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Exercise-induced muscle damage: What is it, what causes it and what are the
nutritional solutions?

Article in European Journal of Sport Science · August 2018

DOI: 10.1080/17461391.2018.1505957

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Title
Exercise-induced muscle damage: what is it, what causes it and what
are the nutritional solutions?

Authors
Daniel J. Owens1, Craig Twist2, James N. Cobley3, Glyn Howatson4,5 and Graeme L. Close1

Author affiliations
1
Research Institute for Sport and Exercise Science, Liverpool John Moores University. Liverpool, UK.
2
Department of Sport and Exercise Sciences, University of Chester, Chester, UK.
3
Department of Diabetes and Cardiovascular Disease, Center of Health Sciences, University of the
Highlands and Islands, Inverness, IV2 3JH. UK.
4
Department of Sport, Exercise & Rehabilitation, Northumbria University, Newcastle upon Tyne, UK
5
Water Research Group, North West University, Potchefstroom, South Africa

Corresponding author
Prof. Graeme L. Close
Research Institute for Sport and Exercise Science, Liverpool John Moores University
Tom Reilly Building
Byrom Street
Liverpool
L3 3AF
Email: [email protected]
Phone: 0151 904 6266
Abstract

Exercise-induced muscle damage (EIMD) is characterised by symptoms that present both

immediately and for up to 14 days after the initial exercise bout. The main consequence of
EIMD for the athlete is the loss of skeletal muscle function and soreness. As such, numerous
nutrients and functional foods have been examined for their potential to ameliorate the effects
of EIMD and accelerate recovery, which is the purpose of many nutritional strategies for the
athlete. However, the trade-off between recovery and adaptation is rarely considered. For
example, many nutritional interventions described in this review target oxidative stress and
inflammation, both thought to contribute to EIMD but are also crucial for the recovery and
adaptation process. This calls into question whether long term administration of supplements
and functional foods used to target EIMD is indeed best practice. This rapidly growing area of
sports nutrition will benefit from careful consideration of the potential hormetic effect of long
term use of nutritional aids that ameliorate muscle damage. This review provides a concise
overview of what EIMD is, its causes and consequences and critically evaluates potential
nutritional strategies to ameliorate EIMD. We present a pragmatic practical summary that can
be adopted by practitioners and direct future research, with the purpose of pushing the field to
better consider the fine balance between recovery and adaptation and the potential that
nutritional interventions have in modulating this balance.

Key words: Muscle, Nutrition, Exercise, Damage

2
Article

1. Introduction

Exercise-induced muscle damage (EIMD) is characterised by symptoms that

present both immediately and for up to ~14 days after the initial exercise bout. The
consequences of EIMD for the athlete is the direct impact on functional capacity,
muscle soreness (Byrne, Eston, & Edwards, 2001), exercise capacity (Marcora &
Bosio, 2007; Twist & Eston, 2009) and disturbed sense of force production and limb
position (Paschalis et al., 2010). The magnitude and time course of these symptoms
and their subsequent impact on performance are variable and depend on the intensity
and duration of the damaging exercise and the individual’s susceptibility to the
damaging stimulus (Reviewed by Douglas, Pearson, Ross, & McGuigan, 2017).

The EIMD associated losses in muscle function and increases in muscle soreness
are important to athletes given their potential to impair performance. Accordingly, the
focus of many sports nutrition strategies is to maximise the recovery from exercise and
prepare for the next exercise bout. Numerous nutrients and functional foods have been
examined for their potential to ameliorate EIMD. However, few studies have examined
the balance between adequate exercise stress to stimulate adaptation and the need
to intervene to avoid inadequate recovery or maladaptation (a phenomenon termed
hormesis), creating difficulty when making assumptions about chronic exposure to
nutritional compounds. In this review, we provide an overview of EIMD, its causes and
consequences and then critically evaluate nutritional strategies that have the potential
to ameliorate muscle damage. We conclude by presenting future research directions
and recommendations for the management of EIMD.

2. Proposed mechanisms of EIMD

High force eccentric muscle actions typically produce ultrastructural muscular

disruption (i.e. Z-line streaming and fibre degradation), delayed onset muscle soreness
(DOMS), increases in specific intramuscular proteins in circulation, swelling of the
affected limb, decreased range of motion and impaired muscle force producing
capacity (Byrne, Twist, & Eston, 2004; Hyldahl & Hubal, 2014; Mackey & Kjaer, 2017).
Modes of exercise that usually result in these symptoms include: resistance training
(Burt, Lamb, Nicholas, & Twist, 2014), prolonged running (Millet et al., 2011), downhill
running (Chen, Nosaka, Lin, Chen, & Wu, 2009), and intermittent, high intensity
exercise (Leeder et al., 2014). The magnitude of damage resulting from eccentric

3
actions is exacerbated when performed at longer muscle length (Child, Saxton, &
Donnelly, 1998; Nosaka & Sakamoto, 2001), with greater forces (Nosaka & Sakamoto,
2001) and at faster angular velocities (Chapman, Newton, Sacco, & Nosaka, 2006). A
muscle’s susceptibility to damage might also be reduced for subsequent bouts where
prior exposure to eccentric exercise has occurred (Stupka, Tarnopolsky, Yardley, &
Phillips, 2001). This protective adaptation is known as the repeated bout effect; RBE
(Reviewed in detail by Hyldahl, Chen, & Nosaka, 2017).

