ArticlePDF AvailableLiterature Review

Potential Mechanisms for a Role of Metabolic Stress in Hypertrophic Adaptations to Resistance Training

Authors:

Abstract and Figures

It is well established that regimented resistance training can promote increases in muscle hypertrophy. The prevailing body of research indicates that mechanical stress is the primary impetus for this adaptive response and studies show that mechanical stress alone can initiate anabolic signalling. Given the dominant role of mechanical stress in muscle growth, the question arises as to whether other factors may enhance the post-exercise hypertrophic response. Several researchers have proposed that exercise-induced metabolic stress may in fact confer such an anabolic effect and some have even suggested that metabolite accumulation may be more important than high force development in optimizing muscle growth. Metabolic stress pursuant to traditional resistance training manifests as a result of exercise that relies on anaerobic glycolysis for adenosine triphosphate production. This, in turn, causes the subsequent accumulation of metabolites, particularly lactate and H(+). Acute muscle hypoxia associated with such training methods may further heighten metabolic buildup. Therefore, the purpose of this paper will be to review the emerging body of research suggesting a role for exercise-induced metabolic stress in maximizing muscle development and present insights as to the potential mechanisms by which these hypertrophic adaptations may occur. These mechanisms include increased fibre recruitment, elevated systemic hormonal production, alterations in local myokines, heightened production of reactive oxygen species and cell swelling. Recommendations are provided for potential areas of future research on the subject.
No caption available
… 
No caption available
… 
Content may be subject to copyright.
1 23
Sports Medicine
ISSN 0112-1642
Volume 43
Number 3
Sports Med (2013) 43:179-194
DOI 10.1007/s40279-013-0017-1
Potential Mechanisms for a Role of
Metabolic Stress in Hypertrophic
Adaptations to Resistance Training
Brad J.Schoenfeld
1 23
Your article is protected by copyright and
all rights are held exclusively by Springer
International Publishing Switzerland. This e-
offprint is for personal use only and shall not
be self-archived in electronic repositories.
If you wish to self-archive your work, please
use the accepted author’s version for posting
to your own website or your institution’s
repository. You may further deposit the
accepted author’s version on a funder’s
repository at a funder’s request, provided it is
not made publicly available until 12 months
after publication.
REVIEW ARTICLE
Potential Mechanisms for a Role of Metabolic Stress
in Hypertrophic Adaptations to Resistance Training
Brad J. Schoenfeld
Published online: 22 January 2013
ÓSpringer International Publishing Switzerland 2013
Abstract It is well established that regimented resistance
training can promote increases in muscle hypertrophy. The
prevailing body of research indicates that mechanical stress
is the primary impetus for this adaptive response and
studies show that mechanical stress alone can initiate
anabolic signalling. Given the dominant role of mechanical
stress in muscle growth, the question arises as to whether
other factors may enhance the post-exercise hypertrophic
response. Several researchers have proposed that exercise-
induced metabolic stress may in fact confer such an ana-
bolic effect and some have even suggested that metabolite
accumulation may be more important than high force
development in optimizing muscle growth. Metabolic
stress pursuant to traditional resistance training manifests
as a result of exercise that relies on anaerobic glycolysis for
adenosine triphosphate production. This, in turn, causes the
subsequent accumulation of metabolites, particularly lac-
tate and H
?
. Acute muscle hypoxia associated with such
training methods may further heighten metabolic buildup.
Therefore, the purpose of this paper will be to review the
emerging body of research suggesting a role for exercise-
induced metabolic stress in maximizing muscle develop-
ment and present insights as to the potential mechanisms
by which these hypertrophic adaptations may occur. These
mechanisms include increased fibre recruitment, elevated
systemic hormonal production, alterations in local myo-
kines, heightened production of reactive oxygen species
and cell swelling. Recommendations are provided for
potential areas of future research on the subject.
1 Introduction
It has been well established that regimented resistance
training can promote increases in muscle hypertrophy. The
prevailing body of research indicates that mechanical stress
is the primary impetus for this adaptive response. These
findings were described in the seminal work of Goldberg
et al. [1], who reported that increased force development is
the critical event in initiating compensatory muscular
growth. Subsequently, numerous studies have confirmed
this finding both in vitro (within the glass), ex vivo (outside
the living), and in vivo (within the living) [26].
Current theory suggests that forces associated with
resistance exercise disturb the integrity of skeletal muscle,
causing mechano-chemically-transduced molecular and
cellular responses in myofibres and satellite cells [7].
Exercise-induced hypertrophy is facilitated by a complex
cascade of anabolic and catabolic signalling pathways,
whereby the effects of mechano-stimulation are molecu-
larly transduced to downstream targets that shift muscle
protein balance to favour synthesis over degradation. Many
anabolic signalling pathways are involved in exercise-
induced gains in muscle mass with certain pathways
functioning in a permissive role while others directly
mediate cellular processes that influence messenger RNA
(mRNA) translation and thus hypertrophy [8]. Pathways
that have been identified as particularly important to
muscle anabolism include mammalian target of rapamycin
(mTOR), mitogen-activated protein kinase (MAPK), and
various calcium-dependent pathways, amongst others.
Although these pathways may overlap at key regulatory
steps, there is evidence that they are synergistic rather than
redundant [9]. However, the precise mechanisms and
interplay between them have yet to be fully elucidated. A
complete discussion of the topic is beyond the scope of this
B. J. Schoenfeld (&)
Department of Health Sciences, Program of Exercise Science,
APEX Building, Room # 265, Lehman College, CUNY,
250 Bedford Park Blvd West, Bronx, NY 10468, USA
e-mail: brad@workout911.com
Sports Med (2013) 43:179–194
DOI 10.1007/s40279-013-0017-1
Author's personal copy
article and interested readers are referred to reviews by
Bassel-Duby and Olson [10], Miyazaki and Esser [11] and
Glass [12]. Figure 1presents a simplified flowchart of
various signalling cascades and their relevance to anabolic
and catabolic processes.
Mechanical stress alone has been shown to directly
stimulate mTOR [13], possibly through activation of the
extracellular regulated kinase/tuberous sclerosis complex 2
(ERK/TSC2) pathway [6]. It is theorized that these actions
are mediated via the synthesis of the lipid second mes-
senger phosphatidic acid (PA) by phospholipase D [13,14].
There also is evidence that PA can phosphorylate the
downstream anabolic translational regulator p70S6 kinase
(p70S6k) independent of mTOR [15], presenting another
potential avenue whereby mechanical stimuli may directly
influence muscle protein synthesis.
Given the dominant role of mechanical stress in muscle
growth, the question arises as to whether other factors may
enhance the post-exercise hypertrophic response. Several
researchers have proposed that exercise-induced metabolic
stress may in fact confer such an effect [1618] and some
have even suggested that metabolite accumulation may be
more important than high force development in optimizing
muscle growth [19]. Other researchers, however, dispute
such claims [20]. Therefore, the purpose of this paper will
be to review the emerging body of research suggesting a
role for exercise-induced metabolic stress in maximizing
muscle development, and present insights as to the poten-
tial mechanisms by which these hypertrophic adaptations
may occur. To carry out this review, English-language
literature searches of the PubMed, EBSCO, and Google
Scholar databases were conducted for all time periods up to
April 2012. Combinations of the following keywords were
used as search terms: ‘metabolic stress’, ‘metabolite
buildup’, ‘metabolite accumulation’, ‘resistance training’,
‘resistance exercise’, ‘weight lifting’, ‘bodybuilding’,
‘powerlifting’, ‘anabolic hormone’, ‘Kaatsu’, ‘occlusion
exercise’, ‘blood flow restricted exercise’ and ‘cell swell-
ing’. The reference lists of articles retrieved in the search
were then screened for any additional articles that had
relevance to the topic. Given the broad scope of this
review, a narrative approach was chosen as the best way to
convey pertinent information and inclusion criteria was
based on applicability to the particular area of discussion.
2 Evidence for a Hypertrophic Effect from Metabolic
Stress
Metabolic stress pursuant to exercise manifests as a result
of the accumulation of metabolites, particularly lactate, Pi
and H
?
[21,22], and acute muscle hypoxia associated with
resistance training may serve to further heighten metabolic
buildup and, hence, stimulate hypertrophic adaptations
[7,23]. It is conceivable that hypoxia may have a direct
effect on contractile protein accretion and thereby con-
tribute to the hypertrophic stimulus, although this has not
been well studied. Other metabolites of possible relevance
to anabolism include calcium and various electrolytes.
Support for the potential hypertrophic role of exercise-
induced metabolic stress can be noted empirically by
examining the moderate-intensity training regimens
Resistance exercise
PI3K/AKT
MAPKs
Ca2+-dependent
FOXO
mTOR
MuRF1
MAFbx
eIF2B
eIF2
P70S6K
eIF4E
4E-BP1
Protein degradation
Protein synthesis
Transcription
Calcineurin
NFATs
Fig. 1 Simplified schematic of intracellular signalling pathways.
Flowchart shows the pathways associated with intracellular signalling
for muscle hypertrophy. Light grey boxes represent anabolic
processes while the dark grey boxes represent catabolic processes.
4E-BP1 4E binding protein-1, AKT protein kinase B, Ca
2?
calcium,
eIF2, 2B and 4E eukaryotic initiation factor 2 and 2B, FOXO forkhead
box O, GSK3 glycogen synthase kinase-3, MAFbx muscle atrophy
F-box, MAPKs mitogen-activated protein kinases, mTOR mammalian
target of rapamycin, MuRF1 muscle ring finger-1, NFATs nuclear
factor of activated T-cells, PI3K phosphatidylinositol 3-kinase,
P70S6K P70S6 kinase
180 B. J. Schoenfeld
Author's personal copy
adopted by a majority of bodybuilders, which are intended
to heighten metabolic buildup at the expense of higher
training intensities [24,25]. Typical hypertrophy-oriented
bodybuilding routines involve the performance of multiple
sets of 6–12 repetitions per set with relatively short inter-
set rest intervals [26]. These routines have been found to
induce significantly more metabolic stress than higher-
intensity regimens typically employed by powerlifters
[2729]. Yet, despite training with reduced intensities,
bodybuilders commonly display extreme levels of muscu-
larity at least as great, if not more so, than that achieved by
powerlifters [25,30]. Indeed, several studies have reported
greater increases in muscle growth from moderate-intensity
bodybuilding-type training protocols as compared with
high-intensity powerlifting-style routines [3133], although
these findings are not consistent across all trials when
equating for volume load [34]. It should be noted that both
bodybuilders and powerlifters are known to use anabolic
steroids and other pharmacological aids, which may con-
found the ability to make firm conclusions on the topic.
The increased metabolic response associated with
moderate-intensity training (*60–80% 1-repetition maxi-
mum [1RM]) can be attributed at least in part to the
increased energy contribution from fast glycolysis, which
results in peripherally as opposed to centrally induced
fatigue (i.e. fatigue related to metabolic and/or biochemical
changes as opposed to reductions in neural drive) [35].
Muscle lactate levels of 91 mmol/kg (dry weight) have
been reported after the performance of 1 set of 12 repeti-
tions to failure (total time under tension mean ±standard
deviation [SD] 37 ±3 s) and these values spiked to
118 mmol/kg after three sets [36]. This is in contrast to
high-intensity protocols (*90% ?1RM), where energy
provision is primarily derived from the phosphagen system
and thus results in minimal metabolic buildup. Moreover,
oxygen delivery to muscle is compromised at moderate
lifting intensities due to persistent compression of arterial
and venous flow over an extended time period, resulting in
acute hypoxia [37]. In combination, these factors cause the
rapid accumulation of metabolites within muscle as well as
lowering intramuscular pH levels [38].
Experimental evidence showing that metabolic stress
contributes to the hypertrophic response can be exempli-
fied by Kaatsu training studies, where resistance exercise
is combined with blood flow restriction. Kaatsu is carried
out at low intensities (generally \40% 1RM) while using
a pressure cuff to induce muscle ischaemia. A large body
of evidence shows that this type of training stimulates
anabolic signalling and protein synthesis [39], and pro-
duces marked skeletal muscle hypertrophy [40] despite
the fact that intensities below *60 1RM are often con-
sidered too low to generate a significant hypertrophic
response [34,41].
Metabolite accumulation is significantly elevated in
Kaatsu [42], suggesting a relationship between metabolic
stress and muscle development. Interestingly, Abe et al.
[43] found that walking with pressure cuffs resulted in a
significant increase in thigh muscle cross-sectional area
(CSA) in college-aged males (4–7%) over a period of just
3 weeks. Such low-intensity aerobic training is generally
not associated with increased muscle size in healthy young
subjects, indicating that factors other than mechanical
stress were responsible for hypertrophic adaptations.
Further evidence for an association between metabolic
stress and muscle hypertrophy can be inferred from studies
where training is carried out in a hypoxic environment.
Kon et al. [44] displayed that performing multiple sets of
low-intensity exercise (*50% 1RM) with moderate inter-
set rest intervals (*1 min) while breathing 13% oxygen
significantly increased metabolite accumulation, as deter-
mined by blood lactate levels compared with similar
normoxic exercise. Support for the potential hypertrophic
ramifications of these findings were provided by Nishimura
et al. [45] who found that performing a typical hypertro-
phy-based protocol (4 sets of 10 repetitions at 70% 1RM)
under acute hypoxic conditions resulted in a significantly
greater increase in muscle CSA of the elbow flexors and
extensors versus comparable training in a normoxic
environment.
3 Potential Mechanisms of Action
The mechanisms theorized to mediate hypertrophic adap-
tations from exercise-induced metabolic stress include
increased fibre recruitment, elevated systemic hormonal
production, alterations in local myokines, heightened pro-
duction of reactive oxygen species (ROS) and cell swelling
[4548]. The following section will discuss each of these
putative mechanisms and explore their potential role in the
hypertrophic response to resistance training. Figure 2pro-
vides an overview of how these factors may combine to
augment muscle growth.
4 Fibre Recruitment
The size principle of recruitment dictates that as training
intensity increases, larger motor units containing fast-
twitch (FT) fibres are progressively recruited to sustain
muscle contraction [49]. Given that fibres must be recruited
in order to respond and adapt to resistance exercise [50], it
would therefore appear necessary to train at very high
levels of intensity to maximize muscular development.
However, there is compelling evidence that meta-
bolic stress does, in fact, increase the recruitment of
Role of Metabolic Stress in Hypertrophic Adaptations 181
Author's personal copy
higher-threshold motor units even under low-loading con-
ditions. Multiple studies have found that recruitment
thresholds diminish during sustained submaximal exercise
with increasing levels of fatigue [5153]. In this way, a
greater number of FT fibres are called into play as the point
of muscular fatigue is reached. Further, studies using
electromyography (EMG) [48,54], glycogen depletion
[55], and organic phosphate splitting [22,38] have all
shown enhanced FT fibre recruitment in Kaatsu training,
and several researchers have proposed that this is the pri-
mary mechanism by which such exercise elicits hypertro-
phic adaptations [56,57].
