The Role of Oxidative, Inflammatory and Neuroendocrinological

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: [email protected]

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.

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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.


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


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


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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