The extent of muscle damage is typically assessed by measuring various indirect

markers. Reduced muscle force after eccentric exercise is the most appropriate
indirect marker (Damas, Nosaka, Libardi, Chen, & Ugrinowitsch, 2016; Paulsen,
Mikkelsen, Raastad, & Peake, 2012; Warren, Lowe, & Armstrong, 1999). Depending
on the factors described above, losses in force after exercise are between 15-60% of
pre-damage values and can persist for ~2 weeks (Hyldahl, Olson, Welling, Groscost,
& Parcell, 2014; Paulsen et al., 2012). The underlying mechanisms are complex and
are attributed to physical damage to the sarcomere and sarcolemma from eccentric
lengthening and excitation-contraction (E-C) coupling failure (see section 2.1). DOMS
is the most commonly assessed marker (Warren et al., 1999), yet the underpinning
mechanism for its appearance is unclear. Sensations of muscle soreness could result
from a complex interaction of damage to the muscle structure, disrupted calcium (Ca2+)
homeostasis, and sensitization of nocioceptors from inflammatory cell infiltrates
(Hyldahl & Hubal, 2014). However, studies reporting increased muscle soreness after
eccentric exercise in the presence of limited inflammation in both animal (Hayashi et
al., 2017) and human models (Yu, Liu, Carlsson, Thornell, & Stal, 2013) challenges
the origins of DOMS. DOMS typically appears between 8 - 24 h after muscle-damaging
exercise, peaks between 24 - 48 h and usually subsides within 96 h (Damas et al.,
2016; Jones, Newham, & Clarkson, 1987). Finally, the appearance of muscle-specific
proteins such as muscle-specific CK in plasma and myoglobin in serum, that peak 2-6
days after the initial insult are typically reported (Byrne et al., 2004; Hyldahl et al., 2014;
Warren et al., 1999). Membrane damage caused by eccentric lengthening leads to
increased membrane permeability and leaking of muscle proteins in to circulation
(Sorichter, Puschendorf, & Mair, 1999), particularly in the immediate EIMD aftermath.
Circulating muscle-specific proteins do, however, show a poor temporal relationship
with muscle function (Friden & Lieber, 2001) and are probably best served as a marker
that tissue damage has occurred rather than to assess its magnitude. The complex
mechanisms associated with EIMD can be simplified into two phases: (i) the initial
phase or primary damage that occurs as a consequence of the mechanical work

4
performed; and (ii) secondary damage that proliferates tissue damage through
processes associated with the inflammatory response.

2.1 Primary muscle damage

Although several metabolic factors have been proposed as mechanisms of

primary damage during eccentric exercise (Tee, Bosch, & Lambert, 2007), mechanical
loading of the muscle during exercise is a more likely candidate (Proske & Morgan,
2001). Eccentric contractions have lower motor unit activation compared to isometric
and concentric contractions for the same force (McHugh, Connolly, Eston, & Gleim,
2000), which places greater mechanical stress on a smaller number of muscle fibers
during eccentric work (Enoka, 1996). It is also thought that faster motor units are
preferentially recruited during lengthening contractions (Nardone, Romano, &
Schieppati, 1989) and consequently, evidence suggests fast-twitch fibres are
damaged (Friden, Sjostrom, & Ekblom, 1983). Sarcomeres lengthen heterogeneously
under tension in a non-uniform manner (so-called inhomogeneity) until they are
beyond myofilament overlap (Morgan & Allen, 1999; Proske & Morgan, 2001). At this
point, some sarcomeres experience “popping” (See “popping sarcomere hypothesis”;
Morgan & Allen, 1999; Proske & Morgan, 2001) and increase tension on passive
structures that result in deformation of non-contractile proteins that has previously
been evidenced by Z-line streaming (Friden et al., 1983). Subsequent repetition of non-
uniform lengthening during eccentric contractions then leads to greater fibre disruption
(Morgan & Allen, 1999; Proske & Allen, 2005).

Failure of the excitation-contraction (E-C) coupling process also contributes to

the primary damage phase (Hyldahl & Hubal, 2014). Reduced force production
immediately and in the days after eccentric exercise have been observed in animal
models alongside reduced sarcoplasmic reticulum (SR) Ca2+ release (Balnave & Allen,
1996; Ingalls, Warren, Williams, Ward, & Armstrong, 1998; Warren, Hayes, Lowe, &
Armstrong, 1993a). Treatment of damage isolated muscle fibers with caffeine, which
acts to stimulate SR Ca2+ release, rescues force lending support to the E-C failure
hypothesis (Warren et al., 1993b). Similarly, ‘low-frequency fatigue’ (LFF) after
damaging exercise in humans is characterized by losses of force at low (10 - 20 Hz)
compared to higher (50 – 100 Hz) surface electromyostimulation frequencies
(Clarkson & Hubal, 2002; Jones, 1996) that suggest reduced SR Ca2+ release
(Dundon, Cirillo, & Semmler, 2008). However, reduced force at low stimulation
frequencies also occurs in over-extended sarcomeres (Allen, 2001), suggesting LFF
might be attributable to structural damage to the myofibril rather than E-C coupling

5
failure (Allen, 2001; Clarkson & Hubal, 2002; Jones, 1996). Although there are
competing theories to explain this phenomenon, it is generally acknowledged that the
initial event after eccentric contraction disrupts the contractile and non-contractile
apparatus, which is followed by membrane damage and subsequent E-C coupling
dysfunction (Proske & Morgan, 2001).

