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Sports Medicine
ISSN 0112-1642
Sports Med
DOI 10.1007/s40279-014-0162-1
Interference between Concurrent Resistance
and Endurance Exercise: Molecular Bases
and the Role of Individual Training
Variables
Jackson J.Fyfe, David J.Bishop & Nigel
K.Stepto
1 23
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REVIEW ARTICLE
Interference between Concurrent Resistance and Endurance
Exercise: Molecular Bases and the Role of Individual Training
Variables
Jackson J. Fyfe •David J. Bishop •Nigel K. Stepto
ÓSpringer International Publishing Switzerland 2014
Abstract Concurrent training is defined as simulta-
neously incorporating both resistance and endurance exer-
cise within a periodized training regime. Despite the
potential additive benefits of combining these divergent
exercise modes with regards to disease prevention and
athletic performance, current evidence suggests that this
approach may attenuate gains in muscle mass, strength, and
power compared with undertaking resistance training alone.
This has been variously described as the interference effect
or concurrent training effect. In recent years, understanding
of the molecular mechanisms mediating training adaptation
in skeletal muscle has emerged and provided potential
mechanistic insight into the concurrent training effect.
Although it appears that various molecular signaling
responses induced in skeletal muscle by endurance exercise
can inhibit pathways regulating protein synthesis and
stimulate protein breakdown, human studies to date have
not observed such molecular ‘interference’ following acute
concurrent exercise that might explain compromised mus-
cle hypertrophy following concurrent training. However,
given the multitude of potential concurrent training vari-
ables and the limitations of existing evidence, the potential
roles of individual training variables in acute and chronic
interference are not fully elucidated. The present review
explores current evidence for the molecular basis of the
specificity of training adaptation and the concurrent
interference phenomenon. Additionally, insights provided
by molecular and performance-based concurrent training
studies regarding the role of individual training variables
(i.e., within-session exercise order, between-mode recov-
ery, endurance training volume, intensity, and modality) in
the concurrent interference effect are discussed, along with
the limitations of our current understanding of this complex
paradigm.
1 Introduction
Skeletal muscle is a highly malleable tissue capable of
significant metabolic and morphological adaptations in
response to disruptions in cellular homeostasis induced by
exercise [1,2]. Resistance and endurance training represent
divergent exercise modes, with each inducing distinct
responses within the muscle milieu that act to minimize
cellular stress during subsequent exercise bouts [3,4]. In
this regard, the skeletal muscle adaptations associated with
exercise training are highly specific to the mode of exercise
performed (i.e., resistance vs. endurance exercise), along
with the frequency, intensity, and duration of the exercise
stimulus [5]. For example, chronic resistance training
promotes enhanced muscle activation and fiber hypertro-
phy, resulting in increased maximal contractile force [6,7].
Conversely, endurance training increases mitochondrial
density and oxidative capacity of the trained muscle fibers
[8], whilst promoting alterations in substrate metabolism
[9], culminating in increased whole-body aerobic capacity
(VO
2max
)[5].
Concurrent training can be defined as the simultaneous
integration of resistance and endurance exercise into a
periodized training regime. Despite the potentially wide-
ranging benefits of combining resistance and endurance
J. J. Fyfe (&)D. J. Bishop N. K. Stepto
Institute of Sport, Exercise and Active Living (ISEAL), Victoria
University, Footscray Park Campus, PO Box 14428, Melbourne,
VIC 8001, Australia
e-mail: jackson.fyfe@live.vu.edu.au
J. J. Fyfe D. J. Bishop N. K. Stepto
College of Sport and Exercise Science, Victoria University,
Melbourne, Australia
123
Sports Med
DOI 10.1007/s40279-014-0162-1
Author's personal copy
exercise, there is considerable evidence that concurrent
training compromises the development of muscle mass,
strength, and power compared with undertaking resistance
exercise alone [10–12]. While the mechanisms of the
interference effect are likely to be multifactorial, presum-
ably endurance exercise either interferes with the ‘quality’
of resistance exercise sessions (via residual fatigue and/or
substrate depletion) [11], and/or compromises the acute
molecular responses activated by resistance exercise that
mediate fiber hypertrophy [13,14].
Insight into the molecular factors that mediate the spe-
cific adaptations to divergent exercise stimuli has emerged
in recent years. Training adaptations in skeletal muscle are
considered the cumulative result of acute signaling
responses and subsequent gene expression initiated after
repeated exercise bouts, resulting in the accumulation of
specific proteins over time and, subsequently, an altered
muscle phenotype [1,15,16]. Although these processes are
incompletely resolved, the mammalian (mechanistic) target
of rapamycin complex 1 (mTORC1) has been identified as
a key mediator of resistance exercise-induced increases in
protein synthesis and subsequently muscle growth [17,18],
whereas the 50adenosine monophosphate (AMP)-activated
protein kinase (AMPK) and Ca
2?
/calmodulin-dependent
kinase II (CaMKII) cascades, among others, are activated
by endurance exercise and converge on the peroxisome
proliferator-activated receptor-ccoactivator-1 (PGC-1a)to
coordinate mitochondrial biogenesis [19,20]. Of particular
relevance to the concurrent interference effect is that var-
ious signaling responses activated by endurance exercise
appear to inhibit those that regulate muscle hypertrophy
[21–23]. Various studies have attempted to detect such
‘molecular interference’ occurring following concurrent
exercise in humans [24–30]; however, to date, these studies
have failed to replicate an acute interference mechanism as
distinct as that observed in rodents [23]. It is therefore
unclear whether this mechanism operates in humans, or,
rather, our understanding is hindered by the limitations of
existing evidence. In addition, given the multitude of
concurrent training variables, the potential roles of specific
training variables in the interference effect are incom-
pletely resolved. As a result, there is substantial difficulty
in deducing practical recommendations from current evi-
dence to simultaneously maximize the benefits of resis-
tance and endurance training.
This review summarizes current evidence for the
molecular basis underlying the specificity of training
adaptation and the concurrent interference effect. Addi-
tionally, the potential role of specific concurrent training
variables in the interference effect is discussed, along with
the limitations of our current understanding of this complex
paradigm.
2 Literature Search
The articles selected for review were obtained via searches
of MEDLINE and SPORTDiscus
TM
between 1957 and
September 2013. The following keywords were searched in
combination: ‘concurrent training,’ ‘molecular,’ ‘interfer-
ence,’ ‘exercise,’ and ‘training adaptation.’ From the
abstracts returned, articles were included for review if they
related to the molecular basis for the specificity of training
adaptation, or interference associated with concurrent
versus single-mode training. Literature cited in each article
chosen was also searched, and additional articles satisfying
the above criteria were likewise included for review.
3 Concurrent Training and the Interference Effect
The concomitant integration of resistance and endurance
training within a periodized training regime is termed
‘concurrent training’ [11,12]. Given the capacity of both
exercise modes to induce adaptations within skeletal
muscle that counteract a number of disorders impacting
upon functional capacity and metabolic health, including
sarcopenia [31–33], type II diabetes, and obesity [34–36],
concurrent training appears to be an attractive exercise
strategy for preventing and counteracting multiple disease
states. Additionally, from an athletic perspective, concur-
rent training is necessary for sports whereby improved
strength, power, and/or hypertrophy are desired concomi-
tant with enhanced aerobic capacity [37].
