Gonzalez 2015
Gonzalez 2015
Gonzalez 2015
DOI 10.1007/s40279-015-0450-4
REVIEW ARTICLE
Darryn S. Willoughby3
Abstract Maintaining skeletal muscle mass and function response to resistance exercise, with particular emphasis on
is critical for disease prevention, mobility and quality of the endocrine response and intramuscular anabolic signal-
life, and whole-body metabolism. Resistance exercise is ing through mTORC1. It appears that resistance exercise
known to be a major regulator for promoting muscle pro- protocols that maximize muscle fiber recruitment, time-
tein synthesis and muscle mass accretion. Manipulation of under-tension, and metabolic stress will contribute to
exercise intensity, volume, and rest elicit specific muscular maximizing intramuscular anabolic signaling; however, the
adaptations that can maximize the magnitude of muscle resistance exercise parameters for maximizing the anabolic
growth. The stimulus of muscle contraction that occurs response remain unclear.
during differing intensities of resistance exercise results in
varying biochemical responses regulating the rate of pro-
tein synthesis, known as mechanotransduction. At the
Key Points
cellular level, skeletal muscle adaptation appears to be the
result of the cumulative effects of transient changes in gene
The endocrine system and intramuscular anabolic
expression following acute bouts of exercise. Thus, maxi-
signaling are primary regulators of muscle growth.
mizing the resistance exercise-induced anabolic response
produces the greatest potential for hypertrophic adaptation Resistance exercise elicits an acute endocrine
with training. The mechanisms involved in converting response and up-regulation of intramuscular
mechanical signals into the molecular events that control signaling proteins; however, the resistance exercise
muscle growth are not completely understood; however, parameters for maximizing the anabolic effect
skeletal muscle protein synthesis appears to be regulated by remain unclear.
the multi-protein phosphorylation cascade, mTORC1
(mammalian/mechanistic target of rapamycin complex 1).
The purpose of this review is to examine the physiological
1 Introduction
& Jay R. Hoffman Maintaining skeletal muscle mass and function is critical
jay.hoffman@ucf.edu for disease prevention [1, 2], mobility and quality of life [3,
1
4], and whole-body metabolism [5]. Skeletal muscle mass
Department of Health Professions, Hofstra University,
is also desired by many types of athletes to enhance athletic
Hempstead, NY, USA
2
performance, increase body size, and improve aesthetic
Institute of Exercise Physiology and Wellness, Sport and appearance. The balance between synthesis and breakdown
Exercise Science, College of Education and Human
Performance, University of Central Florida, of muscle proteins governs muscle mass accretion. If pro-
P.O. Box 161250, Orlando, FL 32816-1250, USA tein synthesis exceeds protein degradation, an increase in
3
Exercise and Biochemical Nutrition Laboratory, Baylor skeletal muscle mass can occur [6]. The rate of protein
University, Waco, TX, USA synthesis appears to be more dynamic than that of protein
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A. M. Gonzalez et al.
breakdown, suggesting that growth of skeletal muscle is ultrasonography [32, 33]. However, Holm et al. [34] found
primarily dictated by regulation of muscle protein synthesis low-intensity loads (15.5 % 1 repetition maximum [RM])
[7]. Hypertrophy is reflected by a greater muscle cross- to be inferior to high-intensity loads (70 % 1 RM) for
sectional area (CSA), which may be attributable to evoking increases in quadriceps CSA assessed via MRI.
increases in myofibrillar volume of individual muscle Similarly, low-intensity loads were also shown to be infe-
fibers [810]. Increases in the number of individual myo- rior to high-intensity loads for increasing muscle fiber
fibers within a muscle, termed hyperplasia, is also a hypertrophy as assessed via histochemistry from muscle
potential mechanism contributing to muscle growth; how- biopsies [35, 36]. Other investigations, however, have
ever, documented reports are primarily in rodents [11]. indicated that lower-intensity loads (4080 % 1 RM) pro-
Muscle protein synthesis and muscle mass accretion are duce greater gains in muscle fiber CSA than high-intensity
affected by several factors, including nutritional support, loads (90 % 1 RM) [37, 38].
cytokines, hormones, and growth factors, yet resistance Defining an intensity load recommendation for
exercise is known to be a major regulator for promoting enhancing muscle hypertrophy is difficult due to the
hypertrophy. Resistance exercise can stimulate an increase inconsistency of findings. Additionally, the contradictory
in muscle protein synthesis for up to 48 h post-exercise nature of these findings may be attributed to the different
[1215], and repeated bouts of resistance exercise (i.e., assessment methods (i.e., MRI, CT, ultrasonography vs.
