, mTORC1
mammalian/mechanistic target
of rapamycin complex 1,
Pphosphorylation, p70S6k
ribosomal S6 kinase 1, Rheb
Ras homolog enriched in brain,
TSC2 tuberous sclerosis
complex 2
Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise
123
following resistance training programs of up to 24 weeks
[115,116]; therefore, there has been considerable specu-
lation about the role of the post-exercise endocrine
response in mediating increases in muscle size [117].
Systemic elevations of circulating hormones presumably
increase the likelihood of interaction with receptors located
within the muscle tissue and have been speculated to
contribute to muscle growth consequent to resistance
training [117]. However, in humans, elevations of the
anabolic hormones do not appear to be necessary for
muscle hypertrophy [118], intramuscular signaling [70,
119], or muscle protein synthesis [70], leading to the
supposition that the mechanisms of muscle hypertrophy are
intrinsically specific to the activated skeletal tissue [69].
Exogenous supra-physiological doses of testosterone have
shown to significantly increase muscle protein synthesis
and lean body mass [120,121], especially when combined
with resistance training [122,123]. Additionally, admin-
istration of exogenous testosterone supplementation to
restore normal physiological values in androgen-deficient
older men is associated with significant increases in muscle
mass [124–129]. However, others have suggested that
physiological fluctuations of hormones are not required for
resistance exercise-induced skeletal muscle hypertrophy
[88]. These hormones, including testosterone, GH, insulin,
IGF-1, and cortisol, have been suggested to be far more
important for developmental growth rather than exercise-
induced muscle growth [88].
Transient hormonal elevations appear to play a per-
missive, rather than stimulatory, role in the regulation of
muscle protein synthesis [130]. Over-expression of Rheb in
skeletal muscle stimulates a PI3K/Akt-independent acti-
vation of mTORC1 that is sufficient to induce muscle
hypertrophy [131]. Although it has been suggested that
growth factor activation of the PI3K/Akt axis is also suf-
ficient for skeletal muscle growth, these mechanisms do not
appear to be necessary for maximizing mTORC1 activation
or the hypertrophic response that occurs in response to
resistance exercise [21,88]. Resistance exercise and
growth factors share the same final step in mTORC1
activation (via phosphorylation of TSC2) (Fig. 2)[88].
Since the end result of both resistance exercise and growth
factors is the movement of TSC2 away from Rheb via
different upstream kinases, resistance exercise and growth
factor exposure may not offer a synergistic effect.
6 Influence of Acute Endocrine and Intramuscular
Signaling Response on Muscle Growth
Substantial evidence indicates that resistance exercise
protocols of high volume (3–6 sets; 8–12 repetitions),
moderate intensity (60–85 % 1 RM), and short rest
intervals (30–90 s), which activate a large muscle mass,
elicit the greatest acute elevations in testosterone and GH
[61–67,132–139]. Studies investigating the acute hor-
monal response following different heavy-resistance exer-
cise protocols are presented in Table 1. Several studies
have also investigated the association between acute
exercise-induced hormone responses and changes in mus-
cle size following a structured resistance training program
(Table 2). McCall et al. [115] found a significant correla-
tion (r=0.70–0.71; p\0.05) between acute exercise-in-
duced GH elevations and the degree of both type I and
type II muscle fiber hypertrophy following 15 weeks of
resistance training in 11 recreationally trained men. Ahti-
ainen et al. [116] reported a significant correlation
(r=0.76; p\0.05) between changes in the acute testos-
terone response and the degree of muscle hypertrophy
following 21 weeks of resistance training in 16 men (eight
strength athletes and eight non-athletes). However, both of
these studies had a relatively small number of subjects,
thereby limiting the ability to draw meaningful conclu-
sions. In a more recent study examining a larger cohort of
56 untrained men, West and Phillips [140] reported that the
acute systemic hormonal response of GH and cortisol were
weakly correlated (r=0.28–0.36; p\0.05) with resis-
tance training-induced changes in muscle fiber CSA
explaining 8 and 12 % of the variance, respectively.
Although cortisol, a catabolic hormone, was weakly cor-
related with changes in lean body mass (r=0.29;
p\0.05), no significant correlations were observed
between GH, testosterone, and IGF-1 and changes in lean
body mass [140]. Additionally, the variability within the
gains of muscle hypertrophy seen in ‘high responders’ and
‘low responders’ could not be explained by the acute
hormone response [140]. However, these investigations are
based on limited blood sampling timepoints following an
acute bout of resistance training. Furthermore, Wilkinson
et al. [118] observed significant gains in hypertrophy in the
absence of systemic changes in GH, testosterone, and IGF-
1[118]. Thus, the effect of changes in the acute anabolic
hormonal response to resistance exercise on muscle growth
is still not well-understood.