Despite the obvious potential benefits of combining
resistance and endurance exercise, since the work of
Hickson [10] it has been well established that concurrent
training often results in compromised adaptation compared
with training for either exercise mode alone [11]. This
phenomenon has been variously described as the interfer-
ence effect or concurrent training effect [12,14]. The
interference effect typically manifests as a compromised
resistance training adaptation compared with undertaking
resistance training alone. For example, previous research
demonstrates that concurrent training, relative to resistance
training only, results in compromised strength [10,38–41],
hypertrophy [10,41,42], and power development [40,41,
43–45]. Conversely, resistance training appears to have
little to no negative impact on endurance performance and
VO
2max
[11,12], although compromised gains in aerobic
capacity with concurrent versus endurance training alone
have been reported [44,46]. However, concurrent training
can augment both short- (\15 min) and long-duration
([30 min) endurance performance, predominantly via
improvements in neuromuscular function and economy
[47,48].
J. J. Fyfe et al.
123
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4 Molecular Basis for Training Adaptation Specificity
Resistance and endurance exercise represent divergent
exercise modes, both with regards to their inherent stimuli
and the subsequent adaptations induced within skeletal
muscle by chronic training. In recent years, insight into the
molecular factors that mediate skeletal muscle adaptations
to divergent exercise modes has emerged [17,23,49,50].
Exercise-induced adaptations in skeletal muscle are con-
sidered the cumulative result of acute molecular signaling
responses and subsequent gene expression initiated after
repeated exercise bouts, leading eventually to the accu-
mulation of specific proteins over time and, subsequently,
an altered muscle phenotype [1,15,16]. It has been sug-
gested that resistance and endurance exercise stimulate
almost distinct activation of specific molecular signaling
pathways and gene networks that mediate the mode-spe-
cific adaptations to chronic exercise training [2,14,23].
The principal adaptation to chronic resistance exercise is
perhaps muscle fiber hypertrophy [51], which is the
cumulative result of transient increases in net protein
synthesis above that of protein breakdown occurring for up
to 48 h post-exercise [52,53]. It is generally accepted that
fiber hypertrophy consequent to resistance exercise is
mediated by the anabolic mTORC1 signaling cascade [17].
The mTORC1 pathway integrates signals from mechanical
stimuli, growth factors, and nutrients to promote increased
net protein synthesis by phosphorylating downstream tar-
gets implicated in translation initiation (i.e., p70S6K
[70 kDa ribosomal protein S6 kinase 1] and 4E-BP1
[eIF4E binding protein 1]) [17,54]. The pivotal role for
mTORC1 in load-induced muscle growth is supported by
evidence that rapamycin (a selective mTORC1 inhibitor)
administration prevents both muscle hypertrophy in vivo
[17] and the increase in muscle protein synthesis following
acute resistance exercise in humans [18].
In contrast to resistance exercise, endurance exercise is
typically characterized by lower intensity, longer-duration
contractile activity that imparts far less mechanical strain
on the active muscle fibers [55]. This presents a significant
metabolic challenge within the muscle milieu, resulting in
perturbations in intracellular concentrations of Ca
2?
, oxy-
gen, lactate, reactive oxygen species (ROS), and increased
AMP:ATP (adenosine triphosphate) and NAD
?
:NADH
(nicotinamide adenine dinucleotide: NAD
?
reduced form)
ratios [2]. These stimuli then initiate a number of intra-
cellular signaling cascades, including the 50AMPK and
Ca
2?
/CaMKII pathways, which converge on PGC-1ato
promote mitochondrial biogenesis [19,49,56], and other
associated adaptations, including improved substrate utili-
zation [9] and capillary density [57], which collectively
enhance oxidative capacity [5].
Early insight into the molecular basis for the specificity
of training adaptation came from the work of Atherton
and colleagues [23]. These workers employed a model in
which isolated rat muscle was electrically stimulated at
either high (six sets of ten 3-s repetitions at 100 Hz for
20 min) or low (3 h at 10 Hz) frequencies to mimic
resistance or endurance exercise, respectively. Their
results indicated selective activation of the anabolic Akt/
mTOR signaling cascade by resistance-like stimulation
with little effect on the AMPK/PGC-1apathway, while
endurance-like stimulation caused increased AMPK acti-
vation and PGC-1aprotein levels [23]. Moreover, endur-
ance-like stimulation inhibited Akt/mTOR and its
downstream targets. Therefore, these authors postulated
that selective activation of either Akt/mTOR or AMPK/
PGC-1acould explain the divergent adaptations associ-
ated with resistance and endurance training, respectively,
in a paradigm termed the ‘AMPK/Akt master switch’
hypothesis [23]. Whilst this is an attractive regulatory
model, the existence of such clear divergence in humans
has, to date, proven elusive [58–62]. This is perhaps not
surprising, given that the ex vivo electrical stimulation rat
model employed by Atherton and colleagues [23] arguably
represents few similarities to contracting human skeletal
muscle during exercise. Indeed, several observations
question the simplistic notion of an AMPK/Akt ‘master
switch’ mediating training adaptation specificity in human
skeletal muscle, whilst highlighting the complexity of
exercise-induced molecular responses. For example, a
number of human studies have failed to detect notable
differences in either mTORC1 or AMPK signaling in the
early recovery period following endurance and resistance
exercise performed separately [58,61,62]. Several studies
have shown increased mTORC1 activity following
endurance exercise in humans [63–65], which may reflect
the putative role for mTORC1 in regulating oxidative
metabolism [66–68], whilst resistance exercise can acutely
activate AMPK [27,60–62,69,70]. Furthermore,
mTORC1 can be activated independently of Akt via
mechanotransduction [71,72] and amino acid provision
[73,74], highlighting the discordance between mTORC1
activation mediated via the canonical insulin/insulin-like
growth factor (IGF)-1/Akt pathway and contractile activity
[75,76]. Regardless of the exercise modality, other
independent factors can modulate the molecular responses
to exercise, including training status [59,60,63,77], age
[78,79], genetic factors [80,81], and nutrient availability
[73,82–84]. The molecular factors mediating the speci-
ficity of training adaptation are clearly more complex than
dictated by a simplistic ‘master switch’ model [23], and
further work is required to more completely define the
mechanisms responsible.
Concurrent Training and Molecular Interference
123
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5 Molecular Basis for the Concurrent Interference
Effect
Although the molecular signaling mechanisms regulating
the specificity of training adaptation are incompletely
resolved, there appear to be multiple signaling responses
induced by endurance exercise capable of inhibiting pro-
tein synthesis and stimulating protein breakdown (Fig. 1).
Given that muscle fiber hypertrophy requires a positive net
balance of protein synthesis above that of protein break-
down [53], the repeated antagonism of these responses by
endurance exercise might contribute to limiting fiber
hypertrophy following concurrent training [13,14,85].
