Post on 29-Mar-2023
REVIEW ARTICLE
The Role of Oxidative, Inflammatory and NeuroendocrinologicalSystems During Exercise Stress in Athletes: Implicationsof Antioxidant Supplementation on Physiological AdaptationDuring Intensified Physical Training
Katie Slattery • David Bentley • Aaron J. Coutts
� Springer International Publishing Switzerland 2014
Abstract During periods of intensified physical training,
reactive oxygen species (ROS) release may exceed the pro-
tective capacity of the antioxidant system and lead to
dysregulation within the inflammatory and neuroendocrino-
logical systems. Consequently, the efficacy of exogenous
antioxidant supplementation to maintain the oxidative bal-
ance in states of exercise stress has been widely investigated.
The aim of this review was to (1) collate the findings of prior
research on the effect of intensive physical training on oxi-
dant–antioxidant balance; (2) summarise the influence of
antioxidant supplementation on the reduction-oxidation sig-
nalling pathways involved in physiological adaptation; and
(3) provide a synopsis on the interactions between the oxi-
dative, inflammatory and neuroendocrinological response to
exercise stimuli. Based on prior research, it is evident that
ROS are an underlying aetiology in the adaptive process;
however, the impact of antioxidant supplementation on
physiological adaptation remains unclear. Equivocal results
have been reported on the impact of antioxidant supplemen-
tation on exercise-induced gene expression. Further research
is required to establish whether the interference of antioxidant
supplementation consistently observed in animal-based and
in vivo research extends to a practical sports setting. More-
over, the varied results reported within the literature may be
due to the hormetic response of oxidative, inflammatory and
neuroendocrinological systems to an exercise stimulus. The
collective findings suggest that intensified physical training
places substantial stress on the body, which can manifest as an
adaptive or maladaptive physiological response. Additional
research is required to determine the efficacy of antioxidant
supplementation to minimise exercise-stress during intensive
training and promote an adaptive state.
Key Points
Exercise-induced increases in reactive oxygenspecies (ROS) act as intracellular messengers toregulate physiological adaptation. However, ifuncontrolled, elevated concentrations of ROS canlead to oxidative damage, and a state of oxidativestress has commonly been reported in athletes whoare in a chronically fatigued state.
Traditionally, antioxidant supplements have beenrecommended to assist in the maintenance ofhomeostatic balance within the oxidative,inflammatory and neuroendocrinological systems ofathletes undergoing intensified training periods.
Excessive intake of antioxidant supplements maysuppress this reduction-oxidation (redox) signallingprocess and therefore reduce the beneficial effects ofexercise at a cellular level. However, to date,equivocal findings have been reported from studiesinvestigating the potential of antioxidantsupplements to interfere with adaptation to exerciseand translate into a reduced performance capacity.
Further research is required to determine the
antioxidant requirements, which optimise the redox
balance in well-trained athletes to allow the
completion of intensive training without interfering
with cellular signalling processes.
K. Slattery � A. J. Coutts
Sport and Exercise Discipline Group, Faculty of Health,
University of Technology, Sydney, NSW, Australia
K. Slattery (&)
NSW Institute of Sport, PO Box 476, Sydney Olympic Park,
NSW 2127, Australia
e-mail: katie.slattery@nswis.com.au
D. Bentley
Human Exercise Performance Laboratory, School of Medical
Science, University of Adelaide, Adelaide, SA, Australia
123
Sports Med
DOI 10.1007/s40279-014-0282-7
1 Introduction
Physical training improves athletic performance in a
stimulus-response manner, dependent on the volume,
intensity and frequency of each exercise bout [1]. Like
other stressors, such as disease, environmental conditions
or trauma, exercise perturbs the homeostatic balance within
the body [2]. In order to retain homeostasis, an upregula-
tion of biological systems occurs, which exceeds the pre-
vious level of function. It is through this process that
adaptation to stress takes place [3]. Imbalances between
exercise-induced stress and recovery may cause these
physiological adaptations to be impaired, leaving an indi-
vidual in a maladaptive state where performance may
stagnate or even decline [4]. Indeed, prolonged periods of
intensified physical training may result in an accumulation
of fatigue, leading to short-term (non-functional over-
reaching) and long-term (overtraining) decrements in per-
formance capacity [4]. Excessive exercise may also
contribute to disturbances in biological function within the
metabolic [5, 6], neuroendocrinological [7], oxidative [8],
physiological [9], psychological [10] and immunological
[11] systems. Collectively, a dysregulation in these systems
may contribute to the signs and symptoms presented in
overreached/overtrained athletes and ultimately lead to
unwanted reductions in performance. Despite extensive
research, the underlying pathophysiological mechanism
and physical training load, which may either maximise
physiological adaptation or cause a state of maladaptation,
are yet to be fully understood.
An increased understanding of the multifactorial rela-
tionship between the oxidative, inflammatory and endo-
crinological systems during intensified training periods will
assist coaches, sports scientists and athletes to better elicit
the desired physiological adaptations to achieve peak per-
formance. Previously, well-written reviews have high-
lighted the potentially detrimental effects of antioxidant
supplementation on reduction-oxidation (redox) signalling
pathways based on research using predominately animal
models or untrained individuals [12–14]. It is important to
apply these findings in a broader practical sporting context.