training) can significantly increase muscle CSA and muscle muscle histochemistry), experimental designs (i.e.,
fiber hypertrophy [1619]. However, the parameters of a within- vs. between-subject designs), activated muscula-
resistance training program for the regulation of muscle ture (i.e., single- vs. multi-joint movements), rest intervals
growth remain unclear [20]. utilized, and protocol parameters (i.e., equated vs. non-
A broad range of resistance exercise intensities, volume, equated volume). A number of researchers equate volume
and rest intervals have been demonstrated to elicit mus- to account for the potentially greater dose response
cular hypertrophy in humans [1619]. The stimulus of associated with hypertrophic adaptation [39]. Further-
muscle contraction that occurs during resistance exercise more, these studies are collectively limited as observa-
results in various biochemical responses regulating the rate tions of early-phase hypertrophic adaptations among
of protein synthesis, known as mechanotransduction [21]. untrained subjects. Greater training experience has been
At the cellular level, skeletal muscle adaptation appears to shown to attenuate post-exercise anabolic responses,
occur from the cumulative effects of transient changes in including muscle protein synthesis rates [4042] and
gene expression following acute bouts of exercise [22]. intracellular anabolic signaling [4245]. Therefore, these
Thus, maximizing the resistance exercise-induced anabolic findings cannot be generalized to a well-trained popula-
response produces the greatest potential for hypertrophic tion. Schoenfeld et al. [46] recently assessed the magni-
adaptation with training. The purpose of this review is to tude of hypertrophy following 8 weeks of a hypertrophy-
examine the physiological response to resistance exercise, style resistance training program versus a volume-equated
with particular emphasis on the endocrine system and strength-style program in resistance-trained men and
intramuscular anabolic signaling through the mammalian/ found no significant differences in muscle thickness of the
mechanistic target of rapamycin complex 1 (mTORC1) biceps brachii assessed via ultrasonography. In a subse-
pathway. quent study by the same research team, muscle thickness
of the elbow flexors, elbow extensors, and quadriceps
femoris assessed via ultrasonography was not signifi-
2 Magnitude of Hypertrophy Following cantly different following 8 weeks of low-load
Resistance Exercise Protocols of Different (2535 RM) versus high- load resistance training
Intensities (812 RM) in resistance-trained men [47]. In conjunction
with training intensity, factors including muscle fiber
Controversy exists regarding a training paradigm that will recruitment [48], time-under-tension [49], and metabolic
maximize hypertrophic adaptation. Long-term studies stress [50] have all been suggested to influence intra-
evaluating the effects of varying exercise intensity on the muscular anabolic signaling. Furthermore, muscular
magnitude of muscle hypertrophy have yielded incon- adaptation following regimented resistance training is
clusive findings. Comparisons of high-intensity versus low- highly variable between individuals [5154]. Several
intensity resistance training programs for up to 12 weeks in factors appear to influence muscle remodeling and the
previously untrained subjects have shown no differences in magnitude of hypertrophy, including nutritional support,
muscle CSA as measured by magnetic resonance imaging muscle fiber-type distribution, and genetic predisposition
(MRI) [2329], computed tomography (CT) [30, 31], [20, 55]. An additional concern when examining diver-
dual-energy x-ray absorptiometry (DEXA) [32], and gent resistance exercise protocols in trained individuals is
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Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise
the novelty of the stimulus, as muscle adaptations may be downstream (i.e., mammalian/mechanistic target of rapa-
enhanced when unaccustomed program variables are uti- mycin [mTOR], ribosomal S6 kinase 1 [p70S6k], RPS6
lized [56]. [ribosomal protein S6]) effectors of mTORC1 signal to
The intensity of training necessary to stimulate muscle promote anabolic and inhibit catabolic cellular functions,
growth has been suggested to be greater than 60 % of an providing a biochemical mechanism for controlling pro-
individuals 1 RM [57, 58], while others have suggested that cesses related to cell differentiation and muscle remodeling
maximal growth occurs at training intensities between 80 (Fig. 1) [75]. The protein kinase mTOR serves as a critical
and 95 % of 1 RM [59]. However, recent research has protein that confers signaling to p70S6k and several other
shown that training intensities as low as 30 % of 1 RM can downstream signaling molecules that regulate protein syn-
be equally as effective at stimulating muscle protein syn- thesis and skeletal muscle mass [21, 75].