Perhaps the most well characterized such mechanism
involves the putative antagonism between the AMPK and
mTORC1 signaling cascades [86–88], thought to be pre-
dominantly involved in endurance and resistance training
adaptation [2,13], respectively. Multiple lines of evidence
suggest AMPK activation has a significant inhibitory effect
on mTORC1 and its downstream signaling targets, thereby
negatively regulating protein synthesis and hypertrophy
[21–23,89–91]. Indeed, AMPK phosphorylation nega-
tively correlates with muscle hypertrophy [92] and is
associated with attenuated hypertrophy [93] in rodent
functional overload models. Activation of AMPK has been
shown to repress mTORC1 signaling via multiple mecha-
nisms in vitro, including direct phosphorylation of the
tuberous sclerosis complex 2 (TSC2) [89,94] and the
mTORC1-associated regulatory protein, raptor [91]. Acti-
vation of TSC2 by AMPK negatively regulates mTORC1
via inhibition of its upstream activator Rheb (Ras homo-
logue enriched in brain), thereby blocking the downstream
activation of regulators of protein translation (i.e., p70S6K
and 4E-BP1), and subsequently inhibiting protein synthesis
Fig. 1 Putative molecular mechanisms by which endurance exercise
potentially ainhibits signaling regulating protein synthesis and bup-
regulates pathways mediating protein degradation, subsequently
limiting muscle fiber hypertrophy following concurrent training.
AMPK adenosine monophosphate-activated protein kinase, CaMKII
calcium/calmodulin-dependent kinase II, eEF2 eukaryotic elongation
factor 2, eEF2K eukaryotic elongation factor 2 kinase, FOX-O3a
forkhead-box O3a, HIF-1ahypoxia-inducible factor-1a,MaFbx
muscle-atrophy f-box (atrogin 1), mTORC1 mammalian (mechanistic)
target of rapamycin complex 1, MuRF-1 muscle ring-finger 1, p70S6K
70 kDa ribosomal s6 protein kinase, REDD1 regulated in DNA
development and damage 1, Rheb Ras homologue enriched in brain,
SIRT1 sirtuin deacetylase 1, TSC2 tuberous sclerosis complex 2,
ULK-1 Unc-51-like kinase 1, 4E-BP1 eIF4E binding protein 1, :
indicates increased/greater, ;indicates decreased/less
J. J. Fyfe et al.
123
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[21,69,89]. This effect is opposed by Akt, which phos-
phorylates and inactivates TSC2, alleviating its inhibition
of mTORC1 [90,95]. Interestingly, the regulation of
mTORC1 by AMPK may be isoform-specific. For exam-
ple, it appears the AMPK-a1 catalytic isoform is selec-
tively responsible for limiting muscle hypertrophy via
mTORC1 inhibition [87,94,96], while AMPK-a2 governs
metabolic adaptations in skeletal muscle [87,94,97].
Indeed, AMPK-a1 is activated following chronic overload
in rodents [94], and genetic knockout of this isoform results
in greater hypertrophy [96], supporting the isoform-specific
role of AMPK in constraining muscle growth. Accumu-
lating in vitro evidence also suggests that, in addition to
suppressing protein synthesis, AMPK activation promotes
protein degradation via both the ubiquitin-proteasome and
autophagy-lysosomal systems [98,99]. AMPK activation
promotes forkhead-box O (FoxO)-dependent transcription
of MaFbx (muscle atrophy f-box [atrogin-1]) and MuRF-1
(muscle ring-finger 1) [99–101] and disrupts the inhibitory
effect of mTORC1 on ULK1 (Unc-51-like kinase 1) whilst
increasing ULK1 activity, leading to autophagy induction
[99,102]. Therefore, the activation of AMPK by endurance
exercise potentially mediates interference via down-regu-
lating protein synthesis and concomitantly up-regulating
protein degradation [2].
Protein synthesis is also regulated in the elongation phase
of protein translation, which is mediated by elongation
factors and is the most energy-consuming stage of protein
synthesis [103]. The eukaryotic elongation factor 2 (eEF2)
is a critical component of the translational machinery
involved in translocation of the ribosome along the mes-
senger RNA (mRNA) [104]. The eEF2 is phosphorylated
(i.e., inactivated) by eEF2 kinase (eEF2K) [105], which is
activated by signaling pathways that respond to increased
energy demand or reduced energy supply, such as the
AMPK and CaMK pathways, both of which are activated
following endurance exercise [106,107]. Conversely, sig-
naling related to resistance exercise (i.e., mTORC1 and
p70S6K activation) inhibits eEF2K activity in vitro, thus
releasing its inhibition of eEF2 and increasing translation
and protein synthesis rates [108–110]. The activation of
eEF2K by endurance exercise is therefore a candidate
inhibitor of muscle protein synthesis and, potentially,
muscle fiber hypertrophy during concurrent training.
Another upstream inhibitor of mTORC1 and subse-
quently protein synthesis is REDD1 (regulated in DNA
damage and development 1) [111,112]. REDD1 is acti-
vated by a number of metabolic stressors including ATP
depletion [111] and hypoxia [113–115], and is induced by
endurance exercise in rat skeletal muscle [116]. Upon
activation, REDD1 inhibits mTORC1 indirectly by releas-
ing the inhibition of TSC2 caused by 14-3-3 protein binding
[114,115]. Overexpression of REDD1 in rodent skeletal
muscle has been shown to cause a 10 % reduction in muscle
fiber size [115], and REDD1 expression is associated with
muscle atrophy in diabetic mice [117]. The expression of
REDD1 mRNA is reduced 3 h following low-intensity
resistance exercise and blood flow restriction in humans,
concomitant with increased mTORC1 mRNA expression
[118]. Thus, activation of REDD1 by endurance exercise
may be an additional mechanism responsible for inhibiting
anabolic responses induced by resistance exercise, and
subsequently hypertrophy during concurrent training.
The sirtuin (SIRT) deacetylase family of proteins are sen-
sitive to metabolic perturbations, including increased NAD
?
and lactate concentrations, and are activated by endurance
exercise in skeletal muscle [119]. Of the SIRT family
expressed in skeletal muscle, SIRT1 has been implicated as a
potential regulator of mitochondrial biogenesis, in part
because it can regulate the activity of AMPK and PGC-1a
[120]. Interestingly, and of potential relevance to concurrent
training, is that SIRT1 negatively regulates mTORC1 in vitro
[121]. Activated SIRT1 interacts with and subsequently
activates TSC2, thereby down-regulating mTORC1 activity
[121], potentially via inhibition of the upstream mTORC1-
activator Rheb [22]. Increased SIRT1 activity induced by
endurance exercise is therefore another potential mechanism
by which the mTORC1 pathway and protein synthesis might
be suppressed following concurrent exercise.
Collectively, there appears to be multiple signaling
responses initiated by endurance exercise with the capacity
to inhibit components of the translational machinery and
subsequently rates of protein synthesis, in addition to
promoting protein breakdown. However, it is important to
consider that many of these putative interference mecha-
nisms have been described in cell culture or animal models,
and often during non-physiological conditions, which may
have limited relevance to human skeletal muscle during
exercise [122]. Many of these mechanisms are poorly
characterized in skeletal muscle, let alone in response to
exercise, and further work is required to confirm their
relevance to training adaptations in human skeletal muscle.
Indeed, few studies have investigated whether these
mechanisms operate in humans following concurrent
exercise, and therefore potentially contribute to compro-
mised fiber hypertrophy following concurrent training.
6 Evidence for Molecular Interference in Human
Skeletal Muscle
6.1 Molecular Interference Following Acute
Concurrent Exercise
Whilst few studies performed to date have investigated
divergences between molecular responses to resistance and
Concurrent Training and Molecular Interference
123
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Table 1 A summary of current evidence regarding acute molecular interference following concurrent resistance and endurance exercise in humans
Study Sample
size
Participant
training status
Study design Exercise protocols Results Conclusions
Endurance
exercise
Resistance
exercise
Recovery
between
modes
Protein
phosphorylation
Gene expression Protein
synthesis
Carrithers
et al.