Several studies have also identified that, whilst in a fati-
gued state, well-trained athletes have an increased sus-
ceptibility to oxidative stress and may benefit from
additional antioxidant supplementation [15–21]. Therefore,
the purpose of this review was to examine the interactions
between the oxidant–antioxidant balance, inflammation
and neuroendocrine regulation during periods of intensified
training that modulate physiological adaption. Relevant
literature was collated using a combination of keyword
search strings (‘exercise’, ‘physical training’, ‘overreach-
ing’, ‘overtraining’, ‘fatigue’, ‘performance’, ‘adaptation’,
‘oxidative stress’, ‘reactive oxygen species’, ‘free radical’,
‘antioxidant’, ‘redox’, ‘gene expression’, ‘homeostasis’,
‘hormesis’, ‘immune’, ‘inflammation’, ‘hormonal’, ‘endo-
crine’), for the time period between January 1985 and June
2014, in the Google Scholar, SPORTDiscus and US
National Library of Medicine PubMed databases. Key
papers were identified, cross-referenced and refined to
focus on investigations in the athletic population.
2 Free Radical Biochemistry and Exercise
2.1 Redox Reactions and Adaptation to Exercise
Free radicals are unstable atoms and molecules with one or
more unpaired electron [22]. Free radicals readily partici-
pate in redox reactions, resulting in a reduction of the free
radical and the subsequent oxidisation of the molecule [23].
The majority of free radicals are either oxygen- or nitro-
gen-based and are referred to as reactive oxygen species
(ROS) and reactive nitrogen species [23]. An increase in
ROS concentration acts as a biological messenger, initiat-
ing cellular signalling cascades via the process of electron
transfer to promote adaptive responses within the body
[24]. However, an uncontrolled oxidisation of molecules
can also lead to lipid, protein and DNA damage, resulting
in impaired cellular function [25]. Consequently, the body
has an elaborate antioxidant defence system to minimise
this oxidative damage from occurring by converting ROS
to less reactive molecules or by removing molecules that
may promote further oxidative reactions [26]. The redox
balance is easily disturbed by the rapid exercise-induced
increase in ROS from the blood and skeletal muscle [27,
28]. It is difficult to measure this ROS release directly
in vivo, leaving investigators reliant on indirect markers or
byproducts of oxidative stress to assess the effects of
exercise on redox balance. This is a major limitation of the
research to date as it is only assumed that increases in these
indirect measures are due to elevations in ROS production.
Nonetheless, the oxidative response to exercise has been
widely researched in relation to both health and athletic
performance.
Exercise-induced alterations in redox balance play an
important role in the modulation of numerous genetic
transcription pathways, which promote adaptations to
physical training (Fig. 1) [24, 29]. Many of these adapta-
tions are designed to protect the cellular structure from
further oxidative insults [30]. ROS release at the onset of
exercise initiates redox signalling cascades to improve
cellular antioxidant protection via the increased gene
transcription of multiple antioxidant enzymes [31]. Indi-
viduals who regularly participate in physical activity
K. Slattery et al.
123
display an augmented endogenous antioxidant enzyme
capacity [32–34] and an increased tolerance to exercise-
induced oxidative stress [35–38]. Redox signalling also
plays a central role in the upregulation of the mitogen-
activated protein kinase (MAPK) family. The MAPK
pathway modulates biological processes, including the
growth and differentiation of skeletal muscle fibres, glu-
cose transport and angiogenesis in a redox-dependent
manner [39]. Additionally, ROS signalling can promote
activation of the nuclear factor-kappa B (NF-jB) pathway
that directly impacts the expression of genes involved in
the acute-phase response, apoptosis, muscle fibre regener-
ation and metabolism [40]. Similarly, ROS can mediate the
heat shock protein (HSP) response to exercise [41].
Increases in HSP expression are necessary to maintain
cellular function in subsequent bouts of stressful exercise
by acting as intracellular chaperones for protein remodel-
ling and synthesis [41]. Furthermore, mitochondrial bio-
genesis is regulated by the redox-sensitive transcription of
peroxisome proliferators-activated receptor c coactivator-
1a (PGC-1a) [42, 43]. These findings emphasise the
importance of redox homeostasis in promoting physiolog-
ical adaptation and improved performance capacity fol-
lowing an exercise stimulus.
The process of redox signalling is complex and an over-
or under-production of ROS can result in a state of mal-
adaptation [44]. Low concentrations of ROS are necessary
for proper regulation of cellular function and adaptation to
exercise stress [45]. However, strenuous exercise can result
in an excessive production of ROS that results in oxidative
damage to cellular lipids, proteins and DNA, a condition
commonly referred to as oxidative stress [22]. During
periods of oxidative stress, the redox homeostatic point
may readjust and impair the redox signalling pathways
[23]. It is likely that during intensified physical training the
redox balance will be disrupted, inducing a state of chronic
oxidative stress which may contribute to a reduction in
athletic performance capacity [15, 16, 23, 46].