thesis and muscle hypertrophy when performed to volitional The mTORC1 complex plays an important regulatory
fatigue in previously untrained men [24, 25, 60]. Moreover, role during the process of skeletal muscle hypertrophy
a majority of the scientific evidence supporting a greater [76]. mTORC1 is involved in many cell processes,
anabolic response following a high-volume, moderate-in- including the regulation of cell size, mRNA translation,
tensity training protocol (i.e., designed to elicit muscle biogenesis of mitochondria and ribosomes, and autophagy
hypertrophy) has emerged from acute investigations indi- [77]. At the cellular level, mTORC1 functions as a critical
cating a superior endocrine response compared to other regulator of translation initiation, the rate-limiting step in
training paradigms [6167]. However, the mechanisms of protein synthesis [72, 75]. It appears that the phosphory-
exercise-mediated muscle hypertrophy have been suggested lation of signaling molecules in response to resistance
to be solely an intrinsic process, which is not influenced by exercise is a prerequisite for increasing translation initi-
transient changes in circulating hormones [54, 6870]. Thus, ation and muscle protein synthesis. The inhibition of
the acute activation of intrinsically located signaling proteins mTOR via rapamycin treatment has been consistently
and the acute elevation of muscle protein synthesis may be demonstrated to blunt increases in muscle protein syn-
more reflective of the potential to increase muscle mass with thesis [7880] and prevent skeletal muscle hypertrophy,
resistance training [69]. Whether a high-volume, moderate- which normally occurs following prolonged resistance
intensity training protocol activates intramuscular anabolic training [76, 81]. In humans, rapamycin treatment has
signaling to a greater degree than other training paradigms been shown to block the acute exercise-induced increase
remains to be determined. in muscle protein synthesis in addition to blunting several
downstream components of the mTORC1 signaling
pathway, including p70S6k [73, 80]. Further, the magni-
3 Role of Mammalian/Mechanistic Target tude of p70S6k phosphorylation has been shown to be a
of Rapamycin Complex 1 (mTORC1) in Skeletal proxy marker of myofibrillar protein synthesis rates [82,
Muscle Adaptation to Resistance Exercise 83], and also corresponds with resistance training-induced
muscle hypertrophy [54, 8486]. Collectively, these
One of the most widely recognized mechanisms for regu- observations suggest that mTOR acts as the primary
lating muscle mass involves mechanical tension [71]. regulator of intracellular anabolic signaling via phos-
Resistance exercise initiates a multifaceted series of events phorylation of p70S6k and several other downstream
converting the stimulus of muscle contraction into bio- signaling molecules that regulate protein synthesis and
chemical responses regulating the rate of protein synthesis, skeletal muscle mass [7375, 87]. Although the exact
known as mechanotransduction [21]. The mechanisms mechanism underlying increased mTORC1 activation
involved in converting mechanical signals into the molecu- following resistance exercise remains relatively elusive,
lar events that control muscle growth are not completely mechanical loading has been suggested to promote
understood; however, phosphorylation of intramuscular mTORC1 activation by increasing the activity of Rheb
signaling molecules appears to play an important role in (Ras homolog enriched in brain) and increasing the
skeletal muscle adaptation to resistance exercise [21]. Pro- abundance of phosphatidic acid (PA) [88].
tein phosphorylation is a reversible post-translational mod- mTORC1 activity is regulated by the modulation of
ification causing conformational changes in protein structure tumor suppressor tuberous sclerosis complex 1/2 (TSC 1/2)
accompanied by an increase or decrease in enzymatic activity [77]. TSC 1/2 negatively regulates mTORC1
activity [72]. Skeletal muscle protein synthesis appears to be activity by converting Rheb into its inactive guanosine
regulated by the multi-protein phosphorylation cascade, diphosphate (GDP)-bound state [89]. Tumor sclerosis
mTORC1 [7375]. Upon activation, phosphorylation of complex 2 (TSC2) acts as the guanosine triphosphatase
upstream (i.e., insulin receptor substrate 1 [IRS1], protein (GTPase)-activating enzyme that keeps Rheb in the GDP-
kinase B [Akt], tumor sclerosis complex 2 [TSC2]) and bound state [90]. TSC2 phosphorylation inactivates the
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A. M. Gonzalez et al.