[25]
12 (6
M, 6 F)
1–2 bouts of
AE and
RE 9/week
Unilateral
cross-over.
All
participants
performed
unilateral AE
then bilateral
RE
90 min unilateral
cycling at 60 %
W
peak
Unilateral leg
press and leg
extension
(3 910 reps
at 80 %
1RM ?one
set to
failure)
performed
on both legs
30 min N/A N/A Myofibrillar
FSR not
different
between the
AE ?RE and
the RE legs
Concurrent
exercise does
not suppress
post-RE
myofibrillar
protein
synthesis rates
independent of
muscle
glycogen
levels
Coffey
et al.
[28]
8 M Regular
concurrent
training
([1 year)
Randomized
cross-over.
All
participants
performed
both AE and
RE in
alternate
orders
30 min continuous
cycling at 70 %
VO
2peak
895 leg
extension
reps at 80 %
1RM
15 min :p-Akt when RE
followed AE.
No significant
order effect was
noted for
p-TSC-2/
mTOR/p70S6K
:MuRF-1
mRNA when
AE followed
RE. Reverse
order resulted
in ;IGF-1
mRNA
expression
N/A Concurrent
training does
not promote
optimal acute
signaling
responses
associated
with each
mode of
exercise
Coffey
et al.
[27]
6 M Regular
concurrent
training
([39/week)
Randomized
cross-over.
All
participants
performed
both AE and
RE in
alternate
orders
10 96-s maximal
cycling
ergometer sprints
against
0.75 Nm torque
-1
kg
-1
(49-s
passive rest
between efforts)
895 leg
extension
reps at 80 %
1RM
15 min Initial RE :
p-p70S6K and
p-rps6 but this ;
when RE
followed
repeated
sprints. :p-Akt
when RE
followed AE.
Changes in
p-TSC2,
p-mTOR, and
p-AMPK
modest and
independent of
order
:MuRF-1
mRNA when
sprints followed
RE. ;IGF-1
mRNA from
rest
independent of
order
N/A Repeated sprints
diminished the
anabolic
response to RE
by attenuating
anabolic and
enhancing
catabolic
responses in
early recovery
J. J. Fyfe et al.
123
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Table 1 continued
Study Sample
size
Participant
training status
Study design Exercise protocols Results Conclusions
Endurance
exercise
Resistance
exercise
Recovery
between
modes
Protein
phosphorylation
Gene expression Protein
synthesis
Wang
et al.
[30]
10 (7 M,
3F)
No
programmed
exercise for
[6 months
Randomized
cross-over.
All
participants
performed
both AE alone
(trial 1) and
AE followed
by RE (trial 2)
60 min continuous
cycling at 65 %
VO
2max
(3-min
rest allowed after
30 min)
Six sets of leg
press at 70,
75, 80, 80,
75, 70 %
1RM
Participants
encouraged
to complete
maximal
reps as
possible up
to 15
15 min :p-mTOR and
p-p70S6K, ;
p-eEF2 after
AE ?RE vs.
AE. Similar :
in p-Akt, and
p-AMPK in
AE ?RE and
AE. No
p-CaMKII after
each protocol.
Heterogenous
p-p38 MAPK
response
:PGC-1aand
PDK-4 mRNA
with AE ?RE
vs. AE alone
N/A Addition of RE
after an acute
AE bout :
mitochondrial
biogenesis and
substrate
metabolism
signaling and
may be a novel
method for
enhancing
aerobic
capacity
Lundberg
et al.
[29]
9 M AE 2–39/
week and/or
RE 1–29/
week for
[1 year
Unilateral
cross-over.
All
participants
performed
unilateral AE
followed by
bilateral RE
6 h post-AE
40 min continuous
unilateral cycling
at 70 % of W
max
.
Workload then
increased by
*20 W for
cycling to
exhaustion
Unilateral leg
press and leg
extension
(2 97 reps
of each
exercise,
90-s rest
between
sets)
performed
on both legs
6h :p-mTOR,
p-p70S6K, with
AE ?RE vs.
RE. p-rps6 and
p-eEF2
unchanged over
time for both
legs, trend for :
p-rps6 with
AE ?RE
:PGC-1a,
VEGF, atrogin-
1 mRNA with
AE ?RE vs.
RE at PRE and
15 min post. ;
Myostatin
levels in
AE ?RE vs.
RE at PRE and
15 min post.
MuRF-1
mRNA similar
across legs
N/A Completing RE
6 h after AE
did not
compromise
mTOR-related
signaling after
leg press and
leg extension
exercise
Concurrent Training and Molecular Interference
123
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Table 1 continued
Study Sample
size
Participant
training status
Study design Exercise protocols Results Conclusions
Endurance
exercise
Resistance
exercise
Recovery
between
modes
Protein
phosphorylation
Gene expression Protein
synthesis
Donges
et al.
[26]
8 M Sedentary
middle-aged
men (no
regular
activity
involving
[30 min/
week for
1 year prior
to study)
Repeated
measures. All
participants
completed 3
trials in
randomized
order: (i) RE
only, (ii) AE
only and (iii)
RE ?AE
combined (50
% volume of
each isolated
session)
40 min continuous
cycling at 55 % of
W
peak
898 leg
extension at
70 % 1RM
None :p-Akt at 1 h
post in CE vs.
RE and AE. No
change in
p-mTOR,
p-p70S6K,
p-AMPK,
p-MAPK, and
p-4E-BP1 at
any time point.
:p-AS160 at 1
and 4 h post for
RE. :p-rps6 at
1 h in RE vs.
CE and AE
MyoG and MyoD
expression :
4 h post RE.
MyoG :[AE
and CE at 1 h
post and[AE
at 4 h post. :
MyoD mRNA
[CE at 1 h
post, and AE at
4 h post. No
change in
myostatin
mRNA
Myofibrillar
FSR during
4-h recovery :
1.8 and 2.2-
fold for RE
and CE trials,
respectively. :
Myofibrillar
FSR for CE/
RE both
significantly
[AE, which
remained
unchanged
CE is as
effective as
either isolated
mode in
stimulating
myofibrillar
and
mitochondrial
FSR in
sedentary
middle-aged
men despite
50 % less
training
volume of
each modality
Apro et al.
[24]
10 M AE 1–29/
week and RE
2–39/week
for
[6 months
Randomized
cross-over.