Mitchell et al. [54] examined post-exercise changes in
anabolic hormone concentrations (testosterone, GH, and
IGF-1) and intramuscular signaling and their association
with muscle fiber hypertrophy following 16 weeks of
training. Post-exercise increases in these circulating hor-
mones following the initial bout of resistance exercise did
not appear to be related to training-induced hypertrophy,
whereas acute increases in p70S6k phosphorylation and
androgen receptor (AR) protein content following the initial
bout of resistance exercise were highly associated
(r=0.54–0.60; p\0.05) with resistance training-induced
hypertrophy [54]. The magnitude of p70S6k
A. M. Gonzalez et al.
123
Table 1 Studies investigating the acute hormonal response following different resistance exercise protocols
Study Participants Crossover
design?
Design Protocols Hormones
measured
Results
Beaven
et al. [134]
15 trained men Yes Full
body
1. 4 910; 70 % 1 RM (2 min rest)
2. 3 95; 85 % 1 RM (3 min rest)
3. 5 915; 55 % 1 RM (1 min rest)
4. 3 95; 40 % 1 RM (3 min rest)
Testosterone
Cortisol
(salivary)
Protocols 1, 2, and 4 elicited significant decreases in cortisol following
exercise. No significant differences in testosterone between protocols
Crewther
et al. [61]
11
recreationally
trained men
Yes Lower
body
1. 8 96; 45 % 1 RM (3 min rest)
2. 10 910; 75 % 1 RM (2 min rest)
3. 6 94; 88 % 1 RM (4 min rest)
Testosterone
Cortisol
(salivary)
Only protocol 2 elicited significant increases in testosterone and cortisol
concentration following exercise
Hakkinen
and
Pakarinen
[62]
10 trained men Yes Lower
body
1. 10 910; 70 % 1 RM (3 min rest)
2. 20 91; 100 % 1 RM (3 min rest)
Testosterone
Cortisol
GH
Protocol 1 elicited significant increases in testosterone, cortisol, and GH
following exercise. Protocol 2 elicited significant increase in GH
following exercise
Kraemer
et al. [67]
9 recreationally
trained men
Yes Full
body
1. 3 910; 10 RM (1 min rest)
2. 5 95; 5 RM (3 min rest)
Testosterone
Cortisol
GH
Protocol 1 elicited significantly greater GH following exercise. Both
protocols significantly increased testosterone; however, not at the same
magnitude and duration (no difference in AUC). Both protocols showed
only random acute increases in cortisol
Linnamo
et al. [63]
8 recreationally
active men
Yes Full
body
1. 5 910; 10 RM (2 min rest)
2. 5 910; 70 % 10 RM (2 min rest)
Testosterone
GH
Only protocol 1 elicited significant increases in GH and testosterone
following exercise
McCaulley
et al. [64]
10 trained men Yes Lower
body
1. 4 910; 75 % 1 RM (1.5 min rest)
2. 11 93; 90 % 1 RM (5 min rest)
Testosterone
Cortisol
Only protocol 1 elicited significant increases in testosterone and cortisol
following exercise
Raastad
et al. [139]
7 trained men Yes Lower
body
1. 3 93; 3 RM (6 min rest) (squat and
front squat) and 3 96; 6 RM (4 min
rest) (leg extension)
2. 3 93; 70 % 3 RM (6 min rest) (squat
and front squat) and 3 96; 76 % 6 RM
(4 min rest) (leg extension)
Testosterone
Cortisol
GH
IGF-1
Insulin
Protocol 1 elicited significantly greater testosterone AUC than protocol 2.
Protocol 1 elicited significantly greater cortisol AUC than protocol 2.