The exact mechanisms whereby metabolic stress
enhances FT fibre recruitment have yet to be elucidated.
There is speculation that effects are mediated by H
?
accumulation, which inhibits muscle contractility and
thereby promotes the recruitment of additional high-
threshold motor units [54,58,59]. In addition, some
researchers have proposed that hypoxia induces the acti-
vation of FT fibres in an attempt to maintain necessary
levels of force generation [60,61]. Another possibility is
that free radical generation, which is increased in meta-
bolically taxing exercise, elicits increased FT recruitment
by hastening the onset of fatigue [59]. Considering the
complexity of exercise-induced muscle fatigue, it seems
plausible that a combination of these factors, and perhaps
others, are ultimately involved in the process.
Although increased fibre recruitment presents a com-
pelling rationale for metabolically induced muscle growth
associated with resistance training, it remains questionable
as to whether this is the only mechanism responsible for
such adaptations. Employing a model that examined
organic phosphate splitting via
31
P-magnetic resonance
spectroscopy, Suga et al. [22] found that FT fibre recruit-
ment occurred in only 31% of subjects who performed
occlusion training at 20% 1RM compared with 70% of
those who trained at 65% 1RM. Given that this low level of
intensity (20% 1RM) has been shown to increase hyper-
trophy when combined with blood flow restriction to a
similar or greater extent as high-intensity resistance train-
ing [62,63], it therefore seems likely that factors other than
recruitment also contribute to the hypertrophic effect of
exercise-induced metabolic stress. To lend further support
to this conclusion, EMG studies have shown that exercise
performed at 80% 1RM produced substantially greater
muscle activity compared with blood flow restricted exer-
cise at 20% 1RM, indicating reduced recruitment at the
lower intensity [64].
5 Systemic Hormonal Production
Another popular theory proposed to explain the hypertro-
phic mechanisms associated with metabolic stress is that a
buildup of metabolites increases growth-oriented hormonal
concentrations, thereby enhancing the anabolic milieu and
subsequent accretion of muscle proteins [46,65]. Theo-
retically, high levels of circulating hormones increase the
Metabolic stress
Increased
fibre
recruitment
Elevated
hormonal
release
Altered
myokine
production
Production of
ROS
Cellular
swelling
Fig. 2 Proposed mechanisms
by which exercise-induced
metabolic stress may mediate
muscle hypertrophy. ROS
reactive oxygen species
182 B. J. Schoenfeld
Author's personal copy
likelihood of interaction with receptors [66], which may
have particular hypertrophic importance in the post-work-
out period when muscles are primed for anabolism. Some
researchers have speculated that these acute hormonal
elevations to training are more critical to tissue growth and
remodelling than chronic changes in resting hormonal
concentrations [67]. Metabolically-induced spikes in insu-
lin-like growth factor (IGF)-1, testosterone, and growth
hormone (GH), in particular, have been implicated as
having a positive effect on post-exercise muscle protein
synthesis. The following is an overview of each of these
hormones and their potential hypertrophic relevance to
resistance exercise that promotes substantial changes in the
intracellular metabolic environment.
5.1 IGF-1
IGF-1 is a homologous peptide hormone that has both
mitogenic and anabolic effects on skeletal muscle [68]. A
clear cause-effect relationship has been established
between IGF-1 and muscle hypertrophy [68], and some
researchers have professed that IGF-1 is the primary
physiological regulator of muscle mass [69]. The anabolic
effects of IGF-1 appear to be magnified in response to
mechanical loading [70] and increases in IGF-1 protein
have been shown to be proportional to increases in muscle
strength following resistance training [71]. However,
research indicates that a functional IGF-1 receptor is not
obligatory for compensatory muscle growth [3].
Three distinct IGF-1 isoforms have been identified: the
systemic forms IGF-1Ea and IGF-1Eb, and a splice variant,
IGF-1Ec. Although each of these isoforms are expressed in
muscle tissue [72], only IGF-1Ec appears to be locally
activated by mechanical signals and thus it has been termed
mechano-growth factor (MGF) [70]. Despite the fact that
MGF functions in an autocrine/paracrine fashion and thus is
not a true hormone, it nevertheless will be discussed in this
section given its close relationship with the other IGF-1
isoforms.
While the liver is the primary site of endocrine IGF-1
production, other non-hepatic tissues including muscle also
express the systemic isoforms. In fact, during intense exer-
cise the majority of IGF-1Ea is actually derived from
working muscles rather than the liver, and most of the cir-
culating IGF-1 is ultimately taken up by the musculature
[73]. The effects of systemically produced IGF-1 on muscle
hypertrophy are not clear, and there is some doubt as to
whether it plays a significant role in post-exercise muscle
protein accretion [74]. It may well be that the primary
hypertrophic role for these isoforms is in stimulating the
fusion of satellite cells with existing muscle fibres, thereby
facilitating the donation of myonuclei and helping to main-
tain optimal DNA-to-protein ratios in muscle tissue [7,75].
Since a muscle’s nuclear-content-to-fibre-mass ratio
remains constant during hypertrophy, the satellite cell-
derived addition of new myonuclei is believed to be
essential for realizing long-term increases in muscle mass
[76]. This is consistent with the concept of myonuclear
domain, which proposes that the myonucleus regulates
mRNA production for a finite sarcoplasmic volume and
any increases in fibre size must be accompanied by a
proportional increase in myonuclei [77]. The relevance of
myonuclear domain remains controversial and those
interested in a detailed discussion of the topic are referred
to the point/counterpoint articles by O’Connor and Pavlath
[78] and McCarthy and Esser [79].
In contrast, locally expressed MGF is believed to be the
isoform principally responsible for compensatory hyper-
trophy [80]. Because of its rapid expression following
mechanical loading, MGF is thought to help ‘kick start’ the
post-exercise hypertrophic response and facilitate local
repair of damaged tissue [73]. MGF carries out signalling
through multiple anabolic cascades including phosphati-
dylinositol 3-kinase-protein kinase B-mammalian target of
rapamycin (PI3K-Akt-mTOR) [81], MAPK-ERK 1/2 [82],
and various calcium-dependent pathways [9], thereby
directly mediating synthesis of muscle proteins. A recent
post hoc cluster analysis by Bamman et al. [83] found that
MGF was differentially expressed across clusters, with
extreme responders to resistance training showing the most
robust increase and non-responders having only a non-
significant upward trend. These results strongly imply that
acute, transient elevations in MGF gene expression are
important cues for hypertrophic adaptations pursuant to
mechanical loading. Furthermore, whereas systemically
produced IGF-1Ea mediates satellite cell fusion [7,75],
locally expressed MGF is believed to activate satellite cells
and mediate their proliferation and differentiation [84,85].
In this way, there seems to be a synergism between local
and systemic isoforms to optimize myonuclear content and
thus promote long-term gains in muscle mass. A complete
discussion of the roles of the various IGF-1 isoforms is
beyond the scope of this paper. Those interested in further
exploration of the topic are referred to recent reviews by
Velloso and Harridge [74] and Philippou et al. [86].
Performance of hypertrophy-type training routines that
generate extensive metabolic buildup have been found to
result in significantly greater elevations of circulating IGF-
1 levels compared with high-intensity protocols that cause
minimal metabolite accumulation [28,29,87], although
these results have not been consistent across all trials [88].
Moreover, some [8991], but not all [92] studies on Kaatsu
have shown increased post-exercise IGF-1 elevations fol-
lowing occlusion exercise, suggesting a metabolically
induced influence on the hormone. The reason for these
discrepancies is not clear and may be a function of
Role of Metabolic Stress in Hypertrophic Adaptations 183
Author's personal copy
methodological differences between protocols. Moreover,
the aforementioned studies primarily investigated systemic
IGF-1 production, making it difficult to assess the potential
hypertrophic ramifications if an association does in fact
exist.
5.2 Testosterone
Testosterone is a cholesterol-derived hormone synthesized
and secreted primarily by the Leydig cells of the testes via
the hypothalamic-pituitary-gonadal axis, with small
amounts derived from the ovaries and adrenals [93]. The
anabolic effects of testosterone on muscle tissue are
incontrovertible [94,95]. For one, testosterone increases
muscle protein synthesis and decreases proteolysis [96,97].
These effects are induced by its binding to the intracellular
androgen receptor, which in turn translocates to the nucleus
where the complex mediates gene transcription [98]. In
addition to these direct anabolic roles, testosterone also has
indirect hypertrophic effects that include potentiating the
release of other anabolic hormones such as GH [66] and
IGF-1/MGF [99], as well as mediating satellite cell acti-
vation and proliferation [100].
There is speculation that acute post-exercise elevations
in testosterone may directly stimulate anabolism by
increasing the protein synthetic rate while inhibiting pro-
teolysis [93]. This is consistent with evidence showing
significant correlations between training-induced eleva-
tions in testosterone and increases in muscle CSA [101].
Results seem to be more pronounced in strength athletes
compared with endurance athletes and sedentary individ-
uals [102], suggesting that the post-exercise testosterone
response may play a greater role as one gains resistance
training experience [103]. However, a causal relationship
between acute testosterone production and hypertrophy has
yet to be established, and there is strong evidence that
post-exercise testosterone elevations are not required for
compensatory muscle growth [104].
Attempts to determine the effects of metabolic stress on
testosterone have been largely inconclusive. Although
several studies have found that hypertrophy-oriented
resistance training programmes cause greater post-exercise
testosterone elevations compared with routines that do not
substantially increase metabolic stress [93,105108], oth-
ers have failed to find significant differences [28,38,109].
Moreover, Kaatsu training has generally failed to demon-
strate significant post-exercise elevations in testosterone
despite high levels of metabolites [91,109,110], calling
into question as to whether the hormone plays a role in the
metabolic stress-induced hypertrophic response. It should
be noted that gender, age, training experience and nutri-
tional status can affect testosterone release [67], and these
factors may account for the inconsistent results seen in the
research to date. Further investigation into the topic is
needed so that a more definitive conclusion can be reached.
5.3 Growth Hormone
GH is a superfamily of polypeptide hormones that act as
repartitioning agents to induce fat metabolism toward
mobilization of triglycerides, as well as stimulating cellular
uptake and incorporation of amino acids into various pro-
teins, including muscle [111]. Despite its name, however,
the direct hypertrophic actions of GH on muscle protein
accretion appear to be negligible, with effects seemingly
limited to synthesis of non-contractile tissue (i.e. collagen)
[112]. It is believed that GH primarily carries out muscle
anabolism by potentiating release of IGF-1 [75], although
some researchers dispute this theory and postulate the
hypertrophic effects of GH and IGF-1 are in fact additive
[113]. There is evidence that recombinant GH adminis-
tration markedly enhances mRNA levels of MGF when
combined with resistance exercise in the elderly [70] but
not in healthy young adults [114]. GH also appears to have
a permissive or perhaps even a synergistic effect on tes-
tosterone-mediated protein synthesis [98]. However, it is
not clear what, if any, effects transient endogenous post-
exercise GH spikes have on levels of MGF or testosterone
at this time. The actions of the GH superfamily are highly
diverse and complex, and a complete discussion is beyond
the scope of this paper. Those interested in further reading
are referred to recent reviews by Ehrnborg and Rosen [115]
and Kraemer et al. [116].
The prevailing body of research supports a strong cor-
relation between exercise-induced metabolic stress and
increased hypophyseal GH secretion [23,4648,90,105,
106]. The absolute magnitude of these hormonal elevations
is substantial. Fujita et al. [91] found that Kaatsu increased
post-exercise GH levels 10-fold above compared with low-
intensity exercise without blood flow restriction while
Takarada et al. [48] reported elevations of 290-fold over
baseline. Post-exercise elevations are presumably mediated
by increased lactate and/or H
?
buildup in the blood
[47,106]. A reduction in pH associated with metabolite
accumulation also may potentiate GH release via chemo-
reflex stimulation mediated by intramuscular metabore-
ceptors and group III and IV afferents [42,110].
While increased hormonal concentrations present an
intriguing hypothesis as to the growth-related effects of
exercise-induced metabolic stress on skeletal muscle, it is
not clear whether such acute elevations do in fact mediate
an enhanced hypertrophic response. Several researchers
have questioned the hormone hypothesis [56,117], with
some speculating that such biological events are intended
to mobilize fuel stores following a bout of exercise rather
than promote tissue anabolism [118]. The anabolic role of
184 B. J. Schoenfeld
Author's personal copy
acute GH production in particular, has been dismissed
largely based on studies showing that exogenous admin-
istration of recombinant GH does not lead to greater
increases in muscle protein accretion [119121]. While this
may be true, it should be noted that exogenous injections
do not mimic the in vivo response to exercise-induced GH
secretions either temporally or in magnitude. The anabolic
milieu is primed during the post-workout period, and it is
possible that large spikes of GH following resistance
exercise, which can approach 300 times that of baseline
levels [48], may facilitate remodelling pursuant to myo-
trauma. Further, recombinant GH is solely made up of the
22-kDa isoform [115] whereas more than 100 molecular
isoforms of GH are produced endogenously [122]. A wide
spectrum of these isoforms peak at the conclusion of
resistance exercise with a greater proportional concentra-
tion of non-22-kD isoforms [115]. Supraphysiological
doses of recombinant GH actually impede post-exercise
stimulation of these alternative isoforms [115], potentially
obscuring hypertrophic effects. Whether these factors have
a significant effect on muscular adaptations is not clear at
this time and requires further study.
West et al. [123] found that transient hormonal spikes
had no effect on post-exercise muscle protein synthesis in
young males when compared with a protocol where hor-
monal levels were low. Furthermore, p70S6k phosphory-
lation was similar between groups, indicating that anabolic
signalling was also unaffected by post-exercise hormonal
elevations. It is important to note, however, that protein
synthesis measured in response to an acute bout of exercise
does not always correlate with chronic upregulation of
causative myogenic signals [124] and is not necessarily
predictive of long-term hypertrophic responses to regi-
mented resistance training [76]. Thus, while these findings
are intriguing, their practical implications are limited.