GTPase-activating enzyme activity of TSC2, repressing the An additional mTORC1 activator associated with
hydrolysis of RhebGTP (guanosine triphosphate) [91]. resistance exercise-induced muscle hypertrophy involves
When Rheb is in its active GTP-bound state, it translocates the lipid second messenger known as PA [97]. Exogenous
to the lysosome, allowing mTORC1 activity to continue administration of PA, or an over-expression of enzymes
[91, 92]. Jacobs et al. [93] showed that TSC2 localizes with that produce PA, results in an increase in mTORC1 acti-
Rheb at rest; however, following resistance exercise, TSC2 vation [98100]. Similarly, limiting PA production atten-
phosphorylation corresponds with the movement of TSC2 uates mTORC1 activity [97]. It has been suggested that PA
away from Rheb. In summary, resistance exercise-induced mediates mTORC1 activation by competing with the
activation of mTORC1 requires the TSC2 complex (a FKBP12 (FK506 binding protein 12)rapamycin complex
negative regulator of Rheb) to be sequestered away from for binding to the FKBP12rapamycin-binding (FRB)
Rheb (Fig. 2). However, it remains unclear what mediates domain of mTOR [101, 102]. PA may also promote
TSC2 phosphorylation following resistance exercise [88]. mTORC1 activation as a primary effector of Rheb [103].
While insulin and growth factors phosphorylate TSC2 GTP-bound Rheb has been shown to activate phospholi-
through Akt, resistance exercise-induced activation of pase D (PLD), an enzyme that generates PA from phos-
mTORC1 appears to be Akt-independent [94]. Several phatidylcholine [103]. PA can be synthesized by various
studies have shown that Akt phosphorylation either does classes of enzymes, such as PLD, diacylglycerol kinase f
not change [43, 45, 49] or decreases [95, 96] following (DGKf), and lysophosphatidic acid acyltransferases
resistance exercise, despite downstream activation of (LPAAT) [74, 98, 104, 105]. Joy et al. [106] found that
mTORC1. stimulating myoblast cells with PA in vitro increased
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Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise
mTORC1 signaling, and trained subjects supplementing away from Rheb [91, 110]. Akt also inhibits PRAS40
with PA significantly improved skeletal muscle hypertro- (proline-rich Akt substrate of 40 kDa), a negative regulator
phy following 8 weeks of resistance training. Thus, evi- of mTORC1 signaling [111]. In summary, similar to
dence suggests that PA is a direct regulator of resistance resistance exercise-induced mTORC1 activation, insulin
exercise-induced mTORC1 signaling promoting muscle and growth factors appear to activate mTORC1 via phos-
hypertrophy. phorylation of TSC2. However, insulin and growth factors
appear to activate mTORC1 through Akt, while resistance
exercise induces an Akt-independent activation of
4 Growth Factor Activation of mTORC1 mTORC1.
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A. M. Gonzalez et al.
following resistance training programs of up to 24 weeks intervals (3090 s), which activate a large muscle mass,
[115, 116]; therefore, there has been considerable specu- elicit the greatest acute elevations in testosterone and GH
lation about the role of the post-exercise endocrine [6167, 132139]. Studies investigating the acute hor-
response in mediating increases in muscle size [117]. monal response following different heavy-resistance exer-
Systemic elevations of circulating hormones presumably cise protocols are presented in Table 1. Several studies
increase the likelihood of interaction with receptors located have also investigated the association between acute
within the muscle tissue and have been speculated to exercise-induced hormone responses and changes in mus-
contribute to muscle growth consequent to resistance cle size following a structured resistance training program
training [117]. However, in humans, elevations of the (Table 2). McCall et al. [115] found a significant correla-
anabolic hormones do not appear to be necessary for tion (r = 0.700.71; p \ 0.05) between acute exercise-in-
muscle hypertrophy [118], intramuscular signaling [70, duced GH elevations and the degree of both type I and
119], or muscle protein synthesis [70], leading to the type II muscle fiber hypertrophy following 15 weeks of
supposition that the mechanisms of muscle hypertrophy are resistance training in 11 recreationally trained men. Ahti-
intrinsically specific to the activated skeletal tissue [69]. ainen et al. [116] reported a significant correlation
Exogenous supra-physiological doses of testosterone have (r = 0.76; p \ 0.05) between changes in the acute testos-
shown to significantly increase muscle protein synthesis terone response and the degree of muscle hypertrophy
and lean body mass [120, 121], especially when combined following 21 weeks of resistance training in 16 men (eight
with resistance training [122, 123]. Additionally, admin- strength athletes and eight non-athletes). However, both of
istration of exogenous testosterone supplementation to these studies had a relatively small number of subjects,
restore normal physiological values in androgen-deficient thereby limiting the ability to draw meaningful conclu-
older men is associated with significant increases in muscle sions. In a more recent study examining a larger cohort of
mass [124129]. However, others have suggested that 56 untrained men, West and Phillips [140] reported that the
physiological fluctuations of hormones are not required for acute systemic hormonal response of GH and cortisol were
resistance exercise-induced skeletal muscle hypertrophy weakly correlated (r = 0.280.36; p \ 0.05) with resis-
[88]. These hormones, including testosterone, GH, insulin, tance training-induced changes in muscle fiber CSA
IGF-1, and cortisol, have been suggested to be far more explaining 8 and 12 % of the variance, respectively.