2.2 Secondary muscle damage

After the primary phase, an uncontrolled movement of Ca2+ into the cytoplasm
causes further damage (Armstrong, 1984; Ebbeling & Clarkson, 1989). High
intracellular Ca2+ concentration activates Ca2+-dependent proteolytic and
phospholipase A2 pathways that result in the degradation of structural proteins (Gissel,
2005; Gissel & Clausen, 2001). Mitochondria maintain homeostasis by excess Ca2+
uptake (For a detailed review see Ebbeling & Clarkson, 1989; Gissel, 2005). However,
mitochondrial Ca2+ overload can lead to inner mitochondrial membrane
permeabilization and opening of the permeabilization transition pore, ultimately
resulting in a large efflux of Ca2+ from the mitochondria, increasing intracellular Ca2+
and causing apoptosis or necrosis (Gissel, 2005). Increased intracellular Ca2+ could
also cause uncontrolled muscle contraction that might be one explanation for
increases in passive tension observed after EIMD (Allen, 2001; Morgan & Allen, 1999;
Proske & Allen, 2005; Proske & Morgan, 2001).

The subsequent inflammatory cascade is a vital process that clears damaged

tissue, and initiates tissue repair and adaptation (Chazaud, 2016). A number of
immune cell types infiltrate the damaged tissue, including mast cells, neutrophils, T
regulatory lymphocytes, eosinophils and CD8 T lymphocytes (Burzyn et al., 2013;
Castiglioni et al., 2015; Cote, Tremblay, Duchesne, & Lapoite, 2008; Heredia et al.,
2013; Zhang et al., 2014) to carry out specific roles in a highly organised, temporal
manner.

Neutrophils are probably the first group of immune cells to infiltrate muscle at
the site of injury (Reviewed by Hyldahl & Hubal, 2014), activated by Ca2+-stimulated
proteolysis (Gissel & Clausen, 2001) and increased intracellular Ca2+ signaling pro-
inflammatory cytokine release (Butterfield, Best, & Merrick, 2006). Neutrophils
phagocytose necrotic myofibres and cellular debris (Pizza, Peterson, Baas, & Koh,
2005). However, neutrophils can also produce high concentrations of cytolytic and
cytotoxic molecules through NADPH oxidase derived - superoxide anion dependent
mechanisms that can aggravate existing damage and are, therefore, implicated in the

6
secondary damage process (Nguyen & Tidball, 2003).

Like neutrophils, macrophages are also capable of producing cytotoxic

enzymes and reactive species (e.g. superoxide anion) that subsequently promote
tissue degradation (Nguyen & Tidball, 2003). However, once engaged by damaged
tissue, macrophages can convert into anti-inflammatory phenotypes responsible for
releasing growth factors such as transforming growth factor β1 (Arnold et al., 2007).
These observations suggest that macrophages do not contribute to membrane
disruption during the inflammatory response, but instead have a role in facilitating
tissue recovery and adaptation (Butterfield et al., 2006).

2.3 Satellite cell involvement in muscle repair

Myofibres lack intrinsic regenerative capacity, so muscle fibre regeneration

relies on resident muscle stem cells, termed satellite cells. Satellite cells reside
juxtaposed to the muscle fibre, between the sarcolemma and basal lamina (Mauro,
1961). Satellite cells remain quiescent until activated by appropriate cues ranging from
intracellular signaling events to local interactions with the extracellular matrix and
circulating systemic factors including inflammatory cells and nitric oxide (Reviewed in
detail by Yin, Price, & Rudnicki, 2013).

The activation and expansion of satellite cells after strenuous muscle activity is
well-documented in humans. Cermak et al. (2013) reported that 24 hours after 300
eccentric contractions, satellite cell content of type II fibres was increased. Similarly,
single bouts of intense resistance exercise such as 45 cm drop jumps combined with
maximal eccentric knee flexions on an isokinetic dynamometer (Crameri et al., 2004),
high volume maximal unilateral eccentric dynamometry of the knee flexors (Dreyer,
Blanco, Sattler, Schroeder, & Wiswell, 2006) and electrical stimulation (Mackey &
Kjaer, 2017) all increase satellite cell activity. As these studies typically employ
eccentric contractions, it has been suggested that it is exclusively eccentric
contractions that lead to satellite cell activation. In a recent trial, a work-matched bout
of repeated sets of eccentric or concentric contractions was employed (40 kJ work total
per condition). The main finding was a 27% increase in satellite cell content at 24 hours
after exercise in the eccentric but not the concentric exercise group, suggesting that
satellite cells are differentially activated depending on contraction type (Hyldahl et al.,
2014).

7
 Collectively, satellite cells are necessary for the remodeling of untrained skeletal
muscle, possibly to maintain an adequate DNA:protein ratio. Since only non-trained or
sub-elite athletes have typically been recruited in existing studies, whether such
observations apply to elite groups is unclear. Interestingly, during periods of
unloading/detraining, the nuclei accumulated by myofibres as a result of satellite cell
activation remain for up to 60 days in humans (Kadi et al., 2004) and mice (Bruusgaard,
Johansen, Egner, Rana, & Gundersen, 2010). These findings indicate that sustained
satellite cell activation provides the muscle with the potential capacity to mount an
augmented response to a repeated challenge to myofibre homeostasis. Facilitating
satellite cell activity in response to damaging exercise may be a route through which
nutritional interventions can modulate recovery.