2.2 Intensified Physical Training Loads and Oxidative
Stress
In well-periodised physical training programmes, an indi-
vidual’s antioxidant defence system is capable of control-
ling exercise-induced oxidant production to promote an
optimal redox balance for muscle contractile function and
physiological adaptation [38, 47]. Each antioxidant sub-
stance acts to delay or prevent the cascade of oxidative
reactions by either donating an electron to stabilise the
reactive molecule or by removing molecules that propagate
oxidative reactions [26]. Numerous investigations have
reported reduced oxidative disturbance following short-
term training interventions, indicating that the individual is
adapting appropriately to the imposed physical training
load [33, 35, 48–50]. In contrast, unaccustomed, high-
intensity, prolonged or strenuous exercise can place a
considerable strain on the antioxidant system and lead to a
state of oxidative stress [21, 25, 51, 52]. Research has
shown that the endothelial cells of well-trained triathletes
who trained at a higher exercise intensity have a reduced
tolerance to oxidative insults than those who regularly train
at a lower intensity [52]. These sustained increases in
Fig. 1 Schematic diagram
illustrating redox signalling
pathways for skeletal muscle
adaptation. AP-1 activator
protein 1, IGF insulin-like
growth factor, GH growth
hormone, H2O2 hydrogen
peroxide, HSF-1 heat shock
factor 1, HSP70 heat shock
protein 70, IL interleukin,
MAPK mitogen-activated
protein kinase, MCP-1
monocyte chemoattractant
protein-1, mRNA messenger
RNA, NF-jB nuclear factor-
kappa B, O2 oxygen, PGC-1aperoxisome proliferators-
activated receptor c coactivator-
1a, PPARc peroxisome
proliferator-activated receptor,
ROS reactive oxygen species,
TNF tumor necrosis factor
Redox Status and Physiological Adaptation
123
oxidant production may lead to disturbances in redox
homeostasis, potentially leading to physiological malad-
aptation [53]. In fact, oxidative stress has been suggested to
be one possible factor underlying non-functional over-
reaching and overtraining in athletes.
Studies examining the oxidant–antioxidant balance in
both endurance and team-sport athletes have identified a
possible relationship between training load and the level of
oxidative stress [15–21]. These investigations have shown
that during intensified training periods, athletes may dis-
play increased levels of oxidative damage and a blunted
antioxidant response to exercise. For instance, Finaud et al.
[16] reported significantly higher oxidative damage (67 %
increase in conjugated diene oxidation) and impaired
antioxidant protection (8.7 % decrease in plasma vitamin
E) in 17 male professional rugby players during a 4-week
intensive training period. Similarly, post-exercise measures
of oxidative damage (lipid peroxidation) were elevated and
antioxidant status was reduced in nine well-trained male
triathletes following a 4-week overtraining period [15].
Collectively, these findings suggest that during periods of
excessive physical training, the antioxidant system may
become overwhelmed by repeated bouts of exercise-
induced oxidant production. This decrease in antioxidant
capacity may leave athletes more susceptible to oxidative
damage and lead to a chronic state of oxidative stress.
Not all investigations have demonstrated this concise
inter-relationship between training load, oxidative stress
and antioxidant defences. Tanskanen et al. [17] reported a
significant increase in oxidative stress (reduced glutathi-
one:glutathione ratio) and lipid peroxidation at rest in 11
overreached military personnel without observing any
changes in resting or post-exercise measures of protein
oxidation or antioxidant capacity. When basal oxidative/
antioxidant measures were collected throughout a com-
petitive season in ten professional handball players,
markers of oxidative stress were elevated and antioxidant
enzymes were upregulated during more strenuous training
periods [20]. Other well-designed investigations have
shown no dose-response effect of intensified training on the
redox balance [47, 54, 55]. The inconsistency of previous
research may be attributed to the relatively low number of
studies focussed on athletic populations, the different bio-
chemical markers used to assess redox balance, and vari-
ations in performance measures, training and testing
procedures. A summary of these previous investigations is
provided in Table 1. These methodological disparities
make it difficult to synthesise the impact of intensified
training on oxidative stress; however, there is evidence to
suggest that ROS are an underlying aetiology in exercise-
induced disturbances in homeostasis. The majority of these
studies show that whilst a moderate level of ROS is a
necessary prerequisite for adaptation to exercise [56],
sustained increases in oxidant production are likely to
impair competitive performance [15, 53, 57, 58]. At pres-
ent, the threshold where oxidative stress becomes detri-
mental, as opposed to beneficial, to performance remains
unclear. Further research examining the relative impact of
increased ROS production on redox signalling pathways
and the regulation of other physiological responses (i.e.
neuroendocrinological) to exercise is warranted [15–19, 47,
53–55, 58–89]
2.3 Antioxidant Supplementation and Adaptation
to Exercise
An antioxidant is a substance which can delay or prevent
the oxidation of other substrates [90]. Antioxidants are
present in both the intra- and extracellular matrix, and form
a complex defence system to protect cells and tissues
against excessive oxidative damage to lipids, proteins and
nucleic acids [90]. During exercise, the elevated oxidant
production in skeletal muscle is controlled by a synergistic
response between the endogenous antioxidant system and
the antioxidant vitamins and minerals consumed as part of
a well-balanced diet [91]. The antioxidant system readily
adapts to physical training stimuli to counterbalance the
potentially harmful effects of excessive exercise-induced
ROS and to maintain the redox-controlled signalling
pathways [31]. However, it has been suggested that as
athletes incur an increased amount of oxidative stress
during repeated bouts of exercise, they may require a
greater amount of exogenous antioxidants to maintain
health and improve performance [54, 92].