important for developmental growth rather than exercise- Although cortisol, a catabolic hormone, was weakly cor-
induced muscle growth [88]. related with changes in lean body mass (r = 0.29;
Transient hormonal elevations appear to play a per- p \ 0.05), no significant correlations were observed
missive, rather than stimulatory, role in the regulation of between GH, testosterone, and IGF-1 and changes in lean
muscle protein synthesis [130]. Over-expression of Rheb in body mass [140]. Additionally, the variability within the
skeletal muscle stimulates a PI3K/Akt-independent acti- gains of muscle hypertrophy seen in high responders and
vation of mTORC1 that is sufficient to induce muscle low responders could not be explained by the acute
hypertrophy [131]. Although it has been suggested that hormone response [140]. However, these investigations are
growth factor activation of the PI3K/Akt axis is also suf- based on limited blood sampling timepoints following an
ficient for skeletal muscle growth, these mechanisms do not acute bout of resistance training. Furthermore, Wilkinson
appear to be necessary for maximizing mTORC1 activation et al. [118] observed significant gains in hypertrophy in the
or the hypertrophic response that occurs in response to absence of systemic changes in GH, testosterone, and IGF-
resistance exercise [21, 88]. Resistance exercise and 1 [118]. Thus, the effect of changes in the acute anabolic
growth factors share the same final step in mTORC1 hormonal response to resistance exercise on muscle growth
activation (via phosphorylation of TSC2) (Fig. 2) [88]. is still not well-understood.
Since the end result of both resistance exercise and growth Mitchell et al. [54] examined post-exercise changes in
factors is the movement of TSC2 away from Rheb via anabolic hormone concentrations (testosterone, GH, and
different upstream kinases, resistance exercise and growth IGF-1) and intramuscular signaling and their association
factor exposure may not offer a synergistic effect. 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
6 Influence of Acute Endocrine and Intramuscular not appear to be related to training-induced hypertrophy,
Signaling Response on Muscle Growth whereas acute increases in p70S6k phosphorylation and
androgen receptor (AR) protein content following the initial
Substantial evidence indicates that resistance exercise bout of resistance exercise were highly associated
protocols of high volume (36 sets; 812 repetitions), (r = 0.540.60; p \ 0.05) with resistance training-induced
moderate intensity (6085 % 1 RM), and short rest hypertrophy [54]. The magnitude of p70S6k
123
Table 1 Studies investigating the acute hormonal response following different resistance exercise protocols
Study Participants Crossover Design Protocols Hormones Results
design? measured
Beaven 15 trained men Yes Full 1. 4 9 10; 70 % 1 RM (2 min rest) Testosterone Protocols 1, 2, and 4 elicited significant decreases in cortisol following
et al. [134] body 2. 3 9 5; 85 % 1 RM (3 min rest) Cortisol exercise. No significant differences in testosterone between protocols
3. 5 9 15; 55 % 1 RM (1 min rest) (salivary)
4. 3 9 5; 40 % 1 RM (3 min rest)
Crewther 11 Yes Lower 1. 8 9 6; 45 % 1 RM (3 min rest) Testosterone Only protocol 2 elicited significant increases in testosterone and cortisol
et al. [61] recreationally body 2. 10 9 10; 75 % 1 RM (2 min rest) Cortisol concentration following exercise
trained men (salivary)
3. 6 9 4; 88 % 1 RM (4 min rest)
Hakkinen 10 trained men Yes Lower 1. 10 9 10; 70 % 1 RM (3 min rest) Testosterone Protocol 1 elicited significant increases in testosterone, cortisol, and GH
and body 2. 20 9 1; 100 % 1 RM (3 min rest) Cortisol following exercise. Protocol 2 elicited significant increase in GH
Pakarinen following exercise
GH
[62]
Kraemer 9 recreationally Yes Full 1. 3 9 10; 10 RM (1 min rest) Testosterone Protocol 1 elicited significantly greater GH following exercise. Both
et al. [67] trained men body 2. 5 9 5; 5 RM (3 min rest) Cortisol protocols significantly increased testosterone; however, not at the same
magnitude and duration (no difference in AUC). Both protocols showed
GH
only random acute increases in cortisol
Linnamo 8 recreationally Yes Full 1. 5 9 10; 10 RM (2 min rest) Testosterone Only protocol 1 elicited significant increases in GH and testosterone
et al. [63] active men body 2. 5 9 10; 70 % 10 RM (2 min rest) GH following exercise
McCaulley 10 trained men Yes Lower 1. 4 9 10; 75 % 1 RM (1.5 min rest) Testosterone Only protocol 1 elicited significant increases in testosterone and cortisol
et al. [64] body 2. 11 9 3; 90 % 1 RM (5 min rest) Cortisol following exercise
Raastad 7 trained men Yes Lower 1. 3 9 3; 3 RM (6 min rest) (squat and Testosterone Protocol 1 elicited significantly greater testosterone AUC than protocol 2.