Direct studies evaluating the effect of acute anabolic
hormonal production on hypertrophy have been contra-
dictory. Madarame et al. [125] found that performing
occlusion training for the lower body musculature after
unilateral arm exercise resulted in a significant increase in
muscle CSA of the elbow flexors compared with identical
arm training routine combined with non-occlusion lower
body exercise. Although differences in GH levels did not
rise to statistical significance, the authors state that this was
likely due to the study being underpowered. Considering
that similar protocols have shown large post-exercise hor-
monal increases [23,4648,90,106], results therefore
seem to suggest that systemic factors may have played a
role in the adaptive response. It also is interesting to note
that no changes in muscle CSA were observed in the non-
trained arm, indicating that acute systemic hormonal
increases have no effect on muscle size in the absence of
mechanical stress. West et al. [126] employed a within-
person design to investigate the role of acute hormonal
elevations on muscle hypertrophy using a traditional
resistance exercise protocol. Twelve untrained men (aged
mean ±SD 21.8 ±1.2 years) trained their elbow flexors
on separate days under two different hormonal environ-
ments: a low hormone condition where one arm performed
arm curl exercise only and a high hormone condition where
the contralateral arm performed the same arm curl exercise
followed immediately by a bout of leg resistance exercises
designed to elicit large increases in circulating hormones.
After 15 weeks, no differences were found between groups
in muscle girth as determined by magnetic resonance
imaging despite significantly greater elevations in circu-
lating IGF-1, GH, and testosterone in the high-hormone
group following exercise.
A recent study by Ronnestad et al. [127] employed a
similar within-subject design to West et al. [126], except
that leg training was performed before the arm curl in the
high-hormone group. In contrast to West et al. [126], those
in the high-hormone group displayed a significantly greater
increase in muscle CSA of the elbow flexors implying that
elevated hormones were responsible for hypertrophic
gains. Interestingly, differences were specific to distinct
regions of elbow flexors, with increases in CSA seen only
at the two middle sections where muscle girth was largest.
Considering the conflicting evidence, it is premature to
draw definitive conclusions as to whether or not the
post-exercise anabolic hormonal response associated with
metabolic stress plays a role in muscle hypertrophy. What
seems apparent from the research is that if such a role does
in fact exist, the overall magnitude of the effect size would
be fairly modest. However, even modest increases in
muscle hypertrophy could potentially be meaningful for
certain populations, particularly bodybuilders and strength
athletes. It is conceivable that acute hormonal elevations
may have a greater effect on satellite cell activity rather
than post-exercise protein synthetic rate, thereby impacting
long-term, as opposed to shorter-term, hypertrophic adap-
tations. If so, the anabolic effects of these hormonal spikes
might be limited by genetic differences in pre-training
satellite cell availability and one’s subsequent ability to
expand the available satellite cell pool [77]. Finally, studies
in trained individuals on the subject are lacking, so it
remains to be elucidated if those with previous training
experience respond differently to acute exercise-induced
hormonal output compared with untrained subjects.
6 Local Myokines
Exercise training results in the synthesis of various cyto-
kines and other peptides within skeletal muscle (a.k.a.
myokines), and an emerging body of evidence indicates
Role of Metabolic Stress in Hypertrophic Adaptations 185
Author's personal copy
that these local factors can significantly contribute to
hypertrophic adaptations [128130]. Many of these agents
can exert effects in an autocrine/paracrine fashion to bring
about unique effects on skeletal muscle adaptation, and
resistance exercise appears to enhance their response [131].
There is speculation that metabolic stress may mediate
muscle hypertrophy by either upregulating anabolic myo-
kines and/or downregulating catabolic myokines.
Interleukin (IL)-6 is an early-stage myokine purported to
influence satellite-cell mediated myonuclear accretion
[130], and it has been postulated that exercise-induced
metabolic stress may stimulate its production [132].
Despite a seemingly sound theoretical rationale, though,
evidence in support of this contention is lacking. Takarada
et al. [48] found that restricted blood flow exercise of the
knee extensors resulted in gradual increase in IL-6, with
levels maintained at an elevated rate 24 h post-exercise
versus controls. The overall effect size was small, however,
with levels reaching only one-fourth of that reported for
higher-intensity eccentric exercise. Fujita et al. [133]
reported a 2.4% increase in muscle/bone CSA of the thigh
musculature following 6 days of Kaatsu despite the fact
that IL-6 levels remained unchanged throughout the train-
ing period. Similarly, studies by Abe et al. [134] and Fry
et al. [39] failed to detect a change in IL-6 levels following
occlusion training. These results cast doubt as to whether
IL-6 is in fact a mechanism by which metabolic stress
induces hypertrophy.
There is some evidence to suggest that metabolic stress
may have a greater impact on compensatory hypertrophy
by reducing local catabolic factors as opposed to increasing
growth-oriented factors. Given that muscle growth repre-
sents the dynamic balance between protein synthesis and
breakdown, a decrease in protein degradation ultimately
leads to an increase in protein accretion. Research on
potential mediators has largely focused on myostatin, a
member of the transforming growth factor-3 super family
that acts as a negative regulator of muscle growth [135].
Kawada and Ishii [136] found that myostatin levels sig-
nificantly decreased in the plantaris muscle of Wistar rats
following restricted blood flow exercise in comparison to a
sham operation group. In contrast, a human trial by
Drummond et al. [92] reported no differences in myostatin
gene expression between Kaatsu training and low-intensity
exercise without blood flow restriction 3 h post-exercise.
Interestingly, Manini et al. [137] found that although
Kaatsu did not reduce myostatin, it significantly down-
regulated various proteolytic transcripts (forkhead box
O3A [FOXO3A], Atrogin-1 and muscle ring finger-1
[MuRF-1]) 8 h post-exercise compared with a control
group that performed non-occluded low-intensity training.
Recently, Laurentino et al. [63] investigated the effects of
Kaatsu on chronic myostatin levels in physically active
males. After 8 weeks of training, Kaatsu produced a sig-
nificant 45% chronic reduction in myostatin gene expres-
sion while low-intensity exercise without blood flow
restriction showed only non-significant decreases.
Given the disparate data, it is difficult to draw firm
conclusions as to whether metabolic stress influences
hypertrophy by altering myokine production. It is impor-
tant to note that many additional myokines have been
identified in the literature (including IL-1, IL-7, IL-8,
IL-10, IL-13, IL-15, fibroblast growth factor, leukaemia
inhibitory factor, and tumour necrosis factor, amongst
others), and the effects of metabolic stress on these myo-
kines have yet to be investigated. Moreover, no studies
could be located that directly compare post-exercise
myokine differences between traditional hypertrophy-ori-
ented routines versus high-intensity strength-oriented reg-
imens. This topic should be a prime area of focus for future
research.
7 Reactive Oxygen Species
ROS presents an intriguing potential mechanism by which
metabolic stress may mediate muscle hypertrophy. The
term ROS collectively includes both oxygen radicals (i.e.
superoxide, hydroxyl, peroxyl and hydroperoxyl radicals)
and non-radical oxidizing agents (i.e. hydrogen peroxide
and hypochlorous acid) [138]. A complete discussion about
the sources of contraction-induced ROS production is
beyond the scope of this paper, but distinctions are made
between ROS produced chronically during resting condi-
tions and those generated transiently during exercise.
Under normal physiological conditions, ROS are primarily
generated by the mitochondrial electron transport chain and
oxidation of polyunsaturated fats, and their production is
significantly influenced by environmental stress and aging
[138]. During exercise, contracting muscles are a promi-
nent source of acute ROS production, with the extent of
elevations dependent on the type and intensity of training
[139]. For further information on the subject, the interested
reader is referred to recent reviews by Powers et al. [140]
and Jackson [141].
Although chronically elevated levels of ROS have been
implicated as having negative effects on various muscle
tissues and may even trigger the onset of sarcopenia
[142,143], acutely they can function as key cellular sig-
nalling molecules in the response to exercise [144147],
potentially mediating post-workout anabolic adaptations.
ROS production has been shown to promote growth in both
smooth muscle and cardiac muscle [148], and it is theo-
rized to have similar hypertrophic effects on skeletal
muscle as well [54]. Transgenic mice with suppressed
levels of selenoproteins, a class of proteins that function as
186 B. J. Schoenfeld
Author's personal copy
potent antioxidants, display increased exercise-induced
muscle growth, suggesting a ROS-mediated hypertrophic
effect through redox sensitive signalling pathways [149].
Although the mechanisms of action have not been fully
elucidated, research has shown that ROS can influence
muscle hypertrophy via enhanced MAPK signalling.
Kefaloyianni et al. [150] displayed that treatment of C2
myoblasts with a ROS variant increases MAPK activation,
with the response of the various MAPK subfamilies (ERK
1/2, c-Jun N-terminal kinase [JNK], and p38-MAPK) dif-
fering over time. In cardiac myocytes, ROS can regulate
phospholipase D and thus potentially mediate protein
synthesis via activation of PA [151]. Whether ROS influ-
ences this pathway in skeletal muscle has not been deter-
mined. There is also evidence that antioxidant treatment
markedly blunts IGF-I-induced phosphorylation of the
IGF-I receptor in C2C12 myocytes treated with ROS,
suggesting that ROS has a critical function in the biological
action of IGF-I [152].
Research supporting the hypertrophic role of ROS in
routines producing metabolic stress remains speculative
and is largely derived from implied data. Mitochondria in
FT fibres have unique properties that promote higher levels
of ROS activity compared with slow twitch fibres [140].
Given that hypertrophy-type training associated with met-
abolic stress would conceivably involve the mitochondria
to a greater degree than high-intensity training, it seems
reasonable to conclude that such exercise would generate
more ROS. Moreover, hypoxia and subsequent reperfusion
heightens ROS production [153,154]. Since the greater
time under tension associated with a hypertrophy-type
routine would necessarily be associated with an increased
ischaemic response compared with high-intensity training,
it stands to reason that higher levels of ROS would be
produced. Whether these differences in ROS production
are sufficient to promote a hypertrophic response is
unknown at this time and requires further study.
The direct effect of exercise-induced metabolic stress on
ROS has not been well studied. Goldfarb et al. [155]
displayed that plasma protein carbonyl levels and blood
glutathione ratio, both markers of oxidative stress, were
significantly greater in a hypertrophy-type routine (3 sets at
*70% 1RM) compared with a low-intensity routine with
blood flow restriction (3 sets at *30% 1RM), suggesting
that muscle damage plays the dominant role in generating
ROS. Support for this hypothesis was demonstrated by
Takarada et al [48], who found no change in post-exercise
lipid peroxide levels following performance of the seated
leg extension combined with vascular occlusion whereby
muscle damage was minimal.
An interesting but relatively unexplored facet of
research in this area involves nitric oxide (NO), a ROS
variant. NO production has been linked to compensatory
muscle hypertrophy [156,157], and there is evidence that it
mediates an increase in satellite-cell activation and prolif-
eration [158], possibly via synthesis of hepatocyte growth
factor [159]. Kawada and Ishii [136] demonstrated that
venous occlusion of the hindlimbs in Wister rats resulted in
an increased expression of NO synthase-1 (NOS-1), an
enzyme that catalyzes the production of NO from L-argi-
nine. However, although levels of NO showed a trend
toward an increase at 2 weeks post-surgery (p =0.10),
results did not rise to statistical significance purportedly
due to a large intersubject variation. Supporting research in
humans is lacking at this time.
ROS may also indirectly influence hypertrophy by
mediating transcription of highly conserved stress proteins
called heat shock proteins (HSPs). Under normal physio-
logical conditions, HSPs act as a chaperone protein, facil-
itating the folding of new peptide chains and translocation
of proteins [160]. When the body is subjected to stress,
however, HSPs are thought to serve a protective role that
includes limiting oxidative damage caused by ROS [161],
and some researchers have theorized that they may play a
role in compensatory muscle hypertrophy as well [136,
162]. A number of HSPs have been identified, each of
which are named according to their molecular mass in
kiloDaltons (i.e. HSP27, HSP60, HSP70, and HSP72, etc).
It should be noted that, in addition to ROS-mediated
transcription, HSPs are also induced by hypoxia, acidosis,
and ischaemia-reperfusion [163] – all byproducts of resis-
tance exercise associated with high levels of metabolic
stress.
Kawada and Ishii [136] found that HSP72 was signifi-
cantly elevated in the plantaris muscle of rats following
2 weeks of vascular occlusion. These findings were asso-
ciated with a significant increase in muscle hypertrophy,
leading researchers to speculate that HSP72 might con-
tribute post-exercise muscular development. Conversely,
Fry et al. [39] found no differences in total protein content
of HSP70 following restricted blood flow exercise at 20%
1RM in elderly males. Further, a recent study by Paulsen
et al. [164] showed that training volume (one set vs. three
sets) had no influence on cytosolic or cytoskeletal levels of
HSP27 and HSP70 in either the vastus lateralis or trapezius
muscles following 11 weeks of progressive hypertrophy-
type training (7–10 RM). Given that higher volumes of
exercise would necessarily result in greater metabolite
accumulation, this argues against the presence of a dose-
response between metabolic stress and HSPs. Perhaps,
most importantly, HSP transcription resultant to resistance
exercise is likely more due to structural and functional
myodamage rather than increased ROS production [165].
The combination of these findings raises doubt as to
whether HSPs are in fact a significant hypertrophic
mechanism associated with exercise-induced metabolic
Role of Metabolic Stress in Hypertrophic Adaptations 187
Author's personal copy
stress, at least with respect to traditional resistance
exercise.
8 Cell Swelling
One of the more novel mechanisms that might be involved
in the hypertrophic response to metabolic stress involves an
increase in intracellular hydration. This phenomenon,
known as cell swelling, is believed to serve as a physio-
logical regulator of cell function [166,167]. Numerous
studies have shown that hydration-mediated cell swelling
results in an increase in protein synthesis and a decrease in
proteolysis in a variety of different cell types, which
include hepatocytes, osteocytes, breast cells and muscle
fibres [168]. With respect to muscle, it has been theorized
that the stimulus associated with cell swelling may trigger
proliferation of satellite cells and facilitate their fusion to
hypertrophying myofibres [169], thereby enhancing
potential long-term hypertrophic adaptations.
The underlying mechanisms for cell swelling-induced
anabolism have yet to be fully determined. It has been
proposed that increased pressure against the cytoskeleton
and/or cell membrane is perceived as a threat to cellular
integrity, which causes the cell to initiate a signalling
response that ultimately leads to reinforcement of its
ultrastructure [24,170]. There is evidence that signalling is
carried out via integrin-associated volume osmosensors
within cells [171]. The sensors, in turn, activate anabolic
protein-kinase transduction pathways, possibly mediated
by autocrine effects of growth factors [172,173]. Research
indicates that anabolic functions are carried out in an
mTOR-independent fashion [174] and there is suggestion
that MAPK modules may be the primary mediator of
swelling-induced anabolism [175,176].