Well-trained athletes generally have an enhanced anti-
oxidant capacity and are less susceptible to perturbations in
redox balance compared with the sedentary population
[35–38, 93, 94]. This supports the benefits of regular
exercise to promote health and well-being. However, fac-
tors such as a sudden increase in physical training load [15,
17, 54], exposure to altitude/hypoxic conditions [56, 95],
prolonged strenuous exercise [51, 62, 96] or pollution [63]
may exceed an athlete’s antioxidant capacity to buffer
oxidant production. Likewise, a low dietary intake of
antioxidants may reduce an athlete’s ability to detoxify
exercise-induced ROS production [97–99]. Insufficient
antioxidant protection may then contribute to elevated
oxidative stress levels, altered neuroendocrine regulation,
excessive skeletal muscle damage and/or an inability to
adapt to continued physical training stimuli (for compre-
hensive reviews, see Tiidus [8, 100–103], Peake et al. [8,
100–103], Fragala et al. [8, 100–103], Duntas [8, 100–103]
and Vollaard et al. [8, 100–103]). Previous research has
also identified that well-trained athletes may be at an
increased risk of oxidative damage due to an insufficient
dietary intake of antioxidants [99]. Consequently, the use
K. Slattery et al.
123
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K. Slattery et al.
123
Ta
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Redox Status and Physiological Adaptation
123
Ta
ble
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nti
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K. Slattery et al.
123
of exogenous antioxidant supplementation to maintain
antioxidant status has been extensively researched. There is
evidence which supports the ability of antioxidant com-
pounds to blunt the oxidative [57, 104–112], inflammatory
[57, 104, 110, 112–116] and hormonal [117–120] response
to exercise. Indeed, 5 days of supplementation with tart
cherry juice (active ingredients: 600 mg phenolic com-
pounds and 560 mg flavonoid compounds) reduced oxi-
dative damage (thiobarbituric acid-reactive substances
[TBARS] and protein carbonyls) and markers of muscle
inflammation (interleukin [IL]-6 and C-reactive protein
[CRP]) 48 h post-marathon in 20 well-trained runners [57].
Similar reductions in post-exercise measures of oxidative
stress (F2-isoprostanes) and muscle damage (creatine
kinase [CK]) have been observed in 12 collegiate soccer
players who consumed a mixture of antioxidant substances
(Resurgex Plus�) for a 3-week period compared with a
placebo (isocaloric equivalent) [109]. These findings sup-
port the hypothesis that antioxidant supplementation may
assist athletes to better cope with intensified training peri-
ods and prevent reductions in performance capacity during
strenuous exercise [54, 85, 92].
Due to the reported protective effects of antioxidants,
many athletes habitually take antioxidant supplements
[121]; however, exogenous antioxidant compounds may
prevent or reduce useful adaptive processes to exercise
from occurring, especially if taken in high doses [122–
126]. Administration of 1,000 mg/day vitamin C and
400 IU/day of vitamin E in 19 untrained and 20 active
males has been shown to inhibit training-induced increases
in skeletal muscle protein concentrations of transcription
factors involved in mitochondrial biogenesis (PGC-1a),
insulin sensitivity (peroxisome proliferator-activated
receptor gamma [PPARc]) and a reduced messenger RNA
(mRNA) concentration of antioxidant enzymes (glutathi-
one peroxidase and superoxide dismutase) when compared
with a placebo [125]. Exercise-induced increases in skel-
etal muscle and lymphocyte HSP expression can be
impeded following antioxidant supplementation [127, 128].
Recent findings have also shown that, compared with a
placebo, resveratrol supplementation (250 mg/day) over an
8-week period impaired the training-induced increases in
maximal oxygen uptake in previously untrained elderly
men [124]. Moreover, depending on the dosage and site of
activity, certain antioxidants exert a pro-oxidant effect, as
demonstrated by the association of large doses of vitamin C
(12.5 mg/kg body weight), with higher levels of exercise-
induced oxidative damage and impaired recovery of mus-
cle function [129]. Based on these findings, it is currently
recommended that rather than using supplements, physi-
cally active individuals should focus on consuming a well-
balanced diet that includes a variety of high-antioxidant
foods [130, 131].
An attenuation of redox signalling and adaptation with
antioxidant supplementation has not been consistently
shown during whole-body exercise in human subjects [65,
110, 132, 133]. Whilst N-acetylcysteine (NAC) infusion
(125 mg/kg/h for 15 min, 25 mg/kg/h throughout exercise)
blocked the post-exercise phosphorlyation of c-Jun N-ter-
minal kinase, no effect was observed within the NF-jB or
MAPK pathways, following a cycle ergometer test in eight
endurance-trained men [133]. Similarly, quercetin supple-
mentation (1,000 mg/day) promoted skeletal muscle
mRNA expression of genes involved in mitochondrial
biogenesis in 26 previously untrained males during a
2-week physical training period [65]. The additional
quercetin also induced a greater increase in muscle mito-
chondrial DNA (4.1 % increase) compared with the pla-
cebo trial (6.0 % decrease) [65]. Indeed, whilst suppression
of transcription factor activation with antioxidant supple-
mentation has been consistently demonstrated in animal
and in vivo investigations [122, 134–137], it is more dif-
ficult to establish similar results in well-trained human
subjects during periods of physical training.