et al. [139] body front squat) and 3 9 6; 6 RM (4 min Cortisol Protocol 1 elicited significantly greater cortisol AUC than protocol 2.
rest) (leg extension) No significant difference in GH, IGF-1, or insulin between protocols
GH
2. 3 9 3; 70 % 3 RM (6 min rest) (squat
Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise
IGF-1
and front squat) and 3 9 6; 76 % 6 RM
(4 min rest) (leg extension) Insulin
b
Smilios 11 trained men Yes Full 1. 9 5; 88 % 1 RM (3 min rest) Testosterone Protocols 2 and 3 elicited significantly greater GH and cortisol following
et al. [65] body b exercise. No significant differences were observed for testosterone for
2. 9 10; 75 % 1 RM (2 min rest) Cortisol
b any protocol
3. 9 15; 60 % 1 RM (1 min rest) GH
Uchida 27 trained men No Upper 1. 4 9 *20; 50 % 1 RM (2 min rest) Testosterone Protocol 2 elicited significantly greater cortisol following exercise. No
et al. [66] body 2. 5 9 *11; 75 % 1 RM (2 min rest) Cortisol differences in testosterone following each protocol
3. 10 9 *4; 90 % 1 RM (2 min rest)
4. 8a 9 *4; 110 % 1 RM (2 min rest)
AUC area under the concentrationtime 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
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A. M. Gonzalez et al.
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 Results
length
(weeks)
McCall et al. 11 recreationally trained 12 Significant correlation between acute GH elevation and the degree of type I
[115] men (r = 0.70) and type II (r = 0.71) muscle fiber hypertrophy
Ahtiainen 8 physically active men; 21 Significant correlation between acute testosterone elevation and change in muscle
et al. [116] 8 strength athletes CSA (r = 0.76)
West and 56 recreationally active 12 Significant correlation between acute GH elevation and the degree of type I fiber
Phillips men hypertrophy (r = 0.36). Significant correlation between acute cortisol elevation
[140] and the degree of type II fiber hypertrophy (r = 0.35) and changes in lean body
mass (r = 0.29)
Mitchell et al. 23 recreationally active 16 No correlation between acute testosterone, GH, or IGF-1 elevation and muscle
[54] men hypertrophy
CSA cross-sectional area, GH growth hormone, IGF-1 insulin-like growth factor-1
phosphorylation has shown to be associated with myofib- despite a 10- to 20-fold lower resting concentration and a
rillar protein synthesis rates (r = 0.310.34; p \ 0.05) [82, blocked exercise-induced testosterone response [153].
83], and its acute phosphorylation following resistance Enhanced hormone-receptor interaction following resis-
exercise has been reported to correlate with muscle hyper- tance exercise may up-regulate the expression of various
trophy following training in both rodents (r = 0.998; muscle-specific genes promoting hypertrophy. However,
p \ 0.05) [84] and untrained men (r = 0.530.89; p \ 0.05) further research has demonstrated that an IGF-1 receptor
[85, 86]. However, not all studies have found such a rela- may not be necessary for resistance exercise-induced
tionship [24]. Still, correlations between transient changes in mTORC1 signaling and muscle growth [154]. Using a
muscular and systemic markers of anabolism following transgenic mouse model, Spangenburg and colleagues
acute bouts of exercise and training-induced muscle hyper- [154] reported that both Akt and p70S6k activation can be
trophy are not evidence of a causative role for cellular induced independently of a functioning IGF-1 receptor.