To date, there is a paucity of research directly inves-
tigating whether cellular hydration pursuant to exercise-
induced metabolite accumulation enhances muscle
growth. However, a compelling case can be made
whereby this occurs. Resistance exercise has been shown
to induce alterations of intra- and extracellular water
balance [177], the extent of which is dependent upon the
type of exercise and intensity of training. Cell swelling is
maximized by exercise that relies heavily on glycolysis,
with the resultant lactate accumulation acting as a
primary contributor to osmotic changes in skeletal muscle
[178,179]. The intramuscular buildup of lactate has been
shown to trigger volume regulatory mechanisms, and
these effects may be magnified by the acidic environment
associated with exercise-induced metabolite accumulation
[168]. Although speculative, the amount of swelling
would seem to be heightened by reactive hyperaemia
subsequent to compression of blood vessels during such
training. FT fibres are particularly sensitive to osmotic
changes, presumably related to a high concentration water
transport channels called aquaporin-4 (AQP4). AQP4 has
been shown to be strongly expressed in the sarcolemma of
mammalian FT glycolytic and FT oxidative-glycolytic
fibres, facilitating the influx of fluid into the cell [179].
Given that FT fibres are most responsive to hypertrophy
[180], it is plausible that cellular hydration influences the
hypertrophic response during resistance training that
includes a strong glycolytic component by producing a
favorable effect on net protein balance and thus enhanc-
ing muscle protein accretion. Consequently, the ‘muscle
pump’ that bodybuilders often strive to achieve may in
fact help to promote a growth response after all and
hypertrophy-oriented training routines may therefore
benefit by maximizing this phenomenon.
Although the cell swelling hypothesis is intriguing, a
recent study by Gundermann et al. [181] provides evidence
to the contrary. The study compared low-intensity resis-
tance training whereby hyperaemia was simulated by a
pharmacological vasodilator to low-intensity blood flow-
restricted exercise. Results showed that occlusion exercise
produced a 49% increase in mixed muscle fractional syn-
thetic rate as well as significant elevations in phosphory-
lation of mTOR, S6K1, and ERK1/2, while those who
performed exercise supplemented by pharmacological
vasodilation reported no changes in any of these variables.
The study was limited by the fact that researchers were
unable to accurately reproduce the immediate (first
*10 min) post-exercise hyperaemic response, making it
difficult to determine whether the initial signal from
increased hydration plays a role in post-exercise protein
synthesis. Further, protein breakdown was not measured,
and an attenuation of proteolysis is believed to be a primary
means by which cellular hydration mediates muscle
hypertrophy.
It is possible that metabolic stress may lead to long-term
hypertrophic gains as a result of increased glycogen stores
mediated by chronic cell swelling. Chronic, consistent
resistance training utilizing a repetition range that relies on
anaerobic glycolysis for energy has been shown to signif-
icantly upregulate glycogen storage capacity [182].
Research also shows that bodybuilders display a 50%
greater intramuscular glycogen content compared with
non-athletes, indicating an adaptive response from hyper-
trophy-type training [21]. Given that glycogen attracts
three grams of water for every gram of glycogen [183], an
increase in glycogen stores may mediate a favourable
muscle protein balance over time via heightened cellular
hydration, thereby enhancing long-term hypertrophic gains.
This theory remains untested and requires further study.
188 B. J. Schoenfeld
Author's personal copy
9 Conclusions
In summary, while mechanical stress is unquestionably a
primary driving stimulus in post-exercise muscle growth,
there is compelling evidence that metabolic stress also may
contribute to hypertrophic adaptations. What is not clear is
whether metabolic stress is additive to mechanically-derived
signalling or perhaps redundant provided a given level of
intensity is achieved. A problem with current research is that
mechanical and metabolic stress occur in tandem, making it
difficult to tease out the effects of one from other. This can
potentially result in misinterpreting metabolic factors as
causal in nature when muscle actions are in fact playing the
dominant hypertrophic role or vice versa.
Furthermore, the mechanisms by which metabolic stress
influences compensatory hypertrophy have yet to be fully
explored. Although increased muscle recruitment appears
to be highly involved, it is doubtful that recruitment alone
is responsible for the full magnitude of growth-related
gains. Rather, the combined integration of multiple local
and systemic factors likely contribute to muscle develop-
ment in a direct and/or permissive manner [184]. In addi-
tion to the mechanisms discussed in this review, it is
possible that other yet-to-be determined factors may also
be involved and additional research is needed to explore
the topic in depth.
Current theory suggests that a given threshold of
mechanical stress is necessary to promote muscular growth,
which is purported to be in the range of approximately
60–65% 1RM [41]. Support for this recommendation can be
inferred from the study by Campos et al. [34], who found
that volume-adjusted high intensity (3–5 RM) and moderate
intensity (9–11 RM) routines promoted significant increases
in muscle CSA of the thigh while a low intensity (20–28
RM) routine did not. Recent studies, however, seem to
contradict these findings. Tanimoto et al. [185] demon-
strated that training at 50% 1RM with slow movement and
tonic force generation (3 s for eccentric and concentric
actions with no relaxation phase) showed comparable
increases in muscle size compared with training at 80%
1RM with a traditional cadence (1 s for concentric and
eccentric actions). Results were attributed to increased
metabolic stress associated with the lower-intensity proto-
col. More recently, Mitchell et al. [186] showed that
10 weeks of resistance exercise of the leg extensors per-
formed at an intensity of 30% 1RM produced a similar
hypertrophic response as training at 80% 1RM, although
results were confounded by a substantially greater volume
in the low-intensity group. In contrast, Holm et al. [187]
reported that a moderate-intensity protocol (70% 1RM)
produced a 3-fold greater increase in muscle hypertrophy
compared with a volume-equated low intensity (15.5%
1RM) over a 12-week training period. Discrepancies
between these studies are likely related to methodology and
require further study. It should be noted that hypertrophy
associated with lower-intensity training is highly dependent
on training to failure. This is likely related to the fact that
fatiguing sets are necessary at lower-intensity to induce
substantial metabolic stress and thereby heighten the asso-
ciated mechanisms responsible for muscle growth.
Future research should seek to elucidate the precise
mechanisms by which metabolic stress mediates compen-
satory muscle growth, including whether or not hypoxia
itself plays a direct role in the process. In addition, attempts
should be made to clarify optimal hypertrophic loading
intensities along the strength-endurance continuum, and
determine the precise role that metabolic stress plays in this
process. Specific focus should be centered on whether a
dose-response relationship exists between metabolic stress
and muscle hypertrophy and, if so, whether an upper
threshold exists beyond which such benefits plateau and/or
results are impaired. Given the large influence of age,
gender and genetics on muscular adaptations, it is likely
that any such threshold would vary based on interindivid-
ual differences. For example, an elderly marathon runner
with a high proportion of type I fibres in the thigh muscles
would seemingly have a different threshold response from
a young sprinter who has predominantly type II fibres.
These issues warrant further study.
A potential confounding issue is that exercise-induced
metabolic stress generally occurs in concert with muscle
damage during hypertrophy-oriented resistance exercise.
Given that myodamage is believed to play a role in post-
exercise muscle growth [188], this may alter results and
thus needs to be addressed in study design. Also, studies to
date have been largely confined to the use of untrained
subjects, therefore limiting the ability to generalize results
to trained populations. Researchers should therefore seek to
carry out future studies on lifters with at least a year or
more of dedicated resistance training experience. An
enhanced understanding of these factors will ultimately
improve our ability to design programs that maximize
hypertrophic adaptations based on the needs, abilities and
genetics of the individual.
Acknowledgements This review was not funded by any outside
organization. Brad Schoenfeld is the sole author of this work. There
are no conflicts of interest present that are directly relevant to the
content of this review.
References
1. Goldberg AL, Etlinger JD, Goldspink DF, et al. Mechanism of
work-induced hypertrophy of skeletal muscle. Med Sci Sports.
1975 Fall;7(3):185–98.
2. Witkowski S, Lovering RM, Spangenburg EE. High-frequency
electrically stimulated skeletal muscle contractions increase
Role of Metabolic Stress in Hypertrophic Adaptations 189
Author's personal copy
p70s6k phosphorylation independent of known IGF-I sensitive
signaling pathways. FEBS Lett. 2010;584(13):2891–5.
3. Spangenburg EE, Le Roith D, Ward CW, et al. A functional
insulin-like growth factor receptor is not necessary for load-
induced skeletal muscle hypertrophy. J Physiol. 2008;586(1):
283–91.
4. Hornberger TA, Stuppard R, Conley KE, et al. Mechanical
stimuli regulate rapamycin-sensitive signalling by a phospho-
inositide 3-kinase-, protein kinase B- and growth factor-inde-
pendent mechanism. Biochem J. 2004;380(Pt 3):795–804.
5. Vandenburgh H, Kaufman S. In vitro model for stretch-induced
hypertrophy of skeletal muscle. Science. 1979;203(4377):265–8.
6. Miyazaki M, McCarthy JJ, Fedele MJ, et al. Early activation of
mTORC1 signalling in response to mechanical overload is
independent of phosphoinositide 3-kinase/Akt signalling.
J Physiol. 2011;589(Pt 7):1831–46.
7. Toigo M, Boutellier U. New fundamental resistance exercise
determinants of molecular and cellular muscle adaptations. Eur J
Appl Physiol. 2006;97(6):643–63.
8. Mayhew DL, Hornberger TA, Lincoln HC, et al. Eukaryotic
initiation factor 2B epsilon induces cap-dependent translation
and skeletal muscle hypertrophy. J Physiol. 2011;589(Pt 12):
3023–37.
9. Tidball JG. Mechanical signal transduction in skeletal muscle
growth and adaptation. J Appl Physiol. 2005;98(5):1900–8.
10. Bassel-Duby R, Olson EN. Signaling pathways in skeletal
muscle remodeling. Annu Rev Biochem. 2006;75:19–37.
11. Miyazaki M, Esser KA. Cellular mechanisms regulating protein
synthesis and skeletal muscle hypertrophy in animals. J Appl
Physiol. 2009;106(4):1367–73.
12. Glass DJ. Skeletal muscle hypertrophy and atrophy signaling
pathways. Int J Biochem Cell Biol. 2005;37(10):1974–84.
13. Hornberger TA, Chu WK, Mak YW, et al. The role of phos-
pholipase D and phosphatidic acid in the mechanical activation
of mTOR signaling in skeletal muscle. Proc Natl Acad Sci USA.
2006;103(12):4741–6.
14. O’Neil TK, Duffy LR, Frey JW, et al. The role of phosphoin-
ositide 3-kinase and phosphatidic acid in the regulation of
mammalian target of rapamycin following eccentric contrac-
tions. J Physiol. 2009;587(Pt 14):3691–701.
15. Lehman N, Ledford B, Di Fulvio M, et al. Phospholipase
D2-derived phosphatidic acid binds to and activates ribosomal
p70 S6 kinase independently of mTOR. FASEB J. 2007;21(4):
1075–87.
16. Rooney KJ, Herbert RD, Balnave RJ. Fatigue contributes to the
strength training stimulus. Med Sci Sports Exerc. 1994;26(9):
1160–4.
17. Schott J, McCully K, Rutherford OM. The role of metabolites in
strength training. II. Short versus long isometric contractions.
Eur J Appl Physiol Occup Physiol. 1995;71(4):337–41.
18. Smith RC, Rutherford OM. The role of metabolites in strength
training. I. A comparison of eccentric and concentric contrac-
tions. Eur J Appl Physiol Occup Physiol. 1995;71(4):332–6.
19. Shinohara M, Kouzaki M, Yoshihisa T, et al. Efficacy of tour-
niquet ischemia for strength training with low resistance. Eur J
Appl Physiol Occup Physiol. 1998;77(1–2):189–91.
20. Folland JP, Irish CS, Roberts JC, et al. Fatigue is not a necessary
stimulus for strength gains during resistance training. Br J Sports
Med. 2002;36(5):370–3.
21. Tesch PA, Colliander EB, Kaiser P. Muscle metabolism during
intense, heavy-resistance exercise. Eur J Appl Physiol Occup
Physiol. 1986;55(4):362–6.
22. Suga T, Okita K, Morita N, et al. Intramuscular metabolism
during low-intensity resistance exercise with blood flow
restriction. J Appl Physiol. 2009;106(4):1119–24.
23. Pierce JR, Clark BC, Ploutz-Snyder LL, et al. Growth hormone
and muscle function responses to skeletal muscle ischemia.
J Appl Physiol. 2006;101(6):1588–95.
24. Schoenfeld BJ. The mechanisms of muscle hypertrophy and
their application to resistance training. J Strength Cond Res.
2010;24(10):2857–72.
25. Fry AC. The role of resistance exercise intensity on muscle fibre
adaptations. Sports Med. 2004;34(10):663–79.
26. Lambert CP, Flynn MG. Fatigue during high-intensity inter-
mittent exercise: application to bodybuilding. Sports Med.
2002;32(8):511–22.
27. Kraemer WJ, Fleck SJ, Dziados JE, et al. Changes in hormonal
concentrations after different heavy-resistance exercise proto-
cols in women. J Appl Physiol. 1993;75(2):594–604.
28. Kraemer WJ, Marchitelli L, Gordon SE, et al. Hormonal and
growth factor responses to heavy resistance exercise protocols.
J Appl Physiol. 1990;69(4):1442–50.
29. Kraemer WJ, Gordon SE, Fleck SJ, et al. Endogenous anabolic
hormonal and growth factor responses to heavy resistance
exercise in males and females. Int J Sports Med. 1991;12(2):
228–35.
30. Katch VL, Katch FI, Moffatt R, et al. Muscular development
and lean body weight in body builders and weight lifters. Med
Sci Sports Exerc. 1980;12(5):340–4.
31. Schmidtbleicher D, Buehrle M. Neuronal adaptation and
increase of cross-sectional area studying different strength
training methods. In: Jonsson GB, editor. Biomechanics X-B
volume 6-B. Champaign: Human Kinetics; 1987. p. 615–20.
32. Choi J, Takahashi H, Itai Y. The difference between effects of
‘power-up type’ and ‘bulk-up type’ strength training exercises:
with special reference to muscle cross-sectional area. Jpn J Phys
Fitness Sports Med. 1998;47(1):119–29.
33. Masuda K, Choi JY, Shimojo H, et al. Maintenance of myo-
globin concentration in human skeletal muscle after heavy
resistance training. Eur J Appl Physiol Occup Physiol. 1999;
79(4):347–52.
34. Campos GER, Luecke TJ, Wendeln HK, et al. Muscular adap-
tations in response to three different resistance-training regi-
mens: specificity of repetition maximum training zones. Eur J
Appl Physiol. 2002;88(1–2):50–60.
35. Robbins DW, Goodale TL, Docherty D, et al. The effects of load
and training pattern on acute neuromuscular responses in the
upper body. J Strength Cond Res. 2010;24(11):2996–3007.
36. MacDougall JD, Ray S, Sale DG, et al. Muscle substrate utili-
zation and lactate production. Can J Appl Physiol. 1999;24(3):
209–15.