Further research is necessary to determine the ability of
antioxidant supplementation to blunt exercise-induced
adaptation in athletes as previous findings are equivocal
and inconclusive [138]. This may be due to the numerous
confounding variables, including varying experimental
designs, supplementation protocols (antioxidant com-
pound, dosage, length of supplementation period), modes
of exercise and previous training history. There is also a
paucity of research conducted in the athletic population,
focusing on the resultant effect of redox-mediated gene
expression on performance capacity. Nonetheless, these
findings highlight the precarious balance within the redox
signalling processes. It is likely that both an insufficient
and an excessive amount of exogenous antioxidant con-
sumption will have a negative effect on the adaptive pro-
cess. Therefore, the consumption of supranutritional
antioxidant supplements may need to be periodised to
provide additional support only when it is required. Ath-
letes may benefit from additional antioxidant intake via
concentrated whole-food sources (i.e. tart cherry or
pomegranate juice) or the use of combined antioxidant
mixtures (i.e. vitamin A, C and E, polyphenols and/or
flavonoids) during short-term periods (4–6 weeks) of
increased exercise-stress (i.e. intensified training blocks or
sojourns to altitude). Likewise, acute loading periods
(1–2 weeks) with antioxidants such as NAC or quercetin
may be useful to gain a potential ergogenic effect during
competitive performances. Further research is required in
well-trained athletes in varied fatigued states to develop an
evidence-based model, which considers the holistic and
interactive effect of antioxidant supplementation on phys-
iological adaptation and performance.
Redox Status and Physiological Adaptation
123
3 Interplay Between Inflammatory, Hormonal
and Oxidative Responses during Exercise
3.1 Oxidants and Exercise-Induced Inflammation
The mechanical and metabolic stress of exercise can result
in damage to the structural integrity of myofibres and cause
temporary reductions in contractile function [139]. Fol-
lowing exercise-induced injury, an inflammatory cascade is
activated via the upregulation of pro-inflammatory cyto-
kines, chemokines and stress hormones that act as chemical
messengers to modulate the repair and regenerative pro-
cesses [140]. Inflammation is characterised by the mobili-
sation and infiltration of phagocytic cells, which release
proteolytic enzymes and ROS to remove necrotic tissue
and cellular debris [141]. This response is associated with
an increased membrane permeability and subsequent
leakage of the intracellular enzymes CK and lactate
dehydrogenase (LDH) from muscle tissue, combined with
the hepatic release of acute-phase proteins such as CRP,
transferrin and a-macroglobulin [140]. Once necrotic tissue
is removed, satellite cells proliferate to regenerate skeletal
muscle tissue through the regulation of transcription factors
[142]. It is through this process that the exercise-induced
inflammation reaction plays an important role in cellular
remodelling and enhancement of the proteolytic pathways
to promote hypertrophic adaptations [143].
The oxidant system is closely involved in the inflam-
matory process and contributes to the aetiology of exer-
cise-induced muscle damage through a number of
mechanisms [144–146]. For example, during skeletal
muscle contraction, the ROS released through mitochon-
drial respiration can cause direct oxidative damage to
protein structure [147]. As a result, oxidised proteins often
become functionally inactive and are highly susceptible to
proteolytic degradation, rendering them unable to perform
normal cellular functions [148]. The damaged proteins are
then removed by the activation of the acute-phase
inflammatory response. At the site of the injury, circulat-
ing neutrophils generate additional ROS via an ‘oxidative
burst’ [149]. This reaction is catalysed by the enzyme
nicotinamide-adenine dinucleotide phosphate (NADPH)
oxidase which reduces extracellular oxygen to form the
superoxide anion [149]. Superoxide can then react to form
other ROS, including hydrogen peroxide, hypochlorous
acid, and the hydroxyl radical [23]. Together, these
unstable oxygen-derived species destroy the apoptotic and
necrotic cells. These powerful oxidants may also cause
damage to the neutrophil itself and healthy cells near the
site of inflammation [149]. Indeed, for up to 48 h post the
initial exercise bout, further ROS generation via NADPH
oxidase activity and increased xanthine oxidase activation
during ischemia reperfusion can continue to cause injury
and inflammation reactions in the skeletal muscle tissue
[150, 151]. However, in properly periodised training pro-
grammes, the exercise-induced inflammatory response is
well controlled and acts to facilitate the repair and resto-
ration of contractile function.
Increased ROS release can also mediate signalling
pathways to modify gene expression of transcription factors
involved in the inflammatory cascade. The redox-sensitive
transcription factor, NF-jB has been extensively researched
in its role as a central mediator of the stress-response to
exercise [39]. Activation of NF-jB has been shown to occur
via a number of exercise-induced stimuli, including ROS,
cytokines, elevated intracellular calcium, thyroid hormones
and the MAPK pathway [152]. NF-jB is located in the cell
cytoplasm bound to IjB inhibitor proteins (IjB). When NF-
jB is activated, the IjB is phosphorylated, allowing the NF-
jB to rapidly dissociate, translocate into the nucleus and
bind to the DNA sequence of target genes [153]. It is in this
manner that NF-jB can trigger the release of pro-inflam-
matory mediators, including chemokines, cytokines, acute-
phase proteins and adhesion molecules, to facilitate the
regenerative responses in damaged skeletal muscle [154].