adaptations in the trained muscle [141]. The extent to which anabolic hormones mediate their
The hormone-receptor complex regulates gene expres- effects directly through the hormone-receptor complex
sion and transcription factors that may promote an increase warrants further investigation.
in net muscle protein balance [129, 142]. Thus, the number The relationship between transient increases in hor-
and sensitivity of receptors in the activated skeletal muscle, monal concentrations and intramuscular anabolic signaling
along with systemic elevations of the circulating hormone, and muscle growth has also been an area of interest of
may mediate the anabolic effects of hormones including several investigations (Table 3). Acute intramuscular ana-
testosterone. An up-regulation of either AR protein content bolic signaling and exercise-induced hypertrophy have
and/or AR mRNA expression has been observed following been examined under different hormonal environments in
resistance exercise [54, 143148], and acute increases in untrained individuals [68, 70, 119, 155]. Experimental
AR protein content appear to correspond with subsequent trials eliciting a high hormonal response have not been
increases in myofibrillar protein [143] and exercise-in- shown to enhance markers of mTORC1 signaling in the
duced hypertrophy [54]. However, others report no chan- vastus lateralis [119] or biceps brachii [70] compared with
ges, or decreases, in AR expression following resistance trials that did not elicit an increase in hormonal concen-
exercise [149, 150]. Moreover, AR expression appears to trations. Furthermore, the experimental trial eliciting a
have a bi-phasic response with an initial down-regulation transient increase in the circulating concentration of ana-
following a bout of resistance exercise followed by an up- bolic hormones did not enhance muscle protein synthesis in
regulation several hours after exercise [151]. Additionally, the biceps brachii [70]. In a subsequent study, untrained
it has been demonstrated that AR expression can vary men performed a 15-week elbow flexor resistance training
between different muscles and muscle fiber types [147]. program, with one arm being grouped into a low hormonal
Further, Inoue et al. [152] showed that down-regulation of environment and the other into a high hormonal environ-
AR expression (via an AR antagonist) suppressed the ment for the duration of the study. Results showed no
hypertrophic response in exercised rats. Alternatively, difference between conditions in training-induced muscle
chemically induced testosterone suppression (via goserelin) hypertrophy of the biceps brachii [68]. However, other
did not blunt AR expression or hypertrophy in young men, investigators provide conflicting evidence. Rnnestad and
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Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise
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
Rnnestad et al. [155] 11 untrained men 11 weeks Significant increase in muscle CSA as a result of elevated circulating
hormones
CSA cross-sectional area
colleagues [155] utilized a similar 11-week research design signaling 4 h post-exercise in recreationally active men. In
and demonstrated that the increased concentrations of contrast, Mitchell et al. [24] found high-intensity loads
serum testosterone and GH occurring prior to performing (80 % 1 RM) to be more effective than lower-intensity
elbow flexor exercises yielded greater increases in CSA of loads (30 % 1 RM) for inducing mTORC1 signaling 1 h
the elbow flexors than elbow flexor exercises performed in post-exercise in untrained men. Regardless, following
a low hormonal environment. The authors hypothesized 10 weeks of training, no differences between the two dif-
that their findings may be related to the exercise order. This ferent training protocols were observed in the magnitude of
contrasts with others who suggest that changes in the post- muscle hypertrophy [24]. The mTORC1 signaling response
exercise circulating concentrations of testosterone, GH, has also shown to be greater following a high volume
and IGF-1, and the subsequent interaction within skeletal (5 9 10 RM) than a lower volume but higher-intensity
muscle, is not influenced by the order of the resistance (15 9 1 RM) bilateral leg press exercise [168]. The lack of
exercises [156]. Evidence to date appears to suggest that any clear relationship between training program design and
exposing activated skeletal muscle to a transient elevation the intramuscular anabolic signaling response suggests that
in circulating hormones does not enhance intramuscular additional factors such as muscle fiber recruitment [48],
signaling. time-under-tension [49], and metabolic stress [50] may
have contributing roles in stimulating the anabolic signal-
ing molecules.