All
participants
performed RE
followed by
AE, or RE
alone
30 min cycling at
70 % VO
2max
10 sets of leg
press
(4 98–10 at
85 % 1RM,
4910–12
at 75 %
1RM, 2 sets
to fatigue at
65 % 1RM)
15 min :p-mTOR and
p-p70S6K and
;p-eEF2
regardless of
condition. ;
p-AMPK and
p-ACC
regardless of
condition
:PGC-1amRNA
after RE ?AE
vs. AE
N/A Endurance
exercise
performed
subsequent to
RE does not
blunt
mTORC1-
related
signaling
ACC acetyl-CoA carboxylase, AE aerobic exercise, AMPK adenosine monophosphate-activated protein kinase, AS160 Akt-substrate 160 kDa, CaMKII calcium/calmodulin-dependent kinase II,
CE concurrent exercise, eEF2 eukaryotic elongation factor 2, Ffemale, FSR fractional synthesis rate, IGF-1 insulin-like growth factor 1, Mmale, MAPK mitogen-activated protein kinase,
mRNA messenger RNA, mTORC1 mammalian (mechanistic) target of rapamycin complex 1, MuRF-1 muscle ring-finger 1, MyoD myogenic differentiation 1, MyoG myogenin, N/A not
available, Nm newton-meters, pphosphorylation/phosphorylated, PDK pyruvate dehydrogenase kinase 4, PGC-1aperoxisome proliferator-activated receptor-ccoactivator-1a,PRE pre-
resistance exercise, p70S6K 70 kDa ribosomal s6 protein kinase, RE resistance exercise, rep(s) repetition(s), rps6 ribosomal protein s6, TSC2 tuberous sclerosis complex 2, VEGF vascular
endothelial growth factor, VO
2max
maximal oxygen consumption, VO
2peak
peak oxygen consumption, Wwatts, W
peak
/W
max
peak power output, 1RM one repetition maximum, :indicates
increased/greater, ;indicates decreased/less
J. J. Fyfe et al.
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endurance exercise in humans [58,61,62,123], more
specifically, limited data are available regarding the acute
molecular responses following concurrent exercise [25–30]
(Table 1). To date, most existing studies have examined
molecular responses induced acutely following concurrent
exercise cessation (i.e., 15 min to 4 h post-exercise) to
investigate whether these responses are altered with con-
current versus single-mode exercise [25–30]. This
approach has provided insight into the existence of acute
‘molecular interference’ in humans, and the potential
impact of the particular concurrent exercise protocol on
chronic training adaptation. However, current evidence is
equivocal with regards to the existence of this phenomenon
in humans. For example, while some studies have sug-
gested that concurrent training promotes acute interference
of anabolic molecular responses [27,28], others have
concluded that either protein synthesis rates [25,26]or
mTORC1 signaling [24] are no different than resistance
exercise alone. Remarkably, there is also evidence that
concurrent exercise ‘potentiates’ acute adaptive responses
to exercise compared with single-mode exercise [30]. For
example, the addition of resistance exercise immediately
following endurance exercise reportedly augments signal-
ing related to mitochondrial biogenesis [30], whilst per-
forming resistance exercise 6-h after endurance exercise
enhances anabolic signaling [29] compared with resistance
exercise alone.
Current data therefore provide limited evidence for
acute molecular interference with concurrent exercise, and
indeed little mechanistic insight into the concurrent train-
ing effect. However, as discussed subsequently (see Sect. 7
of this review), the limitations of existing studies must be
considered when interpreting evidence with regards to the
molecular interference phenomenon in humans. Addition-
ally, given the multitude of variables associated with
concurrent training (e.g., resistance/endurance training
modality, volume and intensity of exercise, length of
between-mode recovery, nutritional and training status of
participants), it is difficult to generalize the findings of
existing studies outside of the particular design employed.
Further work is therefore needed to examine the role of
these additional variables in the concurrent interference
effect, whilst addressing the limitations of current
evidence.
6.2 Molecular Interference Following Short-Term
Concurrent Training
Whilst limited acute molecular concurrent training data
exist, even less information exists regarding the effects of
concurrent training on molecular responses and/or adapta-
tions within skeletal muscle following a period of training
[124,125]. Using a unilateral training model, Lundberg
et al. [124] examined the effect of 5 weeks of concurrent
training versus resistance training alone on muscle fiber
cross-sectional area (CSA), isokinetic/isometric strength
and basal expression of selected regulatory genes (i.e.,
myostatin, MuRF-1, MaFbx, PGC-1a, and vascular endo-
thelial growth factor [VEGF]). Interestingly, these authors
showed more robust quadriceps femoris hypertrophy when
resistance exercise was preceded by aerobic exercise,
compared with resistance training alone, although no
between-limb difference in isometric strength was noted
[124]. No differences in the basal expression of selected
genes were observed after training. However, no measures
of resting protein content or acute signaling responses to
exercise bouts before and after training were obtained,
potentially limiting any mechanistic insight into the adap-
tive outcomes. Similarly, another investigation examined
basal phosphorylation and content of selected proteins
following 8 weeks of concurrent versus single-mode
training [125]. Despite no between-group differences in
measures of muscle strength or quadriceps CSA after
training, the results showed an increase in basal Akt and
AMPK phosphorylation for the resistance- and endurance-
only groups, respectively, whilst the concurrent training
group showed increased p70S6K protein content [125].
However, given that the exercise protocols employed in
these short-term studies were insufficient to cause any
interference effect [124,125], the interpretation of the
observed results is difficult. Further work is required to
evaluate the effect of long-term concurrent training on
anabolic responses and adaptations to concurrent exercise
to provide greater insight into the molecular factors that
potentially mediate the concurrent training effect.
7 Limitations of Existing Molecular Concurrent
Training Evidence
There are currently insufficient human data providing any
evidence of acute molecular interference occurring fol-
lowing concurrent exercise to explain the attenuated
hypertrophy and strength response following concurrent
training. However, it is unclear whether this is a conse-
quence of a lack of the proposed mechanisms operating in
human skeletal muscle, and/or the limitations of existing
evidence, which are briefly discussed below.
7.1 Relationship between Acute Exercise Responses
and Chronic Training Adaptation
Most acute molecular concurrent training studies provide a
brief ‘snapshot’ of the acute adaptive events occurring in
close proximity to concurrent exercise bouts [25–30].
However, many questions remain with regards to the long-
Concurrent Training and Molecular Interference
123
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term molecular regulation of skeletal muscle adaptation
and interference seen with concurrent training. First, there
are limited data indicating a direct coupling between the
acute molecular responses to exercise and the long-term
phenotypic adaptations associated with chronic exercise
training [14]. It is therefore unclear whether the acute
molecular responses following concurrent exercise provide
a valid ‘readout’ of the adaptive phenotype and potential
interference induced if training was repeated long term.
Indeed, the efficacy of the molecular markers commonly
used to gauge the anabolic response to exercise and
nutritional stimuli has been questioned [126,127]. Only
two human studies performed to date have directly mea-
sured protein synthesis rates following acute concurrent
exercise [25,26], whilst others have instead utilized proxy
markers of protein synthesis and/or degradation [24,27–
30]. However, importantly, a direct coupling between
mTORC1 signaling and protein synthesis rates does not
always exist in humans [126], and rates of protein synthesis
can be saturated at approximately 30 % of the maximal
phosphorylation of p70S6K in rodents [128]. Given these
apparent discordances, any minor interference to anabolic
signaling responses following concurrent exercise may not
reflect any potential interference to protein synthesis, and
subsequently chronic muscle hypertrophy. Studies extrap-
olating the anabolic response and potential acute interfer-
ence effect from acute signaling responses alone must
therefore be interpreted with caution. Nevertheless,
p70S6K phosphorylation following resistance exercise
correlates well (r=0.82–0.99) with chronic hypertrophy
in both rat [129] and human [130,131] models, supporting
this as an appropriate proxy for chronic hypertrophy and
potential marker for interference with concurrent training.
Regardless of the methods used to gauge the post-exercise
anabolic response, most acute concurrent exercise studies
have been characterized by poor temporal resolution. For
example, most existing studies have examined acute
molecular responses up to 4 h post-exercise, whereas
mTORC1 signaling persists for up to 24 h post-exercise
[132,133]. These studies may have therefore missed any
potential effects of concurrent exercise on mTORC1 sig-
naling occurring later than 4 h post-exercise. Further work
employing extended time-courses is required to determine
whether mTORC1 signaling is altered by concurrent
exercise during the later recovery period.