The NF-jB pathway also promotes cell protection via the
transduction of antioxidant enzymes (i.e. superoxide dis-
mutase) within skeletal muscle [134]. Combined, these
results demonstrate that the transient activation of the NF-
jB pathway promotes adaptive responses to increase the
functional capacity of skeletal tissue. However, when NF-
jB is chronically activated it can cause dysregulation within
the oxidative and metabolic systems, leading to unwanted
skeletal muscle atrophy and insulin resistance [39]. This
sustained activation of NF-jB may occur due to exercise-
induced oxidative perturbation of the redox balance during
periods of intensified physical training [23].
Eccentric, prolonged, high-intensity, strenuous or
unaccustomed bouts of exercise have been associated with
substantial increases in contractile-induced damage and
inflammation reactions [155]. Following these types of
exercise, the functional performance capacity of skeletal
muscle is likely to be reduced for 24–96 h post the initial
injury [156–158]. Whilst exercise-induced inflammation is
a necessary precursor to muscle growth, the uncontrolled
proliferation of inflammatory cells and oxidants can exac-
erbate muscle damage. Additionally, if the injury stimulus
is repeated prior to restoration of muscle function, a state of
low-grade chronic inflammation may develop [11]. Dys-
regulation in the inflammatory system has been observed in
athletes undergoing intense periods of physical training, as
evidenced by excessive delayed-onset muscle soreness,
muscle stiffness, reduction in muscle strength, increased
CK activity and impaired immune function [159–161]. To
prevent the potential negative effects of inflammation, the
efficacy of nutritional antioxidant interventions to
K. Slattery et al.
123
minimise the exercise-induced oxidative damage has been
widely investigated.
3.2 Effect of Antioxidant Supplementation
on Inflammation
Excessive exercise-induced muscle damage and inflam-
mation can cause significant reductions in athletic perfor-
mance capacity [157, 162] and lead to a reduced tolerance
of demanding physical training loads [11]. The consump-
tion of exogenous antioxidants supplements, such as co-
enyzme Q10 (1,500 mg oral dose over a 3-day period), may
decrease the oxidative insult and subsequent inflammation
reaction to exercise [104]. Studies have investigated the
ability of antioxidant compounds to minimise the inflam-
matory response using an array of exercise modalities.
Antioxidants including flavonoids and polyphenol com-
pounds have been reported to effectively reduce post-
exercise markers of inflammation, such as CRP, and min-
imise the upregulation of pro-inflammatory cytokines [57,
104, 113]. Additionally, exogenous antioxidant supple-
mentation with tart cherry (30 ml twice daily for 10 days)
or pomegranate (250 ml twice daily for 15 days) juice can
accelerate recovery of muscle function following damaging
exercise [107, 163, 164]. It is therefore unsurprising that
prolonged antioxidant supplementation periods have also
been shown to reduce the cumulative inflammatory effects
experienced by athletes during periods of high-intensity
training [116, 132]. Thus, it is evident that an additional
antioxidant intake, whether causally or indirectly, can
decrease the exercise-induced inflammatory response;
however, a reduction in inflammatory mediators with
antioxidant supplementation has not been consistently
shown [112, 165–170].
The differing results from the studies that have exam-
ined the efficacy of antioxidants to combat exercise-
induced inflammation may be due to a number of factors,
including exercise type, antioxidant compound/dosage and
the training status of the participants investigated; for
instance, several studies that have shown no effect of
antioxidant supplementation on the inflammation reaction
using exercise models that were extremely strenuous (i.e.
ultra-marathons, prolonged cycling) [165–168], or utilised
purposefully damaging eccentric exercise bouts [171]. It is
likely that when severe mechanical stress is placed on
contractile fibres, damage and inflammation will occur
irrespective of any additional antioxidant protection. Fur-
thermore, supranutritional doses of antioxidants have been
demonstrated to exert a pro-oxidant effect, which can
exacerbate muscle damage [129]. Prolonged antioxidant
supplementation may also impair redox signalling of
endogenous antioxidant enzyme gene upregulation and
leave cells more susceptible to oxidative damage [134].
Another possible explanation is that an increased level of
inflammation and muscle damage after acute bouts of
exercise may be indicative of a greater amount of work
completed with the support of antioxidant supplements. For
example, when 12 recreationally-trained males consumed
the antioxidant NAC (50 mg/kg/day oral dosage), an
increased level of muscle damage was associated with
significant improvements in repeat-sprint running perfor-
mance [172]. Because of this complex relationship between
redox balance and the exercise-induced inflammatory
response, it is difficult to establish guidelines for antioxi-
dant supplementation in athletes.
Contention exists amongst sport and exercise research-
ers as to whether minimising oxidative stress and inflam-
mation is beneficial or detrimental to physiological
adaptation and athletic performance [122, 173]. Inflam-
mation is an important stage in the repair and regeneration
of damaged skeletal muscle tissue [146]. If the inflamma-
tory response is restricted by antioxidant supplementation,
recovery from exercise-induced skeletal muscle damage
may be impaired, resulting in an increased oxidative stress
response during subsequent bouts of exercise [174]. Con-
versely, the consumption of additional exogenous antioxi-
dant supplements can decrease the exercise-induced
oxidative insult and systemic stress reaction during inten-
sified training periods [54]. For instance, antioxidant sup-
plementation has been associated with a reduced secretion
of the stress hormone cortisol [117, 119, 120]. Supple-
mentation with concentrated fruit juices (i.e. tart cherry or
pomegranate) with potent antioxidant properties appear to
be most effective in reducing exercise-induced inflamma-
tion without unwanted side effects. It is currently not clear
whether this observed reduction in hormone release is due
to a systemic reduction in exercise stress, or a direct
interaction between the redox, inflammatory and neuroen-
docrine systems.