37. Tamaki T, Uchiyama S, Tamura T, et al. Changes in muscle
oxygenation during weight-lifting exercise. Eur J Appl Physiol
Occup Physiol. 1994;68(6):465–9.
38. Suga T, Okita K, Morita N, Yokota T, et al. Dose effect on
intramuscular metabolic stress during low-intensity resistance
exercise with blood flow restriction. J Appl Physiol. 2010;
108(6):1563–7.
39. Fry CS, Glynn EL, Drummond MJ, et al. Blood flow restriction
exercise stimulates mTORC1 signaling and muscle protein
synthesis in older men. J Appl Physiol. 2010;108(5):1199–209.
40. Loenneke JP, Wilson JM, Marin PJ, et al. Low intensity blood
flow restriction training: a meta-analysis. Eur J Appl Physiol.
2012;112(5):1849–59.
41. Kraemer WJ, Adams K, Cafarelli E, et al. American College of
Sports Medicine position stand: progression models in resistance
training for healthy adults. Med Sci Sports Exerc. 2002;34(2):
364–80.
42. Loenneke JP, Wilson GJ, Wilson JM. A mechanistic approach to
blood flow occlusion. Int J Sports Med. 2010;31(1):1–4.
190 B. J. Schoenfeld
Author's personal copy
43. Abe T, Kearns CF, Sato Y. Muscle size and strength are
increased following walk training with restricted venous blood
flow from the leg muscle, Kaatsu-walk training. J Appl Physiol.
2006;100(5):1460–6.
44. Kon M, Ikeda T, Homma T, et al. Effects of low-intensity
resistance exercise under acute systemic hypoxia on hormonal
responses. J Strength Cond Res. 2012;26(3):611–7.
45. Nishimura A, Sugita M, Kato K, et al. Hypoxia increases muscle
hypertrophy induced by resistance training. Int J Sports Physiol
Perform. 2010;5(4):497–508.
46. Goto K, Ishii N, Kizuka T, et al. The impact of metabolic stress
on hormonal responses and muscular adaptations. Med Sci
Sports Exerc. 2005;37(6):955–63.
47. Gordon SE, Kraemer WJ, Vos NH, et al. Effect of acid-base
balance on the growth hormone response to acute high-intensity
cycle exercise. J Appl Physiol. 1994;76(2):821–9.
48. Takarada Y, Nakamura Y, Aruga S, et al. Rapid increase in
plasma growth hormone after low-intensity resistance exercise
with vascular occlusion. J Appl Physiol. 2000;88(1):61–5.
49. Henneman E, Somjen G, Carpenter DO. Functional significance
of cell size in spinal motoneurons. J Neurophysiol. 1965;28:
560–80.
50. Kraemer WJ, Ratamess NA. Fundamentals of resistance train-
ing: progression and exercise prescription. Med Sci Sports
Exerc. 2004;36(4):674–88.
51. Houtman CJ, Stegeman DF, Van Dijk JP, et al. Changes in
muscle fiber conduction velocity indicate recruitment of distinct
motor unit populations. J Appl Physiol. 2003;95(3):1045–54.
52. Sahlin K, Soderlund K, Tonkonogi M, et al. Phosphocreatine
content in single fibers of human muscle after sustained sub-
maximal exercise. Am J Physiol. 1997;273(1 Pt 1):C172–8.
53. Vollestad NK, Vaage O, Hermansen L. Muscle glycogen
depletion patterns in type I and subgroups of type II fibres
during prolonged severe exercise in man. Acta Physiol Scand.
1984;122(4):433–41.
54. Takarada Y, Takazawa H, Sato Y, et al. Effects of resistance
exercise combined with moderate vascular occlusion on mus-
cular function in humans. J Appl Physiol. 2000;88(6):2097–106.
55. Ingemann-Hansen T, Halkjaer-Kristensen J, Halskov O. Skeletal
muscle phosphagen and lactate concentrations in ischaemic
dynamic exercise. Eur J Appl Physiol Occup Physiol. 1981;46(3):
261–70.
56. Loenneke JP, Fahs CA, Wilson JM, et al. Blood flow restriction:
the metabolite/volume threshold theory. Med Hypotheses. 2011;
77(5):748–52.
57. Meyer RA. Does blood flow restriction enhance hypertrophic
signaling in skeletal muscle? J Appl Physiol. 2006;100(5):
1443–4.
58. Miller KJ, Garland SJ, Ivanova T, et al. Motor-unit behavior in
humans during fatiguing arm movements. J Neurophysiol.
1996;75(4):1629–36.
59. Debold EP. Recent insights into the molecular basis of muscular
fatigue. Med Sci Sports Exerc. 2012;44(8):1440–52.
60. Moritani T, Sherman WM, Shibata M, et al. Oxygen availability
and motor unit activity in humans. Eur J Appl Physiol Occup
Physiol. 1992;64(6):552–6.
61. Sundberg CJ. Exercise and training during graded leg ischaemia
in healthy man with special reference to effects on skeletal
muscle. Acta Physiol Scand Suppl. 1994;615:1–50.
62. Yasuda T, Abe T, Sato Y, et al. Muscle fiber cross-sectional area
is increased after two weeks of twice daily KAATSU-resistance
training. Int J KAATSU Train Res. 2005;1(2):65–70.
63. Laurentino GC, Ugrinowitsch C, Roschel H, et al. Strength
training with blood flow restriction diminishes myostatin gene
expression. Med Sci Sports Exerc. 2012;44(3):406–12.
64. Manini TM, Clark BC. Blood flow restricted exercise and
skeletal muscle health. Exerc Sport Sci Rev. 2009;37(2):78–85.
65. Hansen S, Kvorning T, Kjaer M, et al. The effect of short-term
strength training on human skeletal muscle: the importance of
physiologically elevated hormone levels. Scand J Med Sci
Sports. 2001;11(6):347–54.
66. Crewther B, Keogh J, Cronin J, et al. Possible stimuli for
strength and power adaptation: acute hormonal responses. Sports
Med. 2006;36(3):215–38.
67. Kraemer WJ, Ratamess NA. Hormonal responses and adapta-
tions to resistance exercise and training. Sports Med. 2005;35(4):
339–61.
68. Haddad F, Adams GR. Inhibition of MAP/ERK kinase prevents
IGF-I-induced hypertrophy in rat muscles. J Appl Physiol.
2004;96(1):203–10.
69. Stewart CE, Pell JM. Point:Counterpoint: IGF is/is not the major
physiological regulator of muscle mass. Point: IGF is the major
physiological regulator of muscle mass. J Appl Physiol.
2010;108(6):1820,1; discussion 1823-4; author reply 1832.
70. Hameed M, Lange KH, Andersen JL, et al. The effect of
recombinant human growth hormone and resistance training on
IGF-I mRNA expression in the muscles of elderly men. J Phys-
iol. 2004;555(Pt 1):231–40.
71. Kostek MC, Delmonico MJ, Reichel JB, et al. Muscle strength
response to strength training is influenced by insulin-like growth
factor 1 genotype in older adults. J Appl Physiol. 2005;98(6):
2147–54.
72. Philippou A, Papageorgiou E, Bogdanis G, et al. Expression of
IGF-1 isoforms after exercise-induced muscle damage in
humans: characterization of the MGF E peptide actions in vitro.
In Vivo. 2009;23(4):567–75.
73. Goldspink G. Mechanical signals, IGF-I gene splicing, and
muscle adaptation. Physiology (Bethesda). 2005;20:232–8.
74. Velloso CP, Harridge SD. Insulin-like growth factor-I E pep-
tides: implications for aging skeletal muscle. Scand J Med Sci
Sports. 2010;20(1):20–7.
75. Velloso CP. Regulation of muscle mass by growth hormone and
IGF-I. Br J Pharmacol. 2008;154(3):557–68.
76. Timmons JA. Variability in training-induced skeletal muscle
adaptation. J Appl Physiol. 2011;110(3):846–53.
77. Petrella JK, Kim J, Mayhew DL, et al. Potent myofiber hyper-
trophy during resistance training in humans is associated with
satellite cell-mediated myonuclear addition: a cluster analysis.
J Appl Physiol. 2008;104(6):1736–42.
78. O’Connor RS, Pavlath GK. Point:counterpoint: satellite cell
addition is/is not obligatory for skeletal muscle hypertrophy.
J Appl Physiol. 2007;103(3):1099–100.
79. McCarthy JJ, Esser KA. Counterpoint: satellite cell addition is
not obligatory for skeletal muscle hypertrophy. J Appl Physiol.
2007;103:1100–2.
80. Owino V, Yang SY, Goldspink G. Age-related loss of skeletal
muscle function and the inability to express the autocrine form
of insulin-like growth factor-1 (MGF) in response to mechanical
overload. FEBS Lett. 2001;505(2):259–63.
81. Sandri M. Signaling in muscle atrophy and hypertrophy. Phys-
iology (Bethesda). 2008;23:160–70.
82. Barton ER. Viral expression of insulin-like growth factor-I
isoforms promotes different responses in skeletal muscle. J Appl
Physiol. 2006;100(6):1778–84.
83. Bamman MM, Petrella JK, Kim JS, et al. Cluster analysis tests
the importance of myogenic gene expression during myofiber
hypertrophy in humans. J Appl Physiol. 2007;102(6):2232–9.
84. Hill M, Wernig A, Goldspink G. Muscle satellite (stem) cell
activation during local tissue injury and repair. J Anat.
2003;203(1):89–99.
Role of Metabolic Stress in Hypertrophic Adaptations 191
Author's personal copy
85. Yang SY, Goldspink G. Different roles of the IGF-I ec peptide
(MGF) and mature IGF-I in myoblast proliferation and differ-
entiation. FEBS Lett. 2002;522(1–3):156–60.
86. Philippou A, Maridaki M, Halapas A, et al. The role of the
insulin-like growth factor 1 (IGF-1) in skeletal muscle physi-
ology. In Vivo. 2007;21(1):45–54.
87. Rubin MR, Kraemer WJ, Maresh CM, et al. High-affinity
growth hormone binding protein and acute heavy resistance
exercise. Med Sci Sports Exerc. 2005;37(3):395–403.
88. Kraemer WJ, Aguilera BA, Terada M, et al. Responses of IGF-I
to endogenous increases in growth hormone after heavy-resis-
tance exercise. J Appl Physiol. 1995;79(4):1310–5.
89. Abe T, Yasuda T, Midorikawa T, et al. Skeletal muscle size and
circulating IGF-1 are increased after two weeks of twice daily
KAATSU resistance training. Int J Kaatsu Train Res. 2005;1:
6–12.
90. Takano H, Morita T, Iida H, et al. Hemodynamic and hormonal
responses to a short-term low-intensity resistance exercise with
the reduction of muscle blood flow. Eur J Appl Physiol.
2005;95(1):65–73.
91. Fujita S, Abe T, Drummond MJ, et al. Blood flow restriction
during low-intensity resistance exercise increases S6K1 phos-
phorylation and muscle protein synthesis. J Appl Physiol.
2007;103(3):903–10.
92. Drummond MJ, Fujita S, Abe T, et al. Human muscle gene
expression following resistance exercise and blood flow
restriction. Med Sci Sports Exerc. 2008;40(4):691–8.
93. Buresh R, Berg K, French J. The effect of resistive exercise rest
interval on hormonal response, strength, and hypertrophy with
training. J Strength Cond Res. 2009;23(1):62–71.
94. Kadi F. Cellular and molecular mechanisms responsible for the
action of testosterone on human skeletal muscle: a basis for
illegal performance enhancement. Br J Pharmacol. 2008;154(3):
522–8.
95. Bhasin S, Woodhouse L, Storer TW. Proof of the effect of tes-
tosterone on skeletal muscle. J Endocrinol. 2001;170(1):27–38.
96. Zhao W, Pan J, Zhao Z, et al. Testosterone protects against
dexamethasone-induced muscle atrophy, protein degradation
and MAFbx upregulation. J Steroid Biochem Mol Biol.
2008;110(1–2):125–9.
97. Urban RJ, Bodenburg YH, Gilkison C, et al. Testosterone
administration to elderly men increases skeletal muscle strength
and protein synthesis. Am J Physiol. 1995;269(5 Pt 1):E820–6.
98. Vingren JL, Kraemer WJ, Ratamess NA, et al. Testosterone
physiology in resistance exercise and training: the up-stream
regulatory elements. Sports Med. 2010;40(12):1037–53.
99. Sculthorpe N, Solomon AM, Sinanan AC, et al. Androgens
affect myogenesis in vitro and increase local IGF-1 expression.
Med Sci Sports Exerc. 2012;44(4):610–5.
100. Sinha-Hikim I, Cornford M, Gaytan H, et al. Effects of testos-
terone supplementation on skeletal muscle fiber hypertrophy and
satellite cells in community-dwelling older men. J Clin Endo-
crinol Metab. 2006;91(8):3024–33.
101. Ahtiainen JP, Pakarinen A, Alen M, et al. Muscle hypertrophy,
hormonal adaptations and strength development during strength
training in strength-trained and untrained men. Eur J Appl
Physiol. 2003;89(6):555–63.
102. Tremblay MS, Copeland JL, Van Helder W. Effect of training
status and exercise mode on endogenous steroid hormones in
men. J Appl Physiol. 2004;96(2):531–9.
103. Kraemer WJ, Fry AC, Warren BJ, et al. Acute hormonal
responses in elite junior weightlifters. Int J Sports Med.
1992;13(2):103–9.
104. Loenneke JP, Wilson JM, Pujol TJ, et al. Acute and chronic
testosterone response to blood flow restricted exercise. Horm
Metab Res. 2011;43(10):669–73.
105. Gotshalk LA, Loebel CC, Nindl BC, et al. Hormonal responses
of multiset versus single-set heavy-resistance exercise protocols.
Can J Appl Physiol. 1997;22(3):244–55.
106. Hakkinen K, Pakarinen A. Acute hormonal responses to two
different fatiguing heavy-resistance protocols in male athletes.
J Appl Physiol. 1993;74(2):882–7.
107. Smilios I, Pilianidis T, Karamouzis M, et al. Hormonal
responses after various resistance exercise protocols. Med Sci
Sports Exerc. 2003;35(4):644–54.
108. McCaulley GO, McBride JM, Cormie P, et al. Acute hormonal
and neuromuscular responses to hypertrophy, strength and
power type resistance exercise. Eur J Appl Physiol. 2009;105(5):
695–704.
109. Reeves GV, Kraemer RR, Hollander DB, et al. Comparison of
hormone responses following light resistance exercise with
partial vascular occlusion and moderately difficult resistance
exercise without occlusion. J Appl Physiol. 2006;101(6):
1616–22.
110. Viru M, Jansson E, Viru A, et al. Effect of restricted blood flow
on exercise-induced hormone changes in healthy men. Eur J
Appl Physiol Occup Physiol. 1998;77(6):517–22.