3. Dietary Solutions for Exercise-Induced Muscle Damage

3.1 Protein and Amino Acids

Dietary protein intake is undoubtedly a crucial factor in the regulation of muscle

protein turnover, particularly in response to exercise. Adaptive processes to both
resistance and endurance type exercise are enhanced when protein is fed around the
exercise bout (Reviewed in detail by Phillips & Van Loon, 2011). Whether protein
intake around intense/damaging exercise can alleviate aspects of muscle damage is
less clear (Tipton, 2015). Evidence suggests protein or free amino acids fed around
exercise can alleviate markers of muscle damage and accelerate recovery of force
(Buckley et al., 2010; Cockburn, Stevenson, Hayes, Robson-Ansley, & Howatson,
2010; Nosaka, Sacco, & Mawatari, 2006). However, others have not found comparable
effects (Blacker, Williams, Fallowfield, Bilzon, & Willems, 2010; Wojcik, Walber-
Rankin, Smith, & Gwazdauskas, 2001). A recent systematic review concluded that
when protein supplements are provided, acute increases in post-exercise protein
synthesis and anabolic intracellular signalling have not resulted in measureable
reductions in muscle damage and enhanced recovery of muscle function. This is
logical as adaptations in muscle protein turnover are slow (Tipton, Borsheim, Wolf,
Sanford, & Wolfe, 2003) and do not parallel the acute changes in muscle damage
associated with protein supplementation, that typically occur within hours after
damage. However, heterogeneity in study design and markers selected to monitor
muscle damage and recovery of function may account for the lack of a clear
consensus. So, whilst protein is undoubtedly important for adaptive remodelling of
skeletal muscle after any form of exercise, and should never be compromised in the

8
diet, it is unclear whether supplementing with protein after EIMD accelerates recovery.

3.2 Functional Foods

So-called ‘functional foods’ have the potential to exert a positive physiological

effect that is related to improved or preserved human health and disease prevention
(Bell, McHugh, Stevenson, & Howatson, 2014). Exercise scientists, practitioners and
athletes have identified these foods as potential synergistic solutions to manage the
negative effects associated with strenuous physical activity. This is of particular
interest for sports where muscle damage can impact upon subsequent training and
competition. This section of the review will focus on the evidence derived from
selected, contemporary and emerging functional foods applied in exercise recovery
paradigms, with particular reference to foods (or their analogues) that contain dietary
polyphenols and n3 fatty acids.

3.2.1 Dietary polyphenols

Dietary polyphenols are present in numerous fruits and vegetables that are
consumed as part of a balanced diet and have been shown to possess antioxidant
properties, in vitro (Seeram et al., 2008; Traustadottir et al., 2009; Wang, Cao, & Prior,
1997) and anti-inflammatory properties (Seeram, Momin, Nair, & Bourquin, 2001; Tall
et al., 2004; Wang et al., 1999). In addition, many possess the ability to attenuate the
arachadonic acid pathways by inhibiting cyclo-oxygenase (COX) 1 and 2 production
(Seeram et al., 2001) to a similar magnitude to over-the-counter non-steroidal anti-
inflammatory drugs or NSAIDs (Bondesen, Mills, Kegley, & Pavlath, 2004). Polyphenol
enriched nutrients include tea, coffee, grapes, cocoa, nuts, blueberries, cherries, and
pomegranates. Here, we will review whether polyphenol supplementation influences
EIMD before considering potential mechanisms.

From an EIMD perspective, a dietary intervention is unlikely to interact with the

primary phase of the mechanical stress during the exercise bout (Bell et al., 2014;
Howatson & van Someren, 2008). What is more likely is an interaction with the
secondary cascade, which results in inflammation and the production of reactive
oxygen species (ROS) after the damaging exercise; consequently, further
exacerbation of damage may be modulated and aid the subsequent recovery process.
Quercetin is a polyphenol in the group of flavonol compounds present in berries,
grapes, tomatoes and teas. Quercetin has good bioavailability in plasma after
consumption (Egert et al., 2008) and could therefore exert positive effects in vivo.

9
However, limited evidence supports its use in managing EIMD. After three days of high
intensity cycling for 3 hours per day, increases in exercise-induced inflammation and
oxidative stress were reported (McAnulty et al., 2008). Despite 6 weeks of
supplementation, quercetin performed no better than the placebo. Although cycling
could be considered non-damaging, these data concur with previous work examining
quercetin in an EIMD setting (Nieman et al., 2007a; Nieman et al., 2007b; O'Fallon et
al., 2012). Despite some evidence of attenuated pro-inflammatory cytokine mRNA
expression (Nieman et al., 2007b), quercetin failed to improve muscle function or
reduce inflammation, oxidative stress and muscle soreness (Nieman et al., 2007a;
Nieman et al., 2007b; O'Fallon et al., 2012).

Catechins and their derivatives are commonly found in tea and have the
potential to enhance recovery from damaging exercise, although the literature on this
flavonoid is scarce. One study has shown a modest change in post-exercise muscle
soreness, but all other indices of muscle function or muscle damage remained
unaltered compared with a control (Kerksick, Kreider, & Willoughby, 2010). Catechins
and quercetin warrant greater research efforts to elucidate their potential, but at
present their application in managing EIMD is unsupported.