7.2 Effect of Training Status on Acute Molecular
Responses to Exercise
It appears likely that long-term concurrent training would
modulate acute exercise responses (and potentially acute
interference) over time, similar to that seen with single-
mode exercise [59–63,77,134], whereby the acute
molecular profile to unaccustomed exercise bouts may
represent a generalized, unrefined adaptive response [3,
62]. For example, while there is evidence of little diver-
gences in mTORC1 signaling responses between resistance
and endurance exercise in relatively untrained subjects [58,
61,62], the mTORC1 pathway is indeed preferentially
activated by resistance, but not endurance exercise, in
training-accustomed individuals [61]. Additionally, while
resistance exercise performed in the untrained state elicits
comparable increases in both myofibrillar and mitochon-
drial protein synthesis rates, these responses become more
refined following training, whereby only myofibrillar pro-
tein synthesis rates are increased in response to resistance
exercise [62]. Evidence from chronically strength- or
endurance-trained athletes [59,60] also supports the notion
that muscle phenotype, rather than the mode of exercise per
se, can influence the molecular responses to divergent
exercise modes. In this case, current acute concurrent
training evidence in relatively untrained subjects should be
interpreted with caution. Indeed, while most acute molec-
ular concurrent training studies have utilized participants
who were recreationally undertaking both resistance and
endurance training [25,27–29], some have used sedentary
participants [26,30] or participants not accustomed to both
modalities [29]. Observations that early concurrent exer-
cise bouts promote cumulative effects on protein synthesis
and/or mitochondrial biogenesis signaling [26,29,30] may
therefore be more reflective of the unfamiliarity to the
exercise bout [53] rather than suggesting enhanced poten-
tial for chronic adaptation. Moreover, often overlooked is
that the original study by Hickson [10] showed no detect-
able interference effect until the 8th week of concurrent
training, suggesting that interference may not manifest
until a certain training status is attained. Taken together,
these results suggest that participant training status is an
independent influence on exercise-induced molecular
responses, and potentially the interference effect, and must
be taken into consideration when interpreting existing
concurrent training evidence. Future work examining the
existence of molecular interference should employ partic-
ipants who are accustomed to both exercise modes to
account for the potentially confounding effects of training
status on acute post-exercise molecular responses to exer-
cise [59,60]. Moreover, this further exemplifies the need
for chronic ([8 weeks) training studies examining the
potential modulation of acute interference following long-
term concurrent training.
7.3 Effect of Nutrient Availability on Acute Molecular
Responses to Exercise
It has become increasingly clear that nutrient availability
exerts a profound effect on the adaptive responses to
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exercise training in human skeletal muscle [135,136]. For
example, the availability of muscle glycogen has been
reported to modulate early molecular responses to both
endurance and resistance exercise in a divergent manner
[82,84,137]. Low carbohydrate availability appears to
augment early signaling responses governing metabolic
adaptation and mitochondrial biogenesis [84,137,138],
whilst low muscle glycogen may compromise anabolic
responses to resistance exercise [82]. However, the latter
effect was recently questioned by a study showing no effect
of muscle glycogen depletion on anabolic responses to
resistance exercise [139]. Low muscle glycogen is associ-
ated with fatigue development [140,141] and increased
AMPK activity [142], which might inhibit anabolic
responses induced by resistance exercise [82,92]. It is also
well accepted that essential amino acids can independently
stimulate mTORC1 activation and subsequently increase
protein synthesis rates [73,143,144] via interaction with
the Rag GTP-ases (guanosine triphosphate-ases) [74].
Nutrient availability is therefore a potent modulator of
acute molecular responses to exercise and skeletal muscle
adaptations following chronic exercise training [135] and
needs to be considered when interpreting the concurrent
training literature.
Most existing molecular concurrent training studies
have employed designs whereby participants performed
exercise in the fasted state [24,25,27,28,30], or were not
provided with nutrients upon cessation of exercise [29],
presumably to control for the independent effects of
nutrient availability on acute molecular responses within
skeletal muscle [135]. Performing exercise in the fasted
state undoubtedly presents a heightened metabolic chal-
lenge within the muscle milieu, presumably increasing
energy-sensing kinase activity (e.g., AMPK and eEF2K)
with the capacity to suppress protein synthesis [23,92], and
promote autophagy [145]. The ability of amino acid
ingestion to independently stimulate activation of anabolic
signaling responses [73,143,144] suggests adequate
nutrient availability may be essential for attenuating the
potentially negative impact of endurance exercise and the
associated molecular responses on protein synthesis [146].
Indeed, it is well established that ingestion of sufficient
Fig. 2 Conceptual framework
for the potential role of
individual concurrent training
variables ain exacerbating the
interference effect, either by
bcompromising the resistance
exercise stimulus itself via
increasing residual fatigue and/
or substrate depletion, or cby
attenuating the anabolic
response to resistance exercise,
subsequently limiting muscle
fiber hypertrophy. AE aerobic
exercise, AMPK adenosine
monophosphate-activated
protein kinase, eEF2K
eukaryotic elongation factor 2
kinase, MaFbx muscle-atrophy
f-box (atrogin 1), mTORC1
mammalian (mechanistic) target
of rapamycin complex 1,
MuRF-1 muscle ring-finger 1,
RE resistance exercise, :
indicates increased/greater, ;
indicates decreased/less
Concurrent Training and Molecular Interference
123
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protein in the early recovery period following resistance
exercise is required to maximize muscle protein synthesis
and subsequently muscle hypertrophy [135,147]. Further,
as muscle hypertrophy is an energetically demanding pro-
cess, a positive energy balance may be required to support
increases in muscle mass [148], and endurance exercise
almost certainly interferes with this balance via continual
substrate depletion and/or amino acid oxidation [149]. The
potentially confounding effects of altering nutrient avail-
ability on molecular responses to exercise should therefore
be considered when interpreting the concurrent training
literature. Additionally, further work is required to fully
elucidate the importance of nutrient availability on maxi-
mizing concurrent training adaptation.
8 The Role of Concurrent Training Variables
in the Interference Effect
Given the multitude of potential concurrent training vari-
ables, the roles of many of these variables in acute and
chronic interference remain incompletely resolved. Poten-
tially, specific concurrent training variables might exacer-
bate molecular interference, either indirectly by
compromising the ‘quality’ of the resistance exercise
stimulus itself (e.g., via residual fatigue or substrate
depletion), or directly by increasing the activity of proteins
acting to inhibit protein synthesis and/or stimulate protein
breakdown (see Fig. 2). Improving knowledge of the
contribution of these variables to the interference effect is
therefore critical to inform their prescription for maxi-
mizing the simultaneous development of muscle mass,
strength, and endurance. Existing evidence has neverthe-
less begun to shed light on the potential roles of specific
training variables in the concurrent interference effect.