111. Vierck J, O’Reilly B, Hossner K, et al. Satellite cell regulation
following myotrauma caused by resistance exercise. Cell Biol
Int. 2000;24(5):263–72.
112. Doessing S, Heinemeier KM, Holm L, et al. Growth hormone
stimulates the collagen synthesis in human tendon and skeletal
muscle without affecting myofibrillar protein synthesis. J Phys-
iol. 2010;588(Pt 2):341–51.
113. Sotiropoulos A, Ohanna M, Kedzia C, et al. Growth hormone
promotes skeletal muscle cell fusion independent of insulin-like
growth factor 1 up-regulation. Proc Natl Acad Sci USA.
2006;103(19):7315–20.
114. Aperghis M, Velloso CP, Hameed M, et al. Serum IGF-I levels
and IGF-I gene splicing in muscle of healthy young males
receiving rhGH. Growth Horm IGF Res. 2009;19(1):61–7.
115. Ehrnborg C, Rosen T. Physiological and pharmacological basis
for the ergogenic effects of growth hormone in elite sports.
Asian J Androl. 2008;10(3):373–83.
116. Kraemer WJ, Dunn-Lewis C, Comstock BA, et al. Growth
hormone, exercise, and athletic performance: a continued evo-
lution of complexity. Curr Sports Med Rep. 2010;9(4):242–52.
117. Phillips SM. Physiologic and molecular bases of muscle
hypertrophy and atrophy: impact of resistance exercise on
human skeletal muscle (protein and exercise dose effects). Appl
Physiol Nutr Metab. 2009;34(3):403–10.
118. West DW, Phillips SM. Anabolic processes in human skeletal
muscle: restoring the identities of growth hormone and testos-
terone. Phys Sportsmed. 2010;38(3):97–104.
119. Lange KH, Andersen JL, Beyer N, et al. GH administration
changes myosin heavy chain isoforms in skeletal muscle but
does not augment muscle strength or hypertrophy, either alone
or combined with resistance exercise training in healthy elderly
men. J Clin Endocrinol Metab. 2002;87(2):513–23.
120. Yarasheski KE, Campbell JA, Smith K, et al. Effect of growth
hormone and resistance exercise on muscle growth in young
men. Am J Physiol. 1992;262(3 Pt 1):E261–7.
121. Yarasheski KE, Zachwieja JJ, Campbell JA, et al. Effect of
growth hormone and resistance exercise on muscle growth and
strength in older men. Am J Physiol. 1995;268(2 Pt 1):E268–76.
122. Nindl BC, Hymer WC, Deaver DR, et al. Growth hormone
pulsatility profile characteristics following acute heavy resis-
tance exercise. J Appl Physiol. 2001;91(1):163–72.
123. West DW, Kujbida GW, Moore DR, et al. Resistance exercise-
induced increases in putative anabolic hormones do not enhance
muscle protein synthesis or intracellular signalling in young
men. J Physiol. 2009;587(Pt 21):5239–47.
192 B. J. Schoenfeld
Author's personal copy
124. Coffey VG, Shield A, Canny BJ, et al. Interaction of contractile
activity and training history on mRNA abundance in skeletal
muscle from trained athletes. Am J Physiol Endocrinol Metab.
2006;290(5):E849–55.
125. Madarame H, Neya M, Ochi E, et al. Cross-transfer effects of
resistance training with blood flow restriction. Med Sci Sports
Exerc. 2008;40(2):258–63.
126. West DW, Burd NA, Tang JE, et al. Elevations in ostensibly
anabolic hormones with resistance exercise enhance neither
training-induced muscle hypertrophy nor strength of the elbow
flexors. J Appl Physiol. 2010;108(1):60–7.
127. Ronnestad BR, Nygaard H, Raastad T. Physiological elevation
of endogenous hormones results in superior strength training
adaptation. Eur J Appl Physiol. 2011;111(9):2249–59.
128. Nielsen AR, Pedersen BK. The biological roles of exercise-
induced cytokines: IL-6, IL-8, and IL-15. Appl Physiol Nutr
Metab. 2007;32(5):833–9.
129. Quinn LS. Interleukin-15: a muscle-derived cytokine regulating
fat-to-lean body composition. J Anim Sci. 2008;86(14 Suppl.):
E75–83.
130. Serrano AL, Baeza-Raja B, Perdiguero E, et al. Interleukin-6 is
an essential regulator of satellite cell-mediated skeletal muscle
hypertrophy. Cell Metab. 2008;7(1):33–44.
131. Pedersen BK, Edward F. Adolph distinguished lecture: muscle
as an endocrine organ: IL-6 and other myokines. J Appl Physiol.
2009;107(4):1006–14.
132. Febbraio MA, Pedersen BK. Contraction-induced myokine
production and release: is skeletal muscle an endocrine organ?
Exerc Sport Sci Rev. 2005;33(3):114–9.
133. Fujita T, Brechue WF, Kurita K, et al. Increased muscle volume
and strength following six days of low-intensity resistance
training with restricted muscle blood flow. Int J Kaatsu Train
Res. 2008;4:1–8.
134. Abe T, Beekley MD, Hinata S, et al. Day-to-day change in
muscle strength and MRI-measured skeletal muscle size during
7 days KAATSU resistance training: a case study. Int J Kaatsu
Train Res. 2005;1:71–6.
135. Roth SM, Walsh S. Myostatin: a therapeutic target for skeletal
muscle wasting. Curr Opin Clin Nutr Metab Care. 2004;7(3):
259–63.
136. Kawada S, Ishii N. Skeletal muscle hypertrophy after chronic
restriction of venous blood flow in rats. Med Sci Sports Exerc.
2005;37(7):1144–50.
137. Manini TM, Vincent KR, Leeuwenburgh CL, et al. Myogenic
and proteolytic mRNA expression following blood flow
restricted exercise. Acta Physiol (Oxf). 2011;201(2):255–63.
138. Farooqui T. Iron-induced oxidative stress modulates olfactory
learning and memory in honeybees. Behav Neurosci. 2008;
122(2):433–47.
139. Alessio HM, Hagerman AE, Fulkerson BK, et al. Generation of
reactive oxygen species after exhaustive aerobic and isometric
exercise. Med Sci Sports Exerc. 2000;32(9):1576–81.
140. Powers SK, Talbert EE, Adhihetty PJ. Reactive oxygen and
nitrogen species as intracellular signals in skeletal muscle.
J Physiol. 2011;589(Pt 9):2129–38.
141. Jackson MJ. Reactive oxygen species and redox-regulation of
skeletal muscle adaptations to exercise. Philos Trans R Soc
Lond B Biol Sci. 2005;360(1464):2285–91.
142. Simpson PJ, Lucchesi BR. Free radicals and myocardial ische-
mia and reperfusion injury. J Lab Clin Med. 1987;110(1):13–30.
143. Fulle S, Protasi F, Di Tano G, et al. The contribution of reactive
oxygen species to sarcopenia and muscle ageing. Exp Gerontol.
2004;39(1):17–24.
144. Jackson MJ. Free radicals generated by contracting muscle:
by-products of metabolism or key regulators of muscle function?
Free Radic Biol Med. 2008;44(2):132–41.
145. Gomez-Cabrera MC, Domenech E, Vina J. Moderate exercise is
an antioxidant: upregulation of antioxidant genes by training.
Free Radic Biol Med. 2008;44(2):126–31.
146. Ji LL, Gomez-Cabrera MC, Vina J. Exercise and hormesis:
activation of cellular antioxidant signaling pathway. Ann N Y
Acad Sci. 2006;1067:425–35.
147. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell
signaling. Am J Physiol Lung Cell Mol Physiol. 2000;279(6):
L1005–28.
148. Suzuki YJ, Ford GD. Redox regulation of signal transduction in
cardiac and smooth muscle. J Mol Cell Cardiol. 1999;31(2):
345–53.
149. Hornberger TA, McLoughlin TJ, Leszczynski JK, et al. Sele-
noprotein-deficient transgenic mice exhibit enhanced exercise-
induced muscle growth. J Nutr. 2003;133(10):3091–7.
150. Kefaloyianni E, Gaitanaki C, Beis I. ERK1/2 and p38-MAPK
signalling pathways, through MSK1, are involved in NF-kappaB
transactivation during oxidative stress in skeletal myoblasts.
Cell Signal. 2006;18(12):2238–51.
151. Tappia PS, Dent MR, Dhalla NS. Oxidative stress and redox
regulation of phospholipase D in myocardial disease. Free Radic
Biol Med. 2006;41(3):349–61.
152. Handayaningsih A, Iguchi G, Fukuoka H, et al. Reactive oxygen
species play an essential role in IGF-I signaling and IGF-I-
induced myocyte hypertrophy in C2C12 myocytes. Endocri-
nology. 2011;152(3):912–21.
153. Korthuis RJ, Granger DN, Townsley MI, et al. The role of
oxygen-derived free radicals in ischemia-induced increases in
canine skeletal muscle vascularpermeability.Circ Res. 1985;57(4):
599–609.
154. Clanton TL. Hypoxia-induced reactive oxygen species forma-
tion in skeletal muscle. J Appl Physiol. 2007;102(6):2379–88.
155. Goldfarb AH, Garten RS, Chee PD, et al. Resistance exercise
effects on blood glutathione status and plasma protein carbon-
yls: influence of partial vascular occlusion. Eur J Appl Physiol.
2008;104(5):813–9.
156. Smith LW, Smith JD, Criswell DS. Involvement of nitric oxide
synthase in skeletal muscle adaptation to chronic overload.
J Appl Physiol. 2002;92(5):2005–11.
157. Sellman JE, DeRuisseau KC, Betters JL, et al. In vivo inhibition
of nitric oxide synthase impairs upregulation of contractile
protein mRNA in overloaded plantaris muscle. J Appl Physiol.
2006;100(1):258–65.
158. Anderson JE. A role for nitric oxide in muscle repair: nitric
oxide-mediated activation of muscle satellite cells. Mol Biol
Cell. 2000;11(5):1859–74.
159. Tatsumi R, Hattori A, Ikeuchi Y, et al. Release of hepatocyte
growth factor from mechanically stretched skeletal muscle
satellite cells and role of pH and nitric oxide. Mol Biol Cell.
2002;13(8):2909–18.
160. Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular
biology, biochemistry, and physiology. Pharmacol Ther. 1998;
80(2):183–201.
161. Simar D, Malatesta D, Badiou S, et al. Physical activity mod-
ulates heat shock protein-72 expression and limits oxidative
damage accumulation in a healthy elderly population aged 60
90 years. J Gerontol A Biol Sci Med Sci. 2007;62(12):1413–9.
162. Locke M. Heat shock protein accumulation and heat shock
transcription factor activation in rat skeletal muscle during
compensatory hypertrophy. Acta Physiol (Oxf). 2008;
192(3):403–11.
163. Kregel KC. Heat shock proteins: modifying factors in physio-
logical stress responses and acquired thermotolerance. J Appl
Physiol. 2002;92(5):2177–86.
164. Paulsen G, Hanssen KE, Ronnestad BR, et al. Strength training
elevates HSP27, HSP70 and alphaB-crystallin levels in musculi
Role of Metabolic Stress in Hypertrophic Adaptations 193
Author's personal copy
vastus lateralis and trapezius. Eur J Appl Physiol. 2012;
112(5):1773–82.
165. Morton JP, Kayani AC, McArdle A, et al. The exercise-induced
stress response of skeletal muscle, with specific emphasis on
humans. Sports Med. 2009;39(8):643–62.
166. Haussinger D, Lang F, Gerok W. Regulation of cell function by
the cellular hydration state. Am J Physiol. 1994;267(3 Pt
1):E343–55.
167. Haussinger D. The role of cellular hydration in the regulation of
cell function. Biochem J. 1996;313(Pt 3):697–710.
168. Lang F, Busch GL, Ritter M, et al. Functional significance of
cell volume regulatory mechanisms. Physiol Rev. 1998;78(1):
247–306.
169. Dangott B, Schultz E, Mozdziak PE. Dietary creatine monohy-
drate supplementation increases satellite cell mitotic activity
during compensatory hypertrophy. Int J Sports Med. 2000;21(1):
13–6.
170. Lang F. Mechanisms and significance of cell volume regulation.
J Am Coll Nutr. 2007;26(5 Suppl.):613S–23S.
171. Low SY, Rennie MJ, Taylor PM. Signaling elements involved in
amino acid transport responses to altered muscle cell volume.
FASEB J. 1997;11(13):1111–7.
172. Clarke MS, Feeback DL. Mechanical load induces sarcoplasmic
wounding and FGF release in differentiated human skeletal
muscle cultures. FASEB J. 1996;10(4):502–9.
173. Lambert IH, Hoffmann EK, Pedersen SF. Cell volume regula-
tion: physiology and pathophysiology. Acta Physiol (Oxf).
2008;194(4):255–82.
174. Schliess F, Richter L, vom Dahl S, et al. Cell hydration and
mTOR-dependent signalling. Acta Physiol (Oxf). 2006;187(1–2):
223–9.
175. Finkenzeller G, Newsome W, Lang F, et al. Increase of c-jun
mRNA upon hypo-osmotic cell swelling of rat hepatoma cells.
FEBS Lett. 1994;340(3):163–6.
176. Schliess F, Schreiber R, Haussinger D. Activation of extracel-
lular signal-regulated kinases erk-1 and erk-2 by cell swelling in
H4IIE hepatoma cells. Biochem J. 1995;309(Pt 1):13–7.
177. Sjogaard G. Water and electrolyte fluxes during exercise and
their relation to muscle fatigue. Acta Physiol Scand Suppl.
1986;556:129–36.
178. Sjogaard G, Adams RP, Saltin B. Water and ion shifts in skeletal
muscle of humans with intense dynamic knee extension. Am J
Physiol. 1985;248(2 Pt 2):R190–6.
179. Frigeri A, Nicchia GP, Verbavatz JM, et al. Expression of
aquaporin-4 in fast-twitch fibers of mammalian skeletal muscle.
J Clin Invest. 1998;102(4):695–703.
180. Kosek DJ, Kim JS, Petrella JK, et al. Efficacy of 3 days/wk
resistance training on myofiber hypertrophy and myogenic
mechanisms in young vs. older adults. J Appl Physiol.
2006;101(2):531–44.
181. Gundermann DM, Fry CS, Dickinson JM, et al. Reactive
hyperemia is not responsible for stimulating muscle protein
synthesis following blood flow restriction exercise. J Appl
Physiol. 2012.
182. MacDougall JD, Ward GR, Sale DG, et al. Biochemical adap-
tation of human skeletal muscle to heavy resistance training and
immobilization. J Appl Physiol. 1977;43(4):700–3.