An emerging food of interest for managing EIMD is tart Montmorency cherries

(Prunus cerasus). The first study to investigate the efficacy of tart cherries in exercise
recovery used heavy eccentric contractions to induce unilateral muscle damage to the
elbow flexors in a placebo-controlled, randomized, cross-over design with a two-week
washout, whereby the contralateral limb was used as the placebo control (Connolly,
McHugh, Padilla-Zakour, Carlson, & Sayers, 2006). Participants consumed two
servings per day of a cherry juice blend (fresh pressed Montmorency cherries and
proprietary apple juice) for a total of eight days (four days before the damaging bout
and for the duration of recovery period). An accelerated rate of muscle function
recovery and reduced soreness post EIMD was observed. The investigators
speculated that the positive effects were attributable to modulating the secondary
damage phase. However, the influence of the proprietary apple juice in the blend
cannot be excluded as a contributing factor for these positive observations. In addition,
an important, but nonetheless often-overlooked limitation in this study (and many other
damage studies) was the use of a crossover design in a damaging paradigm, which
has been shown to confer a contralateral RBE and hence influence the damage in the
contralateral limb (Howatson & van Someren, 2007; Newton, Sacco, Chapman, &
Nosaka, 2013; Starbuck & Eston, 2012; Xin, Hyldahl, Chipkin, & Clarkson, 2014). In a

10
subsequent study, the same Montmorency cherry juice blend was investigated in a
similar supplementation regimen, but used an independent group design and recorded
measures of oxidative stress and inflammation before and after a marathon (Howatson
et al., 2010). Like Connolly et al. (2006), this study showed an accelerated recovery of
muscle function in the days after the marathon, but importantly indices of inflammation
(interleukin-6; IL-6 and C-reactive protein; CRP) and lipid peroxidation (thiobarbituric
acid; TBARS) were attenuated and hence concluded that the phytochemicals were
modulating EIMD; with the caveat that TBARS is now considered an assay with
marked limitations (Cobley, Close, Bailey, & Davison, 2017; Margaritelis et al., 2016a).
The positive effects of tart cherries on recovery from strenuous damaging exercise
have subsequently been demonstrated with Montmorency cherry juice blends (Kuehl,
Perrier, Elliot, & Chesnutt, 2010), a Montmorency cherry concentrate (Bell et al., 2014;
Bell, Walshe, Davison, Stevenson, & Howatson, 2015; Bowtell, Sumners, Dyer, Fox,
& Mileva, 2011) and other Montmorency cherry analogues (Kastello et al., 2014) after
different exercise paradigms. At the time of this review all published studies data
examining Montmorency cherries as an intervention showed some positive effects.
How these compounds exert beneficial effects is, however, unclear.

Pomegranate and its extracts are a polyphenol-rich fruit that principally contain
ellagitannins (Medjakovic & Jungbauer, 2013). To our knowledge only two studies,
from the same laboratory have examined the application of pomegranate on EIMD
(Trombold, Barnes, Critchley, & Coyle, 2010; Trombold, Reinfeld, Casler, & Coyle,
2011). The first of these studies used elbow flexion eccentric contractions to induce
damage in recreationally active males. In a placebo controlled trial, the authors showed
that the consumption of a pomegranate extract, in the days before and after the
damaging exercise bout, improved recovery of muscle function; however, no other
index of damage or inflammation was different between groups. The second study
damaged both the elbow flexors and the knee extensors in resistance-trained males.
In support of their initial work, an accelerated recovery elbow flexor function, that was
accompanied by less muscle soreness in the pomegranate group. Finally, both studies
used a cross-over design which has previously been highlighted as a potential
limitation owing to the contralateral RBE. Notwithstanding, the positive results with
pomegranate suggest it could be an effective intervention for recreational and well-
trained individuals to promote recovery from EIMD.

From a mechanistic perspective, how polyphenols exert their effects is unclear.

Polyphenols react with free radicals (e.g. superoxide anion, peroxyl radical, aloxyl

11
radical and hydroxyl radical) in vitro to yield polyphenol radicals. While polyphenols
generally have favorable kinetics, whether they accumulate in sufficient amounts to
scavenge free radicals is debatable (not to mention whether scavenging free radicals
is even desirable). For example, copper zinc superoxide dismutase (CuZnSOD) reacts
rapidly with superoxide anion and is present at ~20 µM (Halliwell & Gutteridge, 2015).
Plasma concentrations of “free” polyphenols rarely exceed 1 µM, even assuming a
tissue concentration of 1 µM CuZnSOD still outcompetes polyphenols, which
questions the plausibility of scavenging mechanisms (Schaffer & Halliwell, 2012). Note
tissue polyphenol concentrations above the nanomolar range are unlikely (Forman,
Davies, & Ursini, 2014; Schaffer & Halliwell, 2012). A situation abetted by the fact that
polyphenol metabolism via methylation, sulphation and glucoronidation abrogates their
activity towards free radicals (Goszcz, Duthie, Stewart, Leslie, & Megson, 2017;
Halliwell & Gutteridge, 2015). Further, it is unlikely that polyphenols accumulate at the
sites of free radical generation in an EIMD setting because inflammatory cell infiltrates
release superoxide anion and other reactive species into the phagosome (Winterbourn
et al, 2016), which imposes a spatial restriction. For these reasons, we disfavor
scavenging mechanisms. Instead, we favor the hypothesis that small amounts of
polyphenols are metabolized to electrophiles (e.g. quinones), that then activate the
cyto-protective endogenous antioxidant response via Nrf-2 signaling (Forman et al.,
2014; Goszcz, Deakin, Duthie, Stewart, & Megson, 2017). As reviewed in Forman et
al, 2014, electrophiles can activate Nrf-2 signaling by conjugating reactive cysteine
residues within KEAP-1—an inhibitory protein responsible for sequestering Nrf-2 in the
cytoplasm —via Michael addition. For investigators wanting to disambiguate the
mechanism, limited mechanistic insight can be derived from evaluating oxidized
macromolecule adduct levels at the circulating level (Cobley et al., 2015a; Cobley,
Moult, Burniston, Morton, & Close, 2015c; Cobley et al., 2014; Margaritelis et al.,
2016a, b).