No significant difference in GH, IGF-1, or insulin between protocols
Smilios
et al. [65]
11 trained men Yes Full
body
1.
b
95; 88 % 1 RM (3 min rest)
2.
b
910; 75 % 1 RM (2 min rest)
3.
b
915; 60 % 1 RM (1 min rest)
Testosterone
Cortisol
GH
Protocols 2 and 3 elicited significantly greater GH and cortisol following
exercise. No significant differences were observed for testosterone for
any protocol
Uchida
et al. [66]
27 trained men No Upper
body
1. 4 9*20; 50 % 1 RM (2 min rest)
2. 5 9*11; 75 % 1 RM (2 min rest)
3. 10 9*4; 90 % 1 RM (2 min rest)
4. 8
a
9*4; 110 % 1 RM (2 min rest)
Testosterone
Cortisol
Protocol 2 elicited significantly greater cortisol following exercise. No
differences in testosterone following each protocol
AUC area under the concentration–time curve, GH growth hormone, IGF insulin-like growth factor-1, RM repetition maximum
a
Eccentric only
b
Each was performed using 2, 4, and 6 sets
Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise
123
phosphorylation has shown to be associated with myofib-
rillar protein synthesis rates (r=0.31–0.34; p\0.05) [82,
83], and its acute phosphorylation following resistance
exercise has been reported to correlate with muscle hyper-
trophy following training in both rodents (r=0.998;
p\0.05) [84] and untrained men (r=0.53–0.89; p\0.05)
[85,86]. However, not all studies have found such a rela-
tionship [24]. Still, correlations between transient changes in
muscular and systemic markers of anabolism following
acute bouts of exercise and training-induced muscle hyper-
trophy are not evidence of a causative role for cellular
adaptations in the trained muscle [141].
The hormone-receptor complex regulates gene expres-
sion and transcription factors that may promote an increase
in net muscle protein balance [129,142]. Thus, the number
and sensitivity of receptors in the activated skeletal muscle,
along with systemic elevations of the circulating hormone,
may mediate the anabolic effects of hormones including
testosterone. An up-regulation of either AR protein content
and/or AR mRNA expression has been observed following
resistance exercise [54,143–148], and acute increases in
AR protein content appear to correspond with subsequent
increases in myofibrillar protein [143] and exercise-in-
duced hypertrophy [54]. However, others report no chan-
ges, or decreases, in AR expression following resistance
exercise [149,150]. Moreover, AR expression appears to
have a bi-phasic response with an initial down-regulation
following a bout of resistance exercise followed by an up-
regulation several hours after exercise [151]. Additionally,
it has been demonstrated that AR expression can vary
between different muscles and muscle fiber types [147].
Further, Inoue et al. [152] showed that down-regulation of
AR expression (via an AR antagonist) suppressed the
hypertrophic response in exercised rats. Alternatively,
chemically induced testosterone suppression (via goserelin)
did not blunt AR expression or hypertrophy in young men,
despite a 10- to 20-fold lower resting concentration and a
blocked exercise-induced testosterone response [153].
Enhanced hormone-receptor interaction following resis-
tance exercise may up-regulate the expression of various
muscle-specific genes promoting hypertrophy. However,
further research has demonstrated that an IGF-1 receptor
may not be necessary for resistance exercise-induced
mTORC1 signaling and muscle growth [154]. Using a
transgenic mouse model, Spangenburg and colleagues
[154] reported that both Akt and p70S6k activation can be
induced independently of a functioning IGF-1 receptor.
The extent to which anabolic hormones mediate their
effects directly through the hormone-receptor complex
warrants further investigation.
The relationship between transient increases in hor-
monal concentrations and intramuscular anabolic signaling
and muscle growth has also been an area of interest of
several investigations (Table 3). Acute intramuscular ana-
bolic signaling and exercise-induced hypertrophy have
been examined under different hormonal environments in
untrained individuals [68,70,119,155]. Experimental
trials eliciting a high hormonal response have not been
shown to enhance markers of mTORC1 signaling in the
vastus lateralis [119] or biceps brachii [70] compared with
trials that did not elicit an increase in hormonal concen-
trations. Furthermore, the experimental trial eliciting a
transient increase in the circulating concentration of ana-
bolic hormones did not enhance muscle protein synthesis in
the biceps brachii [70]. In a subsequent study, untrained
men performed a 15-week elbow flexor resistance training
program, with one arm being grouped into a low hormonal
environment and the other into a high hormonal environ-
ment for the duration of the study. Results showed no
difference between conditions in training-induced muscle
hypertrophy of the biceps brachii [68]. However, other
investigators provide conflicting evidence. Rønnestad and
Table 2 Research investigating the association between acute exercise-induced hormone responses and changes in muscle size following a
structured resistance training program
Study Participants Study
length
(weeks)
Results
McCall et al.