183. Chan ST, Johnson AW, Moore MH, et al. Early weight gain and
glycogen-obligated water during nutritional rehabilitation. Hum
Nutr Clin Nutr. 1982;36(3):223–32.
184. Widegren U, Ryder JW, Zierath JR. Mitogen-activated protein
kinase signal transduction in skeletal muscle: effects of exercise
and muscle contraction. Acta Physiol Scand. 2001;172(3):
227–38.
185. Tanimoto M, Sanada K, Yamamoto K, et al. Effects of whole-
body low-intensity resistance training with slow movement and
tonic force generation on muscular size and strength in young
men. J Strength Cond Res. 2008;22(6):1926–38.
186. Mitchell CJ, Churchward-Venne TA, West DD, et al. Resistance
exercise load does not determine training-mediated hypertrophic
gains in young men. J Appl Physiol. 2012.
187. Holm L, Reitelseder S, Pedersen TG, et al. Changes in muscle
size and MHC composition in response to resistance exercise
with heavy and light loading intensity. J Appl Physiol. 2008;
105(5):1454–61.
188. Schoenfeld BJ. Does exercise-induced muscle damage play a
role in skeletal muscle hypertrophy? J Strength Cond Res.
2012;26(5):1441–53.
194 B. J. Schoenfeld
Author's personal copy
... The correct choice of the acute variables is another important component of a resistance training (RT) session (19,20). The combination of intensity and volume is fundamental to determine the dose-response in a RT session (19) and can induce specific metabolic and mechanical stress in the muscle (24,25). Schoenfeld et al., (26) described the duration as the total of the concentric, eccentric, and isometric components of repetition; and is predicated on the tempo at which the repetition is performed. ...
... To the best of the author's knowledge, no study was conducted to measure the acute effects of different durations during the IFPE with the bodyweight in recreationally-trained participants. Different physical conditions have been shown to induce acute cell swelling, the extent of which relies on the type of exercise, level of fatigue, volume, and intensity (24). RT exercises with momentary muscle failure reduce the intramuscular ATP and CP levels (and Pi, ADP, and AMP accumulation), a high glycolytic flux (production of H+ leads to metabolite accumulation), hypoxia (via muscle contraction), and venous pooling leading to cellular swelling (5,25,28,31). ...
... However, in this study, the increase in MT was partially observed as hypothesized. It is well-known that the duration of the exercise can produce higher metabolic and mechanical stress and consequently, might affect cell swelling (24,25). However, it is assumed that trained participants could be more efficient in removing the by-products from the metabolism with less effect on MT. ...
Article
Full-text available
International Journal of Exercise Science 15(6): 676-685, 2022. The primary purpose of this study was to evaluate the acute effects of different durations of the isometric forearm plank exercise (IFPE) on peak force, echo intensity, muscle thickness, and perception of effort in recreationally-trained participants. Fifteen resistance-trained participants (23±3years, 76.4±6.5kg, 173.3±6.5cm) performed the IFPE with bodyweight in one of three durations in a randomized order: a). 1-min, b). 2-min, and c). 3-min. Muscle thickness (MT), echo intensity (EI), peak force (PF), and rating of perceived exertion (RPE) were measured pre-test and post-test. Two-way repeated-measures ANOVAs (2x3) were used to test differences between tests (pre-test and post-test) and treatment (1-min, 2-min, and 3-min) for PF, MT, and EI. One-way ANOVA was used to compare RPE between treatments (1-min, 2-min, and 3-min). There was a significant increase between pre-and post-test only for 3-min IFPE (p=0.008). For EI, there was a significant increase between pre-and post-test only for 3-min IFPE (p<0.001). For PF, there were observed significant reductions on post-test between 1-min vs. 3-min (p<0.001) and 2-min vs. 3-min IFPE (p<0.001). For RPE, there were statistical differences between 1-min vs. 2-min (p<0.001), 1-min and 3-min (p<0.001), 2-min and 3-min (p=0.001). In conclusion, only 3-min IFPE induced an increase in MT and EI and a reduction in PF when compared to 1-min and 2-min (during the post-test). RPE increased with the increase in the duration of the IFPE.
... Apesar da importância desse achado no fluxo sanguíneo, o estudo, mencionado anteriormente, não observou impacto na hipóxia. A literatura tem mostrado que o desvio intracelular do plasma sanguíneo e a hipóxia celular gerados pela restrição de fluxo influenciam significativamente os mecanismos associados ao aumento da força muscular e hipertrofia [18]. ...
... O diferencial do presente estudo foi, além de observar o comportamento da hemoglobina total (indiretamente), ter acompanhado o impacto na hipóxia celular. Identificar o comportamento não linear na hipóxia celular é importante porque parece ser uma condição de estímulo para os mecanismos de hipertrofia muscular [18]. ...
Article
Full-text available
RESUMO Introdução: O exercício contrarresistência com restrição do fluxo sanguíneo (RFS) é um método eficaz para ganho de força e hipertrofia muscular. No entanto, pouco se sabe sobre os efeitos dos diferentes níveis de RFS nas respostas hemodinâmicas. Objetivo: Verificar se as diferentes pressões de restrição ao fluxo sanguíneo aplicadas no membro superior causam alterações na microcirculação vascular em adul-tos jovens saudáveis do sexo masculino. Métodos: Dez jovens do sexo masculino visitaram o laboratório em quatro ocasiões. Na primeira visita, após 10 min de repouso em decúbito dorsal, a pressão de oclusão da artéria braquial (POA) foi identificada através de ultrassom com Doppler. Posteriormente, os parti-cipantes foram submetidos a um protocolo que consistia de 1 min para as medidas basais, 2 min de RFS e 2 min após a liberação da restrição sanguínea. Foi utilizado um manguito colocado na porção proxi-mal do antebraço e inflado com pressões equivalentes a 30% (30RFS), 50% (50RFS) 80% (80RFS) ou 100% (100RFS) do POA em ordem aleatória em dias separados. As medições do índice de saturação do tecido (IST), oxiemoglobina, desoxihemoglobina e hemoglobina total foram coletadas continuamente usando espectrometria de infravermelho próximo. Resultados: Uma ANOVA de duas vias com medidas repetidas demonstrou 1) uma diminuição significativa no IST em todas as condições, com maior queda em 100RFS; 2) um aumento significativo na oxihemoglobina em todas as condições, exceto 100RFS; 3) um aumento semelhante na desoxihemoglobina em todas as condições; 4) um aumento significativo na hemoglobina total em todas as condições, principalmente em 30RFS e 50RFS. Conclusão: As pressões relativas adotadas demonstraram que as alterações hemodinâmicas não ocorrem linearmente com o nível de pressão impos-to pelo manguito insuflado. Palavras-chave: espectroscopia de luz próxima ao infravermelho; dispositivos de oclusão vascular; treinamento de força. ABSTRACT Introduction: Resistance exercise with blood flow restriction (BFR) is an effective method to promote muscle strength gains and hypertrophy. However, little is known about the effects of different BFR levels on hemodynamic responses. Objective: To verify whether the different blood flow restriction pressures applied to the upper limb cause acute changes in vascular microcirculation in young, healthy male adults. Methods: Ten young male visited the laboratory on four occasions. In the first visit, after 10-min rest in supine position, the brachial artery occlusion pressure (AOP) was identified with a Doppler ultrasound. Thereafter, the participants were submitted to a protocol consisting of 1 min for baseline measurements, 2 min of BFR, and 2 min after cuff deflation. It was used a cuff placed on the proximal portion of the forearm and inflated with pressures equivalents to 30% (30BFR), 50% (50BFR) 80% (80BFR), or 100% (100BFR) of the AOP in a random order in separate days. Measurements of tissue saturation index (TSI), oxyhemoglobin, deoxyhemoglobin, and total hemoglobin were collected continuously using near-infrared spectrometry. Results: A two-way ANOVA with repeated measures demonstrated: 1) a significant decrease in TSI in all conditions, with higher decay in 100BFR; 2) a significant increase in oxyhemoglobin in all conditions, but 100BFR; 3) a similar increase in deoxyhemoglobin in all conditions; 4) a significant increase in total hemoglobin in all conditions, mainly in both 30BFR and 50BFR. Conclusion: The relative pressures adopted demonstrated that the hemodynamic changes do not occur linearly with the pressure level imposed by the inflated cuff.
... Fatiguing bouts of resistance exercise are associated with increased metabolite accumulation, 14 endogenous hormone secretion, 15,16 and higher mechanical tension, 17 which may contribute to muscle hypertrophy. 18,19 Likewise, it has recently been shown that high VL thresholds using the squat exercise resulted in an increased basal Ca 2+ /calmodulin II-dependent protein kinase δ D phosphorylation (Thr 286 -CaMKII δ D ), which was associated with muscle hypertrophy and the number of repetitions completed during the training intervention. 20 Therefore, large training volumes and/or Abbreviations: ES, effect size from pretraining to posttraining; MIF, maximal isometric force; PM-RMS, maximal root mean squared value registered during the maximal voluntary isometric contraction for the pectoralis major muscle; TB-RMS, maximal root mean squared value registered during the maximal voluntary isometric contraction for the triceps brachii muscle; RFD, rate of force development; RFD max , maximal RFD; ...
Article
Purpose: To compare the effect of 4 velocity-loss (VL) thresholds-0% (VL0), 15% (VL15), 25% (VL25), and 50% (VL50)-on strength gains, neuromuscular adaptations, and muscle hypertrophy during the bench press (BP) exercise using intensities ranging from 55% to 70% of 1-repetition maximum (1RM). Methods: Fifty resistance-trained men were randomly assigned to 4 groups that followed an 8-week (16 sessions) BP training program at 55% to 70% 1RM but differed in the VL allowed in each set (VL0, VL15, VL25, and VL50). Assessments performed before (pre) and after (post) the training program included (1) cross-sectional area of pectoralis major muscle, (2) maximal isometric test, (3) progressive loading test, and (4) fatigue test in the BP exercise. Results: A significant group × time interaction was found for 1RM (P = .01), where all groups except VL0 showed significant gains in 1RM strength (P < .001). The VL25 group attained the greatest gains in 1RM strength and most load-velocity relationship parameters analyzed. A significant group × time interaction was observed for EMG root mean square in pectoralis major (P = .03) where only the VL25 group showed significant increases (P = .02). VL50 showed decreased EMG root mean square in triceps brachii (P = .006). Only the VL50 group showed significant increases in cross-sectional area (P < .001). Conclusions: These findings indicate that a VL threshold of about 25% with intensities from 55% to 70% 1RM in BP provides an optimal training stimulus to maximize dynamic strength performance and neuromuscular adaptations, while higher VL thresholds promote higher muscle hypertrophy.
... Fatiguing bouts of resistance exercise are associated with increased metabolite accumulation, 14 endogenous hormone secretion, 15,16 and higher mechanical tension, 17 which may contribute to muscle hypertrophy. 18,19 Likewise, it has recently been shown that high VL thresholds using the squat exercise resulted in an increased basal Ca 2+ /calmodulin II-dependent protein kinase δ D phosphorylation (Thr 286 -CaMKII δ D ), which was associated with muscle hypertrophy and the number of repetitions completed during the training intervention. 20 Therefore, large training volumes and/or Abbreviations: ES, effect size from pretraining to posttraining; MIF, maximal isometric force; PM-RMS, maximal root mean squared value registered during the maximal voluntary isometric contraction for the pectoralis major muscle; TB-RMS, maximal root mean squared value registered during the maximal voluntary isometric contraction for the triceps brachii muscle; RFD, rate of force development; RFD max , maximal RFD; ...
Purpose: To compare the effect of 4 velocity loss (VL) thresholds—0%, 15%, 25% (VL25), and 50% (VL50)—on strength gains, neuromuscular adaptations, and muscle hypertrophy during the bench press (BP) exercise using intensities ranging from 55% to 70%, 1-repetition maximum (1RM). Methods: Fifty resistance-trained men were randomly assigned to 4 groups that followed an 8-week (16 sessions) BP training program at 55% to 70% 1RM but differed in the VL allowed in each set (VL 0%, VL 15%, VL25, and VL50). Assessments performed before (pre) and after (post) the training program included: (1) crosssectional area of pectoralis major muscle; (2) maximal isometric test; (3) progressive loading test; and (4) fatigue test, in the BP exercise. Results: A significant group × time interaction was found for 1RM (P = .01), where all groups except VL 0% showed significant gains in 1RM strength (P < .001). The VL25 group attained the greatest gains in 1RM strength and most load–velocity relationship parameters analyzed. A significant group × time interaction was observed for EMG root mean square in pectoralis major (P = .03) where only the VL25 group showed significant increases (P = .02). VL50 showed decreased EMG root mean square in triceps brachii (P = .006). Only the VL50 group showed significant increases in cross-sectional area (P < .001). Conclusions: These findings indicate that a VL threshold of about 25% with intensities from 55% to 70% 1RM in BP provides an optimal training stimulus to maximize dynamic strength performance and neuromuscular adaptations, while higher VL thresholds promote higher muscle hypertrophy.
... Metabolic stress has been reported to be as equally critical as mechanical tension for the induction of muscle growth [61][62][63][64]. To test this hypothesis, Goto and colleagues [65] compared 2 different rest periods, using volume-or intensity-matched resistance exercise, with one protocol having 30 sec rest between sets to minimize metabolite accumulation, while the other protocol did not have rest periods. ...
Article
Background: Aging leads to a number of structural and physiological deficits such as loss of muscle mass and strength. Strength training at ~ 70% of 1 repetition max (RM) is recommended to prevent age-related loss of muscle mass and strength. However, most older adults may not be able to perform 70% of 1RM or higher intensity. An alternative exercise training program combining low intensity resistance exercise with blood flow restriction (BFR) can result in similar acute and chronic benefits to skeletal muscles in older adults. Main body and short conclusion: The potential mechanisms involved are discussed, and include reactive hyperaemia, metabolic stress, and hypoxia. Key issues and safety with the use of BFR in older adults, especially those with chronic conditions are also discussed. Although there has been no reported evidence to suggest that BFR elevates the risk of clinical complications any more than high intensity exercise, it is recommended for individuals to be medically cleared of any cardiovascular risks, prior to engaging in BFR exercise.
... Compared to fullbody routines, the adoption of a SPLIT routine is usually justified by the fact that it may reduce the overall sets of a training session while increasing the number of sets per muscle group and also requiring a reduced time to be performed and a longer recovery period between sessions [3]. Moreover, higher training volumes within the same session would also elicit an increased intramuscular metabolic stress, which may enhance the hypertrophic response to the RT session [4]. ...