Pharmacological interventions are often consumed in doses that are well in

excess of the recommended daily allowance that could result in unwanted side-effects,
and importantly for athletic populations, increases the risk of consuming contaminated
supplements. The use of polyphenolic-rich foods is growing in interest and represents
a realistic alternative for numerous areas of sport and exercise nutrition, not least in
managing muscle damage and exercise recovery. Other polyphenol-rich foods (for
example, chokeberry, beetroot, acai, Concord grapes and blackcurrants) that have not
been explored could provide effective interventions to manage signs and symptoms
associated with EIMD. A caveat to the polyphenol literature discussed here is that

12
many of the studies have removed polyphenols from the diet in order to control the
study and observe whether potential effects are due to the polyphenol supplement.
Whether these effects would persist as a supplement to a polyphenol rich diet is
unknown. At worst, these foods provide vital nutrients; at best, exercise recovery could
be augmented. Pragmatically, a diet rich in polyphenols (fruit and vegetables) may be
the best strategy to augment recovery from damaging exercise.

3.2.2 Omega-3 Polyunsaturated fatty acids

Omega-3 polyunsaturated fatty acids (n-3 PUFA), specifically n-3 PUFA

eicosapentaenoic acid (EPA) and docasahexaenoic acid (DHA) are a group of
nutrients that possess anti-inflammatory properties (Mickleborough, 2013). n-3 PUFA
occur in natural abundance in nuts and oily fish like salmon, mackerel and tuna (Sousa
et al., 2014). Multiple investigations have examined the effects of n-3 PUFA on muscle
function, inflammation and oxidative stress induced by damaging exercise. For the
most part, these have shown a positive effect (DiLorenzo, Drager, & Rankin, 2014;
Gray, Chappell, Jenkinson, Thies, & Gray, 2014; Jouris, McDaniel, & Weiss, 2011;
Marques et al., 2015; Phillips, Childs, Dreon, Phinney, & Leeuwenburgh, 2003;
Tartibian, Maleki, & Abbasi, 2009, 2011) on one or more variables associated with
EIMD. All of these studies tend to use a loading phase of several days that can extend
up to a month, which might go some way to explaining the discrepancies in meaningful
findings. The most comprehensive study to assess loading demonstrated that a
minimum of 2 weeks supplementation with 5 g/day of fish oil capsules (providing 3500
mg EPA and 900 mg DHA) is necessary to permit detectable increases in muscle n-3
PUFA lipid composition (McGlory et al., 2014). Only one study (Lenn et al., 2002)
showed n-3 PUFA to have no effect on muscle function, inflammation or oxidative
stress after damaging eccentric contractions. Taken collectively these studies support
the efficacy of n-3 PUFA as a promising intervention to manage EIMD.

13
 3.3 Vitamin D
Vitamin D is a seco-steroid hormone predominantly obtained in humans by exposure
to ultraviolet B radiation (UVB; sunlight) . Lack of sunlight exposure and predominantly indoor
life styles have led to a large number of vitamin D deficiency cases worldwide (defined as <30
nmol/L 25[OH]D) (reviewed recently in Palacios & Gonzalez, 2014). Professional athletes also
exhibit low 25[OH]D concentrations (Close et al., 2013; Hamilton, Grantham, Racinais, &
Chalabi, 2010; Morton et al., 2012). The canonical role for vitamin D is its role in Ca2+
homeostasis and thus bone mineralization (Holick, 2004). It is now understood that the
biological effects of the seco-steroid are much wider than Ca2+ homeostasis. Of particular
relevance to this review are the emerging data that imply a role in muscle regeneration and
remodeling as vitamin D exerts potent effects on the innate and acquired immune system, as
well as, directly within skeletal muscle.

Few data exist to couple vitamin D’s potential role in modulating the immune response
to EIMD, despite a plethora of data that show vitamin D is a robust regulator of the immune
system (Hewison, 2012). In one trial, the anti-inflammatory cytokine response after intense
exercise correlated with individual’s serum 25[OH]D (Barker et al., 2014). Although serum IL-
10 and IL-13 responses to muscle damage were increased in the vitamin D sufficient group,
the immediate and persistent peak isometric force and peak power output deficits caused by
the intense single leg exercise protocol remained, despite vitamin D sufficiency. In another
observational study, the inflammatory cytokine TNF-α was increased in runners with low
serum 25[OH]D (Willis, 2012), which could be detrimental for cellular homeostasis in muscle.
But this remains speculative in the absence of functional measures.