3.3 Oxidants and the Neuroendocrine Response
to Exercise
The neuroendocrine system plays an important role in
maintaining homeostatic control during exercise bouts
[175]. It is a complex and integrative system of commu-
nication between the central nervous system, endocrine
glands, hormones and target cells [176]. In response to an
exercise stress, hormones are released via the hypotha-
lamic-pituitary-adrenocortical axis and sympathetic-adre-
nal-medullary axis, which bind to specific receptors
expressed on target cells to trigger a physiologic response
[176]. Levels of circulating hormones are rapidly elevated
in response to an acute exercise bout and are influenced by
a multitude of exercise-related factors (i.e. exercise dura-
tion, intensity and mode) and non-exercise-related factors
Redox Status and Physiological Adaptation
123
(i.e. psychological stress, temperature, nutrition, hypoxia,
hydration status and circadian rhythm) [177]. Adaptation
and accommodation within the neuroendocrine stress
response has been observed through an attenuation of
hormone secretion (i.e. cortisol and catecholamines) during
exercise at the same relative workload [7]. In general,
exercise-induced increases in circulating hormones are
transient and levels return to baseline or slightly below
basal values at the cessation of physical activity [176].
However, following extremely stressful exercise or during
intensified periods of training, a prolonged release of hor-
mones is likely to occur [7]. This sustained rise in circu-
lating hormones caused by strenuous exercise may lead to
an increased oxidant release and can negatively affect
homeostasis via the promotion of a catabolic signalling
environment.
Elevations in catecholamine [178] and thyroid hormone
[179] occurs at the onset of exercise to assist in the
regulation of metabolic, muscular and cardiocirculatory
reactions; however, the exercise-induced and/or sustained
elevations in these hormones during periods of chronic
stress may also contribute to a greater amount of oxida-
tive stress. Early research by Misra and Fridovich [180]
demonstrated experimentally that the auto-oxidation of
catecholamines is an additional source of the ROS
superoxide. The increase in circulating catecholamines
during exercise can also bind to b-adrenergic receptors,
which elevate sympathetic activity and augment skeletal
muscle oxidative metabolism [181]. This increase in cel-
lular respiration may result in a greater oxygen flow and
ROS (superoxide) formation through the mitochondrial
electron transport chain [182]. Likewise, elevations in
thyroid hormones can promote a hypermetabolic state,
resulting in an increased oxygen flux and subsequent
superoxide release from the mitochondria [183]. This
additional release of ROS may then start a chain reaction
in which superoxide is the propagating species, resulting
in oxidative cellular damage and the loss of cell function.
Increases in oxidant production have also been linked to
thyroid hormone-induced hyperplasia and hypertrophy of
phagocytic cells, leading to increased superoxide forma-
tion via oxidative burst activity during inflammation
reactions [184]. Furthermore, the thyroid hormones can
induce NF-jB activation, which, if sustained for pro-
longed periods, may cause cachexia and muscle wastage
[185]. These factors combined suggest that exercise-
induced activation of the neuroendocrine system can
contribute to oxidative muscle injury [186].
The neuroendocrine and redox systems are both integral
in coordinating the metabolic response to a stress stimulus.
A synergistic action occurs between exercise-induced
increases in glucocorticoids (i.e. cortisol) and insulin hor-
mones to facilitate glucose transport and promote lipolysis
to meet the energy demands of physical activity [187].
Likewise, ROS signalling has also been demonstrated to, in
part, mediate glucose uptake to the skeletal muscle during
exercise [188]. Additionally, redox-sensitive genes, PPARcand MAPK initiate positive adaptive mechanisms to
increase insulin sensitivity and promote cellular remodel-
ling and regeneration [31, 125]. This metabolic upregula-
tion creates an anabolic environment, which is conducive
to cellular growth and adaptation; however, prolonged
perturbations in both the redox and allostatic balance dur-
ing strenuous training periods can disrupt the normal reg-
ulatory effects of the neuroendocrine system [187, 189]. A
pro-oxidant shift in redox-sensitive signalling pathways
may also impair glucose transport and increase insulin
resistance within skeletal muscle due to altered patterns of
gene expression within pro-inflammatory transcription
factors (i.e. NF-jB) [188, 190]. This resultant increase in
inflammation may promote further oxidative damage and
impair protein translocation and synthesis leading to skel-
etal muscle atrophy [24]. Furthermore, it has been dem-
onstrated that damaged myofibres have a reduced glycogen
resynthesis rate, which may also contribute to metabolic
dysregulation and a reduced performance capacity during
strenuous training periods [191]. These findings highlight
that exercise performance and physiological adaptation are
reliant on the collective inputs from the oxidative,
inflammatory and hormonal systems.
3.4 Hormesis, Exercise, and the Inflammatory,
Neuroendocrine and Oxidative Systems
Significant interplay exists between the oxidative, inflam-
matory and neuroendocrine reaction to an exercise stimuli.