Article
Full-text available
The purpose of this study was to investigate the chronic effects of training each muscle group through a split-body routine on 2 versus 3 days per week on muscle strength and morphological adaptations in recreationally resistance-trained men with the number of sets per muscle group equated between conditions. Twenty healthy men (28.8 ± 6.1 years [range 19 to 37 years]; 172.8 ± 5.1 cm; total body mass = 70.2 ± 7.4 kg; RT experience = 3.5 ± 0.8 years [range 2 to 5 years]; RT frequency = 4.4 ± 0.5 session·wk-1) volunteered to participate in this study. Subjects were randomly assigned into 2 experimental groups: 2 sessions·wk-1 per muscle (G2x, n = 10), in which every muscle was trained twice a week with 9 sets/session, or 3 sessions·wk-1 per muscle (G3x, n = 10), in which every muscle was trained thrice a week with 6 sets/session. All other variables were held constant over the 8-week study period (training intensity: 8-12 maximum repetitions; rest intervals: 60 seconds between sets). No significant difference between conditions was observed for maximal strength in the back squat (G2x: ∆ = 51.5%; G3x: ∆ = 56.3%, p = 0.337) and bench press (G2x: ∆ = 15.4%; G3x: ∆ = 20.5%, p = 0.756), muscle thickness of the biceps brachii (G2x: ∆ = 6.9%; G3x: ∆ = 8.9%, p = 0.495), triceps brachii (G2x: ∆ = 8.4%; G3x: ∆ = 15.7%, p = 0.186), vastus lateralis (G2x: ∆ = 11.2%; G3x: ∆ = 5.0%, p = 0.082 and anterior quadriceps (rectus femoris and vastus intermedius) (G2x: ∆ = 12.1%; G3x: ∆ = 21.0%, p = 0.102). In conclusion, both G2x and G3x can result in significant increases in muscle strength and size in recreationally trained men.
Article
Background Muscle atrophy is common after an injury to the knee and anterior cruciate ligament reconstruction (ACLR). Blood flow restriction therapy (BFR) combined with low-load resistance exercise may help mitigate muscle loss and improve the overall condition of the lower extremity (LE). Purpose To determine whether BFR decreases the loss of LE lean mass (LM), bone mass, and bone mineral density (BMD) while improving function compared with standard rehabilitation after ACLR. Study Design Randomized controlled clinical trial Methods A total of 32 patients undergoing ACLR with bone-patellar tendon-bone autograft were randomized into 2 groups (CONTROL: N = 15 [male = 7, female = 8; age = 24.1 ± 7.2 years; body mass index [BMI] = 26.9 ± 5.3 kg/m2] and BFR: N = 17 [male = 12, female = 5; age = 28.1 ± 7.4 years; BMI = 25.2 ± 2.8 kg/m2]) and performed 12 weeks of postsurgery rehabilitation with an average follow-up of 2.3 ± 1.0 years. Both groups performed the same rehabilitation protocol. During select exercises, the BFR group exercised under 80% arterial occlusion of the postoperative limb (Delfi tourniquet system). BMD, bone mass, and LM were measured using DEXA (iDXA, GE) at presurgery, week 6, and week 12 of rehabilitation. Functional measures were recorded at week 8 and week 12. Return to sport (RTS) was defined as the timepoint at which ACLR-specific objective functional testing was passed at physical therapy. A group-by-time analysis of covariance followed by a Tukey’s post hoc test were used to detect within- and between-group changes. Type I error; α = 0.05. Results Compared with presurgery, only the CONTROL group experienced decreases in LE-LM at week 6 (−0.61 ± 0.19 kg, −6.64 ± 1.86%; P < 0.01) and week 12 (−0.39 ± 0.15 kg, −4.67 ± 1.58%; P = 0.01) of rehabilitation. LE bone mass was decreased only in the CONTROL group at week 6 (−12.87 ± 3.02 g, −2.11 ± 0.47%; P < 0.01) and week 12 (−16.95 ± 4.32 g,−2.58 ± 0.64%; P < 0.01). Overall, loss of site-specific BMD was greater in the CONTROL group ( P < 0.05). Only the CONTROL group experienced reductions in proximal tibia (−8.00 ± 1.10%; P < 0.01) and proximal fibula (−15.0±2.50%, P < 0.01) at week 12 compared with presurgery measures. There were no complications. Functional measures were similar between groups. RTS time was reduced in the BFR group (6.4 ± 0.3 months) compared with the CONTROL group (8.3 ± 0.5 months; P = 0.01). Conclusion After ACLR, BFR may decrease muscle and bone loss for up to 12 weeks postoperatively and may improve time to RTS with functional outcomes comparable with those of standard rehabilitation.
Article
Full-text available
Purpose To evaluate the efficacy of an automated pneumatic torniquet pump and its ability to automatically calculate the limb occlusion pressure (LOP), as compared with the manual Doppler ultrasound technique. Methods Participants presenting to a Sports Medicine clinic were evaluated for study enrollment. Participants were fitted with a pneumatic tourniquet for the upper and lower extremity. LOP measurements were taken with a Doppler ultrasound or automated SmartCuffs PRO device in a randomized order. Results Final analysis was performed on 96 limbs (48 upper extremities and 48 lower extremities). The study population had a mean age 37.1 ± 14.7 years old and a mean body mass index of 25.47 ± 3.80. The mean measured LOP pressure on the upper extremity with Doppler ultrasound was 174.0 ± 48.7 mm Hg with a range from 120 to 282 mm Hg, whereas the mean measured LOP by the automated pump was 184.0 ± 44.9 mm Hg with a range from 135 to 266 mm Hg. There was no statistically significant difference found between the Doppler LOP and the Smart Cuff upper extremity LOP (P = .29). When evaluating LOP pressure on the lower extremity the mean LOP found with the Doppler ultrasound was 195.0 ± 31.9 mm Hg with a range from 160 to 272 mm Hg, whereas the automated pump the mean LOP was 205.0 ± 27.1 mm Hg with a range from 168 to 278 mm Hg. There was no statistically significant difference found between the Doppler LOP and the automated pump lower extremity LOP (P = .09). Conclusions No difference in the personalized LOP measurement was found when comparing an automated pump with the current gold standard of manual Doppler ultrasound. No patients companied of pain or discomfort during the LOP measurement. Level of Evidence Level II, diagnostic: prospective cohort study.
Article
Full-text available
Background Metabolic stress is considered a key factor in the activation of hypertrophy mechanisms which seems to be potentiated under hypoxic conditions.This study aimed to analyze the combined effect of the type of acute hypoxia (terrestrial vs simulated) and of the inter-set rest configuration (60 vs 120 s) during a hypertrophic resistance training (R T ) session on physiological, perceptual and muscle performance markers. Methods Sixteen active men were randomized into two groups based on the type of hypoxia (hypobaric hypoxia, HH: 2,320 m asl; vs normobaric hypoxia, NH: FiO 2 of 15.9%). Each participant completed in a randomly counterbalanced order the same R T session in four separated occasions: two under normoxia and two under the corresponding hypoxia condition at each prescribed inter-set rest period. Volume-load (load × set × repetition) was calculated for each training session. Muscle oxygenation (SmO 2 ) of the vastus lateralis was quantified during the back squat exercise. Heart rate (HR) was monitored during training and over the ensuing 30-min post-exercise period. Maximal blood lactate concentration (maxLac) and rating of perceived exertion (RPE) were determined after the exercise and at the end of the recovery period. Results Volume-load achieved was similar in all environmental conditions and inter-set rest period length did not appreciably affect it. Shorter inter-set rest periods displayed moderate increases in maxLac, HR and RPE responses in all conditions. Compared to HH, NH showed a moderate reduction in the inter-set rest-HR (ES > 0.80), maxLac (ES > 1.01) and SmO 2 (ES > 0.79) at both rest intervals. Conclusions Results suggest that the reduction in inter-set rest intervals from 120 s to 60 s provide a more potent perceptual, cardiovascular and metabolic stimulus in all environmental conditions, which could maximize hypertrophic adaptations in longer periods of training. The abrupt exposure to a reduced FiO 2 at NH seems to reduce the inter-set recovery capacity during a traditional hypertrophy R T session, at least during a single acute exposition. These results cannot be extrapolated to longer training periods.
Article
Full-text available
This study aimed to evaluate the local temperature, lactate, and blood glucose in three strength training methods. The study included 12 male subjects; (22.15 ± 5.77 years, 76.85 ± 9.15 kg, 1.72 ± 0.09 m), with minimum of 12 months of strength training experience, and all participated in the three training methods: the occlusion training (Kaatsu); the tension training (Tension); and the traditional training (Traditional). The Kaatsu training consisted in 3 sets of 10RM with occlusion device in both arms inflated to a 130% occlusion pressure. In addition, the tension method was performed with 30% of 1RM and the traditional training, consisted in 10 repetitions with 80% RM. Regarding the temperature variation, differences were observed between the Kaatsu and Traditional methods in relation to Tension (p = .049, η 2 p = 0.187). While for blood glucose (p = .351, η 2 p = 0.075) and lactate (p = .722, η 2 p = 0.022) there were no differences between the methods. Regarding the temperature (°C) measured by thermography and asymmetry, the right side showed a decrease in the post-test, in relation to the pre-test, in all methods (p < .05, η 2 p > 0.150). The left (p = .035, η 2 p = 0.301) and right (p = .012, η 2 p = 0.324) sides showed a decrease in temperature, in the post-test in relation to the pre-test, in the Kaatsu and traditional method. In asymmetry, the three methods showed an increase in the post-test in relation to the pre-test (p = .042, η 2 p = 0.158). In conclusion, tension method seems to stimulate greater heat production than the other methods. This information can help coaches to choose among these training methods according to the desired physiological response.
Article
Full-text available
The endocrine system plays an important role in strength and power development by mediating the remodelling of muscle protein. Resistance training scheme design regulates muscle protein turnover by modifying the anabolic (testosterone, growth hormone) and catabolic (cortisol) responses to a workout. Although resistance exercise increases the concentrations of insulin-like growth factor 1 in blood following exercise, the effect of scheme design is less clear, most likely due to the different release mechanisms of this growth factor (liver vs muscle). Insulin is non-responsive to the exercise stimulus, but in the presence of appropriate nutritional intake, elevated blood insulin levels combined with resistance exercise promotes protein anabolism. Factors such as sex, age, training status and nutrition also impact upon the acute hormonal environment and, hence, the adaptive response to resistance training. However, gaps within research, as well as inconsistent findings, limit our understanding of the endocrine contribution to adaptation. Research interpretation is also difficult due to problems with experimental design (e.g. sampling errors) and various other issues (e.g. hormone rhythms, biological fluid examined). In addition to the hormonal responses to resistance exercise, the contribution of other acute training factors, particularly those relating to the mechanical stimulus (e.g. forces, work, time under tension) must also be appreciated. Enhancing our understanding in these areas would also improve the prescription of resistance training for stimulating strength and power adaptation.
Article
In this study, the difference between the effects of "power-up type" and "bulk-up type" strength training exercise was investigated by analyzing parameters such as structural and functional adaptations in the neuromuscular system. Eleven subjects were divided into power-up and bulk-up groups. The power-up group comprised five male subjects who performed 5 sets at 90% of one repetition maximum (1 RM) with a 3-min rest between sets (repetition method). The bulk-up group comprised six male subjects who performed 9 sets at 80-60-50%, 70-50-40%, and 60-50-40% of 1 RM with rest intervals between sets of either 30 s or 3 min (interval method). Both groups performed isotonic knee extension exercise twice a week for 8 weeks. The power-up group showed a lower rate of improvement than the bulk-up group in terms of cross-sectional area (CSA) of the quadriceps femoris at levels 30% , 50% and 70% from the top of the femur, and also in average isokinetic strength (Isok. ave.; 180 deg/s, 50 consecutive repetitions). However, the power-up group showed a greater rate of improvement in 1 RM, maximal isometric strength (Isom. max), and maximal isokinetic strength (Isok. max ; 60, 180, 300 deg/s). Furthermore, the rate of reduction in strength over 50 consecutive isokinetic repetitions decreased in the bulk-up group. On the other hand, the power-up group showed no significant changes in the above throughout the entire training program. These results indicate that the characteristics of the two types of training exercise are as follows:(1) power-up exercise is effective mainly for improving muscular strength and anaerobic power, and (2) bulk-up exercise is effective mainly for improving hypertrophy and anaerobic endurance. These findings support the idea that "power-up type" and "bulk-up type" strength training exercises should be applied appropriately according to the training aim.
Article
In spite of the widespread abuse of androgenic steroids by athletes and recreational body-builders, the effects of these agents on athletic performance and physical function remain poorly understood. Experimentally induced androgen deficiency is associated with a loss of fat-free mass; conversely, physiologic testosterone replacement of healthy, androgen-deficient men increases fat-free mass and muscle protein synthesis. Testosterone supplementation of HIV-infected men with low testosterone levels and of older men with normally low testosterone concentrations also increases muscle mass. However, we do not know whether physiologic testosterone replacement can improve physical function and health-related quality of life, and reduce the risk of falls and disability in older men or those with chronic illness. Testosterone increases maximal voluntary strength in a dose-dependent manner and thus might improve performance in power-lifting events. However, testosterone has not been shown to improve performance in endurance events. The mechanisms by which testosterone increases muscle mass are not known, but probably involve alterations in the expression of multiple muscle growth regulators.
Article
The purpose of this study was to examine the daily skeletal muscle hypertrophic and strength responses to one week of twice daily KAATSU training, and follow indicators of muscle damage and inflammation on a day-to-day basis, for one subject. KAATSU training resulted in a 3.1% increase in muscle-bone CSA after 7 days of training. Both MRI-measured maximum quadriceps muscle cross-sectional area (Q-CSA max) and muscle volume can be seen increasing after the first day of KAATSU training, and continuously increasing for the rest of the training period. Following 7 days KAATSU resistance training, the increases in Q-CSA max and muscle volume were 3.5% and 4.8%, respectively. Relative strength (isometric knee extension strength per unit Q-CSA max) was increased after training (before, 3.60 Nm/cm2; after, 4.09 Nm/cm2). There were very modest increases in CK and myoglobin after a single bout of KAATSU exercise in the first day of the training, but the values were return towards normal at 2 days after the training. IL-6 remained unchanged throughout the training period. In conclusion, our subject gained absolute strength and increased muscle size after only one week of low intensity KAATSU resistance training. Indicators of muscle damage and inflammation were not elevated by this training. KAATSU training appears to be a safe and effective method to rapidly induce skeletal muscle strength and hypertrophy.
Article
Biopsies (biceps) were examined in 8 bodybuilders across a typical arm-curl training session (80% 1-RM). [PCr] and [glycogen] decreased 62 and 12% after 1 set (n = 4), and 50 and 24% after 3 sets (n = 4). [Lactate] was 91 and 118 mmol &times kg-1, respectively, after 1 and 3 sets. Fatigue was probably partially caused by decreased [PCr] and increased [H+] (first set) and by decreased [H+] in subsequent sets.