Data suggest vitamin D may be important in the intrinsic repair process after muscle
damage. Initial insights were provided in a randomized controlled study that assessed the
potential relationship between vitamin D and functional recovery of muscle after strenuous
exercise. After 10 sets of 10 repetitive eccentric-concentric jumps on a custom horizontal plyo-
press at 75% of body mass with a 20 second rest between sets, individuals with higher
circulating 25[OH]D, the main marker of vitamin D status, demonstrated a faster recovery of
maximal force in the recovery phase after exercise (Barker, Schneider, Dixon, Henriksen, &
Weaver, 2013). Using a systems approach in young, recreationally active vitamin D insufficient
males, we later confirmed that supplemental vitamin D (4,000 IU/day) could augment the
recovery of maximal force after eccentric unilateral exercise compared to a placebo control
group (Owens et al., 2015). Moreover, skeletal myoblasts were obtained via a muscle biopsy
from the vitamin D insufficient participants and demonstrated improved migration, fusion and
hypertrophic capacity of skeletal myoblasts in the presence of 1α,25-dihydroxyvitamin D3 (the

14
active vitamin D metabolite). These data provided good evidence for a role of vitamin D in
muscle repair at the whole muscle and cellular level. With regards to muscle soreness,
nociceptors also express the vitamin D receptor (VDR) making them a potential vitamin D
target. Indeed, vitamin D deficiency may lead to selective alterations in target innervation,
resulting in possible nociceptor hyper-innervation of skeletal muscle, which in turn is likely to
contribute to muscular hypersensitivity and pain (Tague et al., 2011).

It appears that a daily as opposed to weekly or monthly vitamin D supplementation

strategy is more effective and doses up to 4,000 IU/day vitamin D3 during the winter months
are adequate (Owens et al., 2017). Higher doses and mega bolus supplementation protocols
often implemented are likely to produce unwanted effects due to negative feedback in the
vitamin D metabolic pathway (Owens et al., 2017).

3.4. Vitamin C and Vitamin E

Vitamin C (i.e. ascorbic acid, AA) and vitamin E (α-tocopherol, α-TOC) are two
essential nutrients, with pleiotropic redox-dependent and independent biochemical
functionality (reviewed in Cobley, McHardy, Morton, Nikolaidis, & Close, 2015b; Niki, 2014).
Several studies have investigated whether AA and α-TOC supplementation in combination or
isolation ameliorates EIMD in humans, on the theoretical premise that they prevent cell
damage inflicted by inflammatory cell infiltrates by scavenging free radicals. With few
exceptions, the general consensus is that AA and α-TOC have limited ability to offset EIMD
induced decrements in muscle function (reviewed in McGinley, Shafat, & Donnelly, 2009). For
example, AA supplementation fails to improve muscle function, as assessed by isokinetic
dynamometry (IKD), post EIMD (Thompson et al., 2004; Thompson et al., 2003; Thompson et
al., 2001). The literature is mixed with regards to muscle soreness, some studies report no
effect and others positive effects (reviewed in Close, Ashton, McArdle, & Maclaren, 2005).
Whether potentially improving muscle soreness justifies their use to improve EIMD against a
background of negligible effects on muscle function is debatable; especially when AA
supplementation can delay recovery from EIMD (Close et al., 2006).
From a mechanistic perspective, use of AA and α-TOC is primarily based on their
ability to “scavenge” free radicals—both nutrients have limited reactivity with non-radicals to
generate a less reactive AA and α-TOC radical owing to electron delocalisation (Halliwell &
Gutteridge, 2015). With a few exceptions (e.g. rapid reaction of α-TOC with lipid peroxyl
radicals in the cell membrane Niki, 2014) whether they react with biologically meaningful free
radicals near their site of generation and with a sufficient rate constant to outcompete
endogenous reactants is unclear (Cobley et al., 2015b). In an EIMD setting, spatial constraints
are particularly important. For example, α-TOC would have to accumulate at phagosome

15
membranes. If it did, it would likely protect the invading inflammatory cell infiltrate from
oxidative damage, which may promote superoxide anion generation. Likewise, AA may
potentiate superoxide anion generation by reducing Fe3+ to Fe2+ in NADPH oxidase (NOX)
thereby enabling NOX to bind and reduce oxygen. Resolving the influence of AA and α-TOC
is complicated by the difficulties associated with measuring free radical and non-radical
species (Cobley et al., 2017; Halliwell & Whiteman, 2004). Notwithstanding, we suggest that
AA and α-TOC are unlikely to directly scavenge free radicals in the phagosome to significantly
interfere with the inflammatory responses.

Overall, no evidence based rationale exists to justify their use in an adaptive setting in
AA and α-TOC sufficient athletes (Close & Jackson, 2014). It has been suggested that vitamin
C and E could be considered for their use to offset muscle soreness during competitive
situations when maximising adaption is inconsequential (Cobley, McGlory, Morton, & Close,
2011). However, a recent Cochrane review suggests only moderate to low quality evidence
supports the use of ‘antioxidant’ supplements in reducing DOMS (Ranchordas, Rogerson,
Soltani, & Costello, 2017). The use of vitamin C and E supplements in an EIMD setting
therefore appears to lack support, especially when AA and α-TOC may interfere with certain
exercise adaptations to non-damaging exercise (Gomez-Cabrera et al., 2008; Paulsen et al.,
2014a; Paulsen et al., 2014b; Ristow et al., 2009). A graphical representation of the muscle
damage-repair process and nutritional interventions that may interact with one or more of these
events to augment recovery can be found in Figure 1.