[115]
11 recreationally trained
men
12 Significant correlation between acute GH elevation and the degree of type I
(r=0.70) and type II (r=0.71) muscle fiber hypertrophy
Ahtiainen
et al. [116]
8 physically active men;
8 strength athletes
21 Significant correlation between acute testosterone elevation and change in muscle
CSA (r=0.76)
West and
Phillips
[140]
56 recreationally active
men
12 Significant correlation between acute GH elevation and the degree of type I fiber
hypertrophy (r=0.36). Significant correlation between acute cortisol elevation
and the degree of type II fiber hypertrophy (r=0.35) and changes in lean body
mass (r=0.29)
Mitchell et al.
[54]
23 recreationally active
men
16 No correlation between acute testosterone, GH, or IGF-1 elevation and muscle
hypertrophy
CSA cross-sectional area, GH growth hormone, IGF-1 insulin-like growth factor-1
A. M. Gonzalez et al.
123
colleagues [155] utilized a similar 11-week research design
and demonstrated that the increased concentrations of
serum testosterone and GH occurring prior to performing
elbow flexor exercises yielded greater increases in CSA of
the elbow flexors than elbow flexor exercises performed in
a low hormonal environment. The authors hypothesized
that their findings may be related to the exercise order. This
contrasts with others who suggest that changes in the post-
exercise circulating concentrations of testosterone, GH,
and IGF-1, and the subsequent interaction within skeletal
muscle, is not influenced by the order of the resistance
exercises [156]. Evidence to date appears to suggest that
exposing activated skeletal muscle to a transient elevation
in circulating hormones does not enhance intramuscular
signaling.
7 Effect of Resistance Exercise Variables
on Activation of mTORC1
Resistance exercise evokes a robust activation of mTORC1
signaling in untrained and recreationally active men in both
fed [157–161] and fasted states [73,85,162–164]. Resis-
tance exercise-induced mTORC1 activation has also been
observed in experienced, resistance-trained men [45,165,
166], yet the training design (i.e., manipulation of acute
training variables: intensity, volume, and rest) for maxi-
mizing the anabolic response remains unclear.
Multiple-set resistance exercise elicits greater intra-
muscular anabolic signaling than single-set exercise, indi-
cating that exercise volume can influence the muscle
protein signaling response to exercise [83,167]. Low-
versus high-intensity unilateral leg extensions performed to
volitional fatigue have yielded inconclusive results [24,
60]. Burd et al. [60] reported that low-intensity resistance
exercise (30 % 1 RM) was more effective than higher-in-
tensity loads (90 % 1 RM) for inducing mTORC1
signaling 4 h post-exercise in recreationally active men. In
contrast, Mitchell et al. [24] found high-intensity loads
(80 % 1 RM) to be more effective than lower-intensity
loads (30 % 1 RM) for inducing mTORC1 signaling 1 h
post-exercise in untrained men. Regardless, following
10 weeks of training, no differences between the two dif-
ferent training protocols were observed in the magnitude of
muscle hypertrophy [24]. The mTORC1 signaling response
has also shown to be greater following a high volume
(5 910 RM) than a lower volume but higher-intensity
(15 91 RM) bilateral leg press exercise [168]. The lack of
any clear relationship between training program design and
the intramuscular anabolic signaling response suggests that
additional factors such as muscle fiber recruitment [48],
time-under-tension [49], and metabolic stress [50] may
have contributing roles in stimulating the anabolic signal-
ing molecules.
Exercise-induced metabolic stress may also play a role
in acute activation of mTORC1 signaling. Metabolic stress
results from exercise that primarily relies on anaerobic
glycolysis as its major energy provider. Lactate directly
affects muscle cells in vitro by increasing satellite cell
activity as well as mTOR and p70S6k phosphorylation
[169]. Elevations in blood lactate have also been demon-
strated to be weakly associated (r=0.38; p\0.05) with
intramuscular anabolic signaling following resistance
exercise in trained men [50]. Lactate production may
contribute to increased mTORC1 signaling [170]; however,
the mechanisms by which metabolic stress influences
anabolic signaling are not fully elucidated and warrant
further investigation.