Physiological changes in response to acute bouts of exer-
cise and training-induced adaptations are reliant on the
proper functioning and cohesion amongst the respective
systems. At the onset of exercise, rapid alterations in the
intracellular redox milieu occur, which acts to regulate
biological responses and mediate cellular adaptation via the
induction of gene transduction pathways [24]. It is through
these adaptive processes that the body is able to tolerate
progressive increases in training load. However, an over- or
underproduction of ROS may cause interference with
redox-sensitive signalling cascades, resulting in a state of
chronic inflammation and dysregulation within the neuro-
endocrine system [2]. The theory of hormesis explains the
apparent dichotomy in the occurrence of both positive and
negative physiological responses in reaction to perturba-
tions within the redox balance [44]. A hormetic effect is
characterised by a bidirectional dose-response relationship,
whereby at a low dose, potentially toxic substances stim-
ulate beneficial effects, yet a high dose of the same sub-
stance is inhibitory [192]. Indeed, the principle of hormesis
K. Slattery et al.
123
can also be extrapolated to encompass a variety of the
observed exercise-induced pathophysiological reactions to
physical training and the resultant impact on performance
capacity (Fig. 2).
The concentration of ROS has been shown to exert a
hormetic response during skeletal muscle contraction. For
instance, a low myofibril concentration of ROS can
enhance calcium release from the sarcoplasmic reticulum
and increases force production [193]. However, high con-
centrations of ROS have been linked to decreases in con-
tractile force due to an inhibition of calcium sensitivity
[194], dysregulation of muscle Na?/K?-pump activity [89]
and reduced mitochondrial integrity [195]. Hormesis is also
evident in the inflammatory response to exercise. Whilst
the inflammatory reaction is an important step in the
regeneration of damaged muscle fibres, chronic activation
of inflammatory mediators may lead to immunosuppression
and skeletal muscle atrophy [8, 11]. Similarly, exercise-
induced secretion of glucocorticoid hormones can exert
both a stimulatory anabolic effect on glucose metabolism
and a catabolic effect by the inhibition of protein synthesis
[7]. In essence, exercise is also an example of hormesis.
Habitual physical activity stimulates upregulation of the
antioxidant defence system and greatly benefits health and
well-being [196]. In contrast, excessive exercise can lead to
a sustained increase in oxidative stress, resulting in a
greater susceptibility to illness and an impaired perfor-
mance capacity [8]. These examples highlight the impor-
tance of finding a balance between physical training loads
and recovery periods to provide the optimal hormetic dose
of exercise stimuli, which improves performance in a
practical sports setting.
4 Limitations and Directions for Future Research
Despite considerable research investigating the stress
response and adaptation to exercise, the physical training
dose required to produce an optimal performance for each
individual remains unclear. A major confounding factor is
the complex nature of exercise adaptation. Most bioactive
substances can induce both a positive and negative
physiological response. It is therefore important to
investigate the respective changes in a variety of biolog-
ical systems to ensure an accurate and holistic assessment
of training-induced perturbation. To date, comparatively
few studies have examined the synergistic response within
oxidative, inflammatory and neuroendocrine systems to
exercise stress in well-trained athletes [15, 197]. In
addition, a large number of studies have utilised animal
models to assess the process of physiological adaptation
during relatively short periods (1–3 months), which may
have limited relevance to an athletic population [134,
173]. These animal-based experiments have provided
valuable insight and an increased understanding of
adaptation at a transcriptional level. However, an upreg-
ulation in gene expression may not directly transfer to an
increase in post-translational protein synthesis and/or
performance improvements [24]. Further research is
required to gain a more in-depth understanding of the
Fig. 2 The hormetic effect of
exercise parameters on
performance. : indicates
increase, ; indicates decrease,
ROS reactive oxygen species,
redox reduction-oxidation
Redox Status and Physiological Adaptation
123
synergistic responses within the oxidative, inflammatory
and neuroendocrine systems to modulate exercise-induced
physiological adaptation.
5 Summary and Conclusions
Exercise triggers a systemic stress response and upregula-
tion of biological systems to meet the additional work
demands. This disruption in homeostasis activates a series
of signalling cascades designed to restore balance and
increase tolerance to subsequent bouts of exercise. It is
through this process that physical training improves ath-
letic performance capacity. Indeed, exercise-induced
changes within the oxidative, inflammatory and neuroen-
docrine systems are heavily involved in the adaptive pro-
cess to a training stimulus. The proper functioning of these
systems may be impaired during acute bouts of strenuous
exercise, and chronic dysregulation has been observed in
excessively fatigued athletes. It has been suggested that
exogenous supplementation of antioxidants may reduce the
stress response to exercise and assist athletes to cope with
increased training loads; however, a reduction in exercise-
stress may also attenuate redox-mediated adaptive pro-
cesses. Further examination is therefore required to
appropriately titrate the additional antioxidant require-
ments for individuals during periods of increased training
stress, which will promote redox-regulated gene tran-
scription and enhance athletic performance.
Acknowledgments No funding or sponsorship was provided for the
preparation of this manuscript. Katie Slattery, David Bentley and
Aaron Coutts have no conflicts of interest. All authors contributed
fully to the preparation of this manuscript. All human and animal
studies have been approved by the appropriate Ethics Committee and
have therefore been performed in accordance with the Helsinki
Declaration. All participants provided informed consent prior to
inclusion in the study.
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