8.1 Within-Session Exercise Order
A common and time-efficient concurrent training approach
is to perform divergent exercise bouts together within a
single exercise session. The order in which these exercise
modes are performed may potentially modulate interfer-
ence. However, minimal work has been done to ascertain
whether an order-effect-dependent interference effect
exists when concurrently training [150–155]. From a first-
principles perspective, it would appear that if substrate
depletion and/or residual fatigue [11,156] from prior
endurance training bouts compromises performance during
subsequent resistance exercise, then undertaking resistance
exercise prior to endurance exercise may alleviate these
negative residual effects. However, given that metabolic
signaling responses to endurance exercise that inhibit
protein synthesis (e.g., AMPK activation) are generally
relatively transient (\3h)[157,158] compared with ana-
bolic responses (i.e., mTOR and p70S6K phosphorylation)
to resistance exercise ([24 h) [132,133], performing
resistance exercise after endurance exercise may allow
these anabolic responses to proceed unimpeded during
early recovery. Nevertheless, current performance-based
evidence suggests that the effect of within-session exercise
order on chronic interference may be limited [150–152],
although performing resistance exercise prior to endurance
exercise appears to augment neuromuscular and cardiore-
spiratory adaptations in the elderly [153,155].
Two studies [27,28] have addressed this question by
examining acute signaling responses and gene expression
after consecutive resistance and endurance training ses-
sions completed in an alternating order (i.e., resistance
prior to endurance exercise, and vice versa). The initial
study [28] employed consecutive leg extension exercise
(8 95 repetitions at 80 % 1RM) and continuous cycling
(30 min at 70 % VO
2peak
) and noted a greater increase in
MuRF-1 mRNA when cycling followed resistance exer-
cise, while the reverse order caused increased phosphory-
lation of Akt and decreased IGF-1 mRNA expression [28].
No significant order effect was noted for TSC-2/mTOR/
p70S6K activation and for the modest increases in PGC-1a
mRNA. Taken together, the results provided little evidence
for any order-effect-dependent molecular interference,
whilst the authors suggested that concurrent exercise did
not promote optimal acute signaling responses associated
with each exercise mode [28]. However, the lack of a
single-exercise mode condition within this design [28]
makes it difficult to speculate on the magnitude of any
potential interference relative to resistance exercise alone.
A subsequent study from the same group [27] incorpo-
rated a resistance exercise session identical to the first [28],
but combined this with a repeated-sprint cycling protocol
(10 96-s sprints) performed either before or after the
resistance exercise. These workers reported that concurrent
repeated-sprint and resistance exercise promotes acute
interference by attenuating translation initiation signaling
(i.e., p70S6K and its downstream target, rps6 [ribosomal
protein s6]), and increasing the mRNA abundance of
mediators of protein degradation (i.e., MuRF-1). Divergent
p70S6K phosphorylation responses were noted between
exercise modes and with alternate exercise orders. Spe-
cifically, initial resistance exercise promoted increased
p70S6K activation, whilst this response was attenuated
when resistance exercise was performed after repeated
sprints [27]. These authors concluded that performing
repeated-sprint exercise in close proximity to resistance
exercise attenuated anabolic signaling and increased cata-
bolic activity, which likely represents acute interference of
pathways governing resistance training-related adaptation
[27]. Consequently, it was recommended that both exercise
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modes be performed with a significant intervening recov-
ery period to minimize acute interference, and that resis-
tance training precede repeated sprints if performed within
the same session.
8.2 Between-Mode Recovery Length (Proximity)
Given that performing concurrent exercise bouts in close
proximity may represent a sub-optimal training scenario
[27,28], the recovery length allowed between undertaking
concurrent exercise sessions is another important practical
consideration. Potentially, residual fatigue and/or substrate
(i.e., muscle glycogen) depletion from endurance training
bouts may impact negatively upon force/power production
[11,156] and anabolic signaling responses [82] to sub-
sequent resistance exercise, respectively. For example,
following a bout of endurance exercise, force production of
the exercised musculature is reduced for at least 6 h [43,
159–161], returning to baseline by 24 h post-exercise
[160]. Compromised force/power production during resis-
tance exercise would theoretically limit activation of
higher-threshold (i.e., type IIx/IIb) motor units and fibers
[162,163], known to be most responsive to hypertrophy
[7]. Indeed, the phosphorylation of p70S6K [70,164] and
mTORC1 [165] after resistance exercise is more pro-
nounced in type II than in type I muscle fibers. Residual
fatigue from prior endurance exercise also reduces the
volume of work performed during subsequent resistance
exercise [161], presumably limiting the potential for mus-
cle hypertrophy. Finally, the transient activation of various
proteins by endurance exercise that inhibit protein syn-
thesis (e.g., AMPK and eEF2K) [92,166] and mediate
protein degradation (e.g., MaFbx and MuRF-1) suggests
that commencing resistance exercise in closer proximity to
endurance exercise may further compromise the anabolic
response to resistance exercise. Allowing adequate recov-
ery between concurrent exercise sessions may therefore
attenuate any negative residual effects from endurance
exercise on subsequent training bouts, consequently alle-
viating any interference. This approach also provides
opportunity for carbohydrate and/or amino acid ingestion,
essential to replenish muscle glycogen stores [167] and
counteract the potentially detrimental impact of endurance
exercise and associated molecular responses on protein
synthesis [23,92,168], respectively.
The concept of between-mode recovery has been sig-
nificantly under-researched in the concurrent training lit-
erature [12,169]. In their meta-analysis of concurrent
training literature, Wilson and colleagues [12] noted a
trend (non-statistically significant) towards greater hyper-
trophy gains in concurrent training studies when resistance
and endurance training were performed on separate days
compared with on the same day. Most existing molecular
concurrent training studies have employed designs
whereby concurrent resistance and endurance training
bouts are performed in succession following only a brief
recovery (e.g., 15–30 min) [25–28,30]. These studies
therefore provide little mechanistic insight into the effect of
longer between-mode recoveries on both force/power
production and anabolic responses to subsequent resistance
exercise bouts. Work by Lundberg et al. [29] examined
acute molecular responses to resistance exercise (2 97
bilateral leg press and leg extension repetitions) performed
6 h after aerobic exercise (40 min of continuous unilateral
cycling at 70 % peak power output [W
max
]) compared with
that seen after resistance exercise alone. These authors
noted that divergent exercise modes performed after a
significant intervening recovery period in the fed state
resulted in elevated anabolic signaling (i.e., increased
mTORC1 and p70S6K phosphorylation) and lowered
myostatin gene expression compared with resistance
exercise alone. Moreover, the addition of resistance exer-
cise appeared to accentuate early PGC-1amRNA abun-
dance, whilst prior endurance exercise did not compromise
force and power production during resistance exercise. It
was therefore concluded that divergent exercise modes can
be successfully performed on the same day without com-
promising performance or the molecular responses medi-
ating protein synthesis and mitochondrial biogenesis [29].
However, whether shorter recovery lengths would have
exacerbated any putative molecular interference is unclear.
Further work is therefore required to determine the role of
between-mode recovery in concurrent interference, in
addition to recovery strategies that may be employed dur-
ing this period. Such information may help to develop
practical training recommendations for the structuring of
concurrent resistance and endurance exercise sessions to
support maximal simultaneous development of resistance
and endurance adaptation.
8.3 Endurance Training Intensity
Another important practical consideration is the intensity
of endurance training employed in a concurrent training
regimen. Recently, high-intensity interval training (HIT)
has emerged as a potent exercise strategy for inducing
signaling related to mitochondrial biogenesis (i.e., PGC-1a
expression) and associated health benefits (e.g., improved
insulin sensitivity) typically associated with longer-dura-
tion, lower-intensity endurance exercise [138,170–176].
Therefore, HIT represents a time-efficient strategy for
promoting mitochondrial biogenesis and associated
improvements in oxidative capacity and metabolic health.