Acute activation of mTORC1 signaling may also be
influenced by mode of contraction. Eccentric-only resis-
tance exercise has been suggested to provide a stronger
anabolic stimulus than concentric-only resistance exercise
[171–174], and eccentric contractions have been demon-
strated to produce a more rapid rise in myofibrillar muscle
Table 3 Research investigating the relationship between transient increases in hormonal concentrations and intramuscular anabolic signaling
and muscle growth
Study Participants Study length Results
Acute
Spiering et al. [119] 7 physically active men 2 trials No additive effect from elevated circulating hormones on
intramuscular anabolic signaling
West et al. [70] 8 recreationally active men 2 trials No additive effect from elevated circulating hormones on
intramuscular anabolic signaling or muscle protein synthesis
Prolonged
West et al. [68] 12 untrained men 15 weeks No additive effect from elevated circulating hormones on whole-
muscle, type I, or type II CSA
Rønnestad et al. [155] 11 untrained men 11 weeks Significant increase in muscle CSA as a result of elevated circulating
hormones
CSA cross-sectional area
Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise
123
protein synthesis than concentric only contractions [171,
172]. In addition, maximal eccentric contractions have also
been demonstrated to significantly activate p70S6k and
RPS6 up to 2 h into recovery, while maximal concentric
and submaximal eccentric contractions failed to induce
changes in Akt, mTOR, p70S6k, or RPS6 phosphorylation
status [173]. Additional support was recently provided by
Rahbek et al. [174], who demonstrated that maximal
eccentric contractions triggered a greater acute anabolic
signaling response than concentric contractions. However,
despite the greater anabolic signaling response, no differ-
ences were noted in myofibrillar protein synthesis rates or
in exercise-induced hypertrophy following 12 weeks of
high-volume resistance training [174]. Increases in muscle
size following 9 weeks of unilateral resistance training
have also been shown to be unrelated to muscle contraction
type when matched for both exercise intensity and total
external work [175]. Thus, eccentric contractions, which
emphasize greater tension and stretching of the muscle,
may yield a greater acute anabolic response, yet whether it
translates into greater muscle hypertrophy with training
remains questionable.
It is important to note that the anabolic response fol-
lowing resistance exercise appears to be highly variable
between individuals [43,52,53,176]. A number of factors
influence the muscle remodeling process following resis-
tance exercise, including nutritional intake and genetic
predisposition [88,177]. Nevertheless, several studies have
suggested that training status can also impact resistance
exercise-induced intramuscular anabolic signaling. Coffey
et al. [43] reported that prior training history blunts the
anabolic signaling responses involved in the adaptation to
resistance exercise. Chronic resistance training in rats also
attenuates p70S6k phosphorylation following an acute
exercise bout [178]. Similarly, in humans, the duration of
protein synthesis following a bout of resistance exercise was
reduced following 8 weeks of resistance training [42].
Additionally, our laboratory recently demonstrated that
highly trained, stronger individuals have an attenuated acute
anabolic response following a high-volume resistance
exercise protocol [45]. Thus, a potential lower adaptive
ability among highly trained individuals may, in part,
account for the diminished hypertrophic adaptation among
experienced, resistance-trained individuals [179,180].
8 Conclusion
Despite the plethora of information regarding the impact of
resistance exercise on muscle hypertrophy, the mechanisms
involved in converting mechanical signals into the
molecular events that control muscle growth are not com-
pletely understood. However, skeletal muscle adaptation
appears to be the result of the cumulative effects of tran-
sient changes in gene expression following acute bouts of
exercise [22]. Specifically, skeletal muscle protein syn-
thesis appears to be regulated by the multi-protein phos-
phorylation cascade mTORC1; thus, maximizing resistance
exercise-induced mTORC1 signaling should yield the
greatest potential for hypertrophic adaptation with training
[54,84–86]. A majority of the research to date shows that
mTORC1 signaling is not influenced by transient eleva-
tions in circulating hormones [54,68–70]; hence, the
design of a resistance training program based on a hor-
monal response may be futile. However, resistance exer-
cise-induced mTORC1 activation appears to be a
multifaceted process, which is influenced by a number of
factors. The resistance exercise parameters for maximizing
the anabolic response remain unclear, and it is unknown
whether different resistance exercise paradigms used by
strength and power athletes differentially stimulate intra-
muscular anabolic signaling. Resistance exercise protocols
that maximize muscle fiber recruitment, time-under-ten-
sion, and metabolic stress appear to contribute to intra-
muscular anabolic signaling; however, there does not
appear to be a minimal threshold or optimal training
scheme per se for maximizing muscle hypertrophy.
Compliance with Ethical Standards
Funding No sources of funding were used to assist in the prepa-
ration of this article.
Conflict of interest Adam Gonzalez, Jay Hoffman, Jeffrey Stout,
David Fukuda, and Darryn Willoughby declare that they have no
conflicts of interest relevant to the content of this review.
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