7 Effect of Resistance Exercise Variables Exercise-induced metabolic stress may also play a role
on Activation of mTORC1 in acute activation of mTORC1 signaling. Metabolic stress
results from exercise that primarily relies on anaerobic
Resistance exercise evokes a robust activation of mTORC1 glycolysis as its major energy provider. Lactate directly
signaling in untrained and recreationally active men in both affects muscle cells in vitro by increasing satellite cell
fed [157161] and fasted states [73, 85, 162164]. Resis- activity as well as mTOR and p70S6k phosphorylation
tance exercise-induced mTORC1 activation has also been [169]. Elevations in blood lactate have also been demon-
observed in experienced, resistance-trained men [45, 165, strated to be weakly associated (r = 0.38; p \ 0.05) with
166], yet the training design (i.e., manipulation of acute intramuscular anabolic signaling following resistance
training variables: intensity, volume, and rest) for maxi- exercise in trained men [50]. Lactate production may
mizing the anabolic response remains unclear. contribute to increased mTORC1 signaling [170]; however,
Multiple-set resistance exercise elicits greater intra- the mechanisms by which metabolic stress influences
muscular anabolic signaling than single-set exercise, indi- anabolic signaling are not fully elucidated and warrant
cating that exercise volume can influence the muscle further investigation.
protein signaling response to exercise [83, 167]. Low- Acute activation of mTORC1 signaling may also be
versus high-intensity unilateral leg extensions performed to influenced by mode of contraction. Eccentric-only resis-
volitional fatigue have yielded inconclusive results [24, tance exercise has been suggested to provide a stronger
60]. Burd et al. [60] reported that low-intensity resistance anabolic stimulus than concentric-only resistance exercise
exercise (30 % 1 RM) was more effective than higher-in- [171174], and eccentric contractions have been demon-
tensity loads (90 % 1 RM) for inducing mTORC1 strated to produce a more rapid rise in myofibrillar muscle
123
A. M. Gonzalez et al.
protein synthesis than concentric only contractions [171, appears to be the result of the cumulative effects of tran-
172]. In addition, maximal eccentric contractions have also sient changes in gene expression following acute bouts of
been demonstrated to significantly activate p70S6k and exercise [22]. Specifically, skeletal muscle protein syn-
RPS6 up to 2 h into recovery, while maximal concentric thesis appears to be regulated by the multi-protein phos-
and submaximal eccentric contractions failed to induce phorylation cascade mTORC1; thus, maximizing resistance
changes in Akt, mTOR, p70S6k, or RPS6 phosphorylation exercise-induced mTORC1 signaling should yield the
status [173]. Additional support was recently provided by greatest potential for hypertrophic adaptation with training
Rahbek et al. [174], who demonstrated that maximal [54, 8486]. A majority of the research to date shows that
eccentric contractions triggered a greater acute anabolic mTORC1 signaling is not influenced by transient eleva-
signaling response than concentric contractions. However, tions in circulating hormones [54, 6870]; hence, the
despite the greater anabolic signaling response, no differ- design of a resistance training program based on a hor-
ences were noted in myofibrillar protein synthesis rates or monal response may be futile. However, resistance exer-
in exercise-induced hypertrophy following 12 weeks of cise-induced mTORC1 activation appears to be a
high-volume resistance training [174]. Increases in muscle multifaceted process, which is influenced by a number of
size following 9 weeks of unilateral resistance training factors. The resistance exercise parameters for maximizing
have also been shown to be unrelated to muscle contraction the anabolic response remain unclear, and it is unknown
type when matched for both exercise intensity and total whether different resistance exercise paradigms used by
external work [175]. Thus, eccentric contractions, which strength and power athletes differentially stimulate intra-
emphasize greater tension and stretching of the muscle, muscular anabolic signaling. Resistance exercise protocols
may yield a greater acute anabolic response, yet whether it that maximize muscle fiber recruitment, time-under-ten-
translates into greater muscle hypertrophy with training sion, and metabolic stress appear to contribute to intra-
remains questionable. muscular anabolic signaling; however, there does not
It is important to note that the anabolic response fol- appear to be a minimal threshold or optimal training
lowing resistance exercise appears to be highly variable scheme per se for maximizing muscle hypertrophy.
between individuals [43, 52, 53, 176]. A number of factors
Compliance with Ethical Standards
influence the muscle remodeling process following resis-
tance exercise, including nutritional intake and genetic Funding No sources of funding were used to assist in the prepa-
predisposition [88, 177]. Nevertheless, several studies have ration of this article.
suggested that training status can also impact resistance
exercise-induced intramuscular anabolic signaling. Coffey Conflict of interest Adam Gonzalez, Jay Hoffman, Jeffrey Stout,
David Fukuda, and Darryn Willoughby declare that they have no
et al. [43] reported that prior training history blunts the conflicts of interest relevant to the content of this review.
anabolic signaling responses involved in the adaptation to
resistance exercise. Chronic resistance training in rats also
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