This high-intensity approach is also favored in condition-
ing programs tailored for enhancing anaerobic capacity
and/or repeated sprint ability [37].
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Despite the relevance of HIT for health and performance
outcomes [172], little is currently known regarding the
effects of incorporating HIT in a concurrent training
regime on acute molecular interference and subsequent
chronic adaptation to long-term concurrent training.
Indeed, studies independently examining the effect of
endurance exercise intensity on concurrent interference are
scarce [177]. One study suggested no role for endurance
exercise intensity on interference in physically active
females [177]; however, training volume and frequency
were comparably low and may have limited any potential
interference effect seen with higher training volumes [12,
178,179]. Most existing molecular research has employed
low-to-moderate intensity endurance exercise protocols
(e.g., 30–60 min at 65–70 % VO
2max
, 40–90 min at
55–70 % W
max
)[24–26,28–30], whilst none have directly
examined the effect of endurance exercise intensity on
acute molecular and chronic performance interference. As
aforementioned, Coffey and colleagues [27] observed that
repeated sprints attenuated the anabolic response when
performed concurrently with resistance exercise, and
seemingly more so than in a previous study employing
moderate-intensity continuous cycling [28]. However, little
is known regarding the role of more practical HIT models
involving longer work intervals interspersed with periods
of active or passive recovery [170,175,180] on acute
interference and subsequent chronic adaptation when per-
formed concurrently with resistance training.
From a molecular perspective, higher-intensity endur-
ance exercise (i.e., HIT) may exacerbate acute molecular
interference when compared with lower-intensity (i.e.,
continuous) endurance exercise. For example, the activity
of selected negative regulators of protein synthesis, such as
AMPK and 4E-BP1, is increased by endurance exercise in
an intensity-dependent manner [181,182]. Moreover, the
AMPK-a1 catalytic isoform, which purportedly plays a
selective role in mTORC1 inhibition [94,96], may be
preferentially activated by higher [182], but not lower
[183], endurance exercise intensities. Higher-intensity
endurance exercise also appears to inhibit subsequent force
production [43,159], whilst lower-intensity continuous
exercise may cause less residual fatigue [184]. Finally,
higher exercise intensities are associated with increased
glycogen depletion occurring predominantly in type II
muscle fibers [185], which may exacerbate residual fatigue
[140] and increase inhibitory AMPK activity [142]. Whe-
ther the capacity of higher-intensity exercise to cause
greater metabolic perturbation in type II muscle fibers [185,
186] plays any role in potentially blunting anabolic
responses within these fibers following subsequent resis-
tance exercise remains to be determined. Regardless, given
the potency of HIT for inducing favorable adaptations in
skeletal muscle [187], along with the importance of HIT
for athletic performance [37], more work is required to
delineate the role of endurance exercise intensity in the
concurrent interference effect.
8.4 Endurance Training Volume
The possibility also exists that the total volume of endur-
ance exercise, rather than the intensity per se, may be more
crucial in mediating concurrent interference [12,178,179].
A role for volume-dependent interference is supported by
studies reporting no interference with smaller endurance
training frequencies (B2 sessions per week) [40,42,188],
whilst others have observed attenuated maximal strength
with larger endurance training volumes (C3 sessions per
week) [10,38,41,44,179]. Greater attenuation of strength
and hypertrophy (estimated via limb girth) has been shown
to occur with greater frequencies of concurrent endurance
exercise (3 days per week for each mode) than when
endurance exercise was performed once per week [179].
Nevertheless, it remains to be determined whether the total
weekly endurance training volume, or the training fre-
quency per se, is the more critical factor mediating con-
current interference. If endurance exercise volume is key,
low-volume HIT protocols [171,180] might confer benefit
when incorporated into a concurrent training regimen by
limiting any potential volume-dependent interference
effect, whilst also offering similar metabolic and perfor-
mance benefits to traditional endurance exercise [171,
172]. Further work in this area is required to inform the
manipulation of concurrent endurance training volumes
and/or intensities in order to minimize their potentially
negative impact on resistance training adaptations.
8.5 Endurance Training Modality
The endurance training modality employed in a concurrent
training regime may also modulate interference following
long-term concurrent training [11,12]. Interestingly, the
majority of concurrent training studies reporting an inter-
ference effect have incorporated running, and less often
cycling, as the endurance training modality [11,12]. It
remains unclear what might account for any mode-specific
interference effect, although it has been suggested that this
may relate to the similarity between cycling and many
strength outcome measures [12,189], and/or the greater
eccentric muscle damage induced by running compared
with cycling [12]. Whether running exercise has the
capacity to induce greater catabolic molecular activity and/
or exacerbate residual neuromuscular fatigue in contrast to
cycling, which may in turn exacerbate interference, is
currently unclear. Relatively little is known regarding the
impact of running exercise on acute post-exercise adaptive
responses in skeletal muscle compared with cycling.
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Indeed, no studies performed to date have examined the
molecular responses to concurrent exercise incorporating
running as the endurance training modality. Given that the
majority of team-sport athletes (e.g., Australian football,
soccer, rugby, etc.) employ running as the predominant
endurance training modality and the anecdotal popularity
of running in recreational concurrent training regimes,
further work is required to examine the potential conse-
quences of the endurance exercise modality on acute
molecular interference and subsequent long-term adapta-
tion to concurrent training.
9 Conclusion
While considerable performance-based evidence exists for
the concurrent interference effect, limited data are available
regarding the molecular factors responsible and the role of
specific training variables in this phenomenon. The majority
of current molecular data suggests that endurance exercise
does not compromise early anabolic responses to resistance
exercise, consequently providing little mechanistic insight
into the interference effect seen following long-term con-
current training. However, findings from existing research
are complicated by the multitude of potential concurrent
training variables and the numerous independent factors
capable of influencing acute molecular responses to exer-
cise in human skeletal muscle. Thus, there is substantial
difficulty in deducing practical training recommendations
from existing research for minimizing interference between
concurrent resistance and endurance exercise. Moreover,
whilst considerable advances have been made with regards
to our understanding of the molecular factors mediating
training adaptation in skeletal muscle, these complex pro-
cesses are incompletely resolved. Observations that ana-
bolic signalling responses to exercise are not always
directly coupled to protein synthesis, and that these acute
responses are not necessarily predictive of chronic training
adaptations, represent significant limitations to acute-based
concurrent training studies. The possibility remains, there-
fore, that solely utilising early molecular responses to
concurrent exercise to extrapolate any putative chronic
interference effect may provide limited insight into factors
mediating interference following long-term concurrent
training. However, further elucidation of the molecular
factors mediating the specificity of training adaptation in
human skeletal muscle is warranted, which in turn may
provide additional mechanistic insight into the concurrent
interference phenomenon. Ultimately, improved under-
standing of the roles of individual concurrent training
variables, including within-session exercise order, length of
between-mode recovery, and endurance training volume,
intensity and modality, in modulating the interference effect
is required to guide exercise prescription for simultaneously
maximising divergent training adaptations. Future work
should aim to further clarify the roles of these training
variables in acute and particularly chronic interference in
trained individuals to inform practical recommendations for
minimising interference between concurrent resistance and
endurance exercise.
Acknowledgments No funding was used to assist in the preparation
of this review. The authors have no conflicts of interest to declare that
are directly relevant to the contents of this review. The authors would
like to thank Keith Baar (University of California Davis) for pro-
viding insightful comments on drafts of this manuscript.
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