3.4 Creatine Monohydrate

Creatine monohydrate supplementation shows positive effects on satellite cell number and
myonuclear content in response to heavy resistance exercise. When administered at a dose of 24
g (4 x 6 g servings) per day for 7 days followed by 6 g per day for the following 15 weeks, satellite
cell number and myonuclear content were increased above that of a 20 g whey protein supplement
or a no training/no supplement control (Olsen et al., 2006). The signaling mechanism by which this
occurs is still elusive; however, the data are supported by in vitro insights that show creatine
monohydrate induces differentiation (myotube formation) of skeletal myoblasts (Vierck, Icenoggle,
Bucci, & Dodson, 2003).

<<< FIGURE 1 HERE >>>

4. Practical nutritional considerations to modulate exercise-induced muscle

damage

16
 The long-term use of recovery strategies on adaptation to training and athletic
development is an area of interest, and perhaps concern. The basis for this is predominantly
concerned with interventions reducing the exercise-induced stress response, which may
reduce adaptive potential—assuming the two are related. Many of the nutritional interventions
highlighted here may modulate oxidative stress and inflammation, which are known to be
important in the adaptive response to an exercise stimulus. As an example, blunting the pro-
inflammatory phase of the repair process may be problematic as a decrease in the number of
immune cell infiltrates leads to a decrease in the diameter of new myofibers and to the
development of fibrosis (Bondesen et al., 2004; Shen, Li, Tang, Cummins, & Huard, 2005).
This calls in to question whether long-term supplementation might bring about a maladaptive
response and affect long-term athletic development.

With pragmatism in mind, a balanced diet that is rich in fruits and vegetables is always
necessary. However, when training and competition stress is high and recovery is unlikely to
be achieved before the next competition or high intensity training session, there is certainly
rationale to supplement with additional foods that could help manage the negative effects of
the exercise stressor. If the primary aim is to maximize the training stimulus, then a degree of
caution is needed, whereby athletes and practitioners need to consider a periodised approach
to nutrition to adequately support training and competition to maximize the potential for
adaptation (see Figure 2). This notion can be conceptualized with the idea of hormesis, which
was first applied to exercise paradigms by (Radak, Chung, & Goto, 2005). This idea suggests
that biological systems respond in a bell-shaped fashion, where a positive adaptive response
is experienced when exposed to a stimulus. However, when the exposure becomes too great
(i.e. when EIMD impairs function for an extended period) a need to intervene to negate
potential negative effects exists. Given that EIMD can shape our fundamental understanding
of skeletal muscle adaptation (Hyldahl et al., 2017), ascertaining how nutritional strategies
might impact differently on adaptation to damaging resistance and endurance training is
important.

<<< FIGURE 2 HERE >>>

5. Future directions
The field of sports nutrition is rapidly growing, and we are gaining greater insights into how
nutrition interacts with physiological phenomena that are important for athletic development
and performance. However, there is still much to be unveiled regarding nutrition as it relates
to muscle damage and repair. Particularly lacking is our understanding of the underpinning

17
mechanisms of how functional foods and their derivatives exert their effects. Understanding
these mechanisms will allow researchers and practitioners to better identify how nutritional
interventions may be applied to maximize recovery and avoid performance impairments.

It is also important to understand whether foods with anti-inflammatory properties

negatively interfere with the pro-inflammatory phase of muscle repair and consequently blunt
the repair process. The same can be said for foods with “antioxidant” properties, as recent
research highlights the fundamental importance of oxidative stress in exercise adaptations
(Margaritelis et al., 2017). A major challenge to the field will be in defining how nutritional
interventions targeted to alleviate muscle damage and accelerate repair should be translated
to the real-world setting, in which the aim of nutrition interventions is highly dependent upon
the goal of the session and whether it is more important to recover quickly or adapt.

Future studies must employ appropriate test measures when investigating functional foods
and muscle function. We have highlighted how important the selection of laboratory assays
can be for redox exercise biology studies (Cobley et al., 2017). Given many of the nutritional
strategies described here are purported to have an impact on redox processes, particular
attention should be paid to assay/method selection.

6. Conclusion
This review sought to provide a concise overview of what EIMD is, its causes and
consequences and to critically evaluate potential nutritional strategies to ameliorate muscle
damage. It is clear that the aetiology of EIMD is complex and some of the contributing factors
are a double-edged sword. On the one hand, oxidative stress and inflammation may amplify
tissue damage, but on the other hand both processes play important roles in the resolution of
function and in adaptation. With this in mind, the majority of nutritional strategies presented
here should be adopted with pragmatism. It is crucial to find the balance between recovery
and adaptation and for this reason, a periodised approach to nutrition should yield the greatest
benefit for the athlete.

18
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Figure 1. A) Time course of events following a bout of muscle damaging exercise and B) nutritional
interventions that may interact with one or more of these events to augment recovery. Coloured
spheres in figure 1B related to figure 1A to denote where the interventions may target. The strength
of evidence for these interventions is expressed with stars on a scale of 0-3 depending on the
depth and consistency of evidence.

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 Figure 2. Theoretical framework for the hormesis theory in the context of nutritional interventions
for the management of EIMD. This framework suggests that the adaptive response to EIMD
presents as a bell-shaped curve; A positive effect of the exercise stress exists to a point when the
exposure becomes too great, thereafter there is an impaired adaptive response. Using this theory,
we suggest a conceptual region for intervention (yellow text box) where the exercise stress impairs
timely return to training & competition or is detrimental to adaptation.

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