original research

International Journal of Sport Nutrition and Exercise Metabolism, 2011, 21, 451  -461
© 2011 Human Kinetics, Inc.

N-Acetylcysteine’s Attenuation of Fatigue

After Repeated Bouts of Intermittent Exercise:
Practical Implications for Tournament Situations
James N. Cobley, Chris McGlory, James P. Morton, and Graeme L. Close

Production of reactive oxygen species (ROS) during muscle contractions is associated with muscle fatigue and
damage in the short term and adaptive responses in the long term. When adaptation is inconsequential acute
antioxidant supplementation may be able to attenuate muscle fatigue and damage to enhance performance. This
study aimed to determine the effects of acute oral N-acetylcysteine (NAC) supplementation on Yo-Yo Intermit-
tent Recovery Test Level 1 (YIRT-L1) performance after repeated bouts of damaging intermittent exercise. In
a pair-matched design, 12 recreationally trained men engaged in 6 d of either NAC (n = 6) or placebo (n = 6)
supplementation. After a treatment-loading day, participants completed 3 testing sessions, on alternating days,
consisting of a preexercise isokinetic dynamometry (IKD) test, a damaging intermittent-exercise protocol,
YIRT-L1, and a postexercise IKD test. Another IKD test was completed on the 2 intervening d. NAC treatment
resulted in a significant preservation of YIRT-L1 performance (p ≤ .0005). IKD performance significantly
deteriorated over time at all contraction speeds, and this deterioration was not influenced by treatment group.
Plasma creatine kinase values increased significantly over time (p = .002) and were significantly greater in
the NAC group than in the placebo group (p = .029). NAC induced mild gastrointestinal side effects. NAC
supplementation may be a useful strategy to enhance performance during short-term competitive situations
when adaption is inconsequential. Titration studies to elucidate a treatment dose that enhances performance
without inducing side effects are now required.

Keywords: NAC, DOMS, free radical, ROS, eccentric, soreness

Transient accumulation of reactive oxygen spe- is essential, such as during competitive tournament situ-
cies (ROS) during muscle contractions is associated ations that are characterized by short recovery intervals
with muscle fatigue and damage in the short term and between demanding excise bouts. It follows that acute
the promotion of adaptive responses in the long term antioxidant supplementation may be beneficial in these
(Ferreira & Reid, 2008; Powers, Durate, Kavazis, & situations, although this hypothesis has yet to be fully
Talbert, 2010). ROS can activate signal-transduction explored.
pathways to induct a stress-resistance response that N-acetylcysteine (NAC) is a promising candidate
protects against some of the toxic outcomes of ROS to attenuate fatigue and muscle damage during suc-
generation (Powers et al., 2010). This response involves cessive bouts of damaging high-intensity contractions.
the up-regulation of antioxidant enzymes and heat- NAC may act in several ways to influence cellular redox
shock proteins (Powers & Jackson, 2008). Reports of state. NAC deacetylation releases cysteine, which can
diminished adaptation to exercise training with long- be used to support glutathione synthesis, a process
term antioxidant supplementation have confirmed that rate-limited by cysteine availability (Ferreira & Reid,
ROS can function as essential signaling biomolecules 2008). Glutathione is an abundant cellular thiol that can
in vivo (Gomez-Cabrera, Borrás, Pallardó, Sastre, Ji, & serve as a substrate for the hydrogen peroxide scavenger
Viña, 2005; Gomez-Cabrera et al., 2008; Ristowet al., glutathione peroxidize and recycle vitamins C and E
2009). It is therefore apparent that chronic antioxidant (Ferreira & Reid, 2008). In addition, NAC can scavenge
supplementation is ill advised when training adaptation several reactive species directly and inhibit S-thiolation of
is desired (Powers et al., 2010). There are, however, redox-sensitive enzymes and proteins that may preserve
scenarios in which training adaptation is inconsequential, their function during contractions (Lee, West, Phillips,
and ameliorating the negative short-term effects of ROS & Britz-McKibbin, 2010).
Several authors have reported that acute NAC admin-
istration delays fatigue during submaximal endurance-
type exercise in humans (Lee et al., 2010; Matuszczak et
The authors are with the School of Sport and Exercise Sciences, al., 2005; McKenna et al., 2006; Medved, Brown, Bjork-
Liverpool John Moores University, Liverpool, UK. sten, & McKenna, 2004; Reid, Stokic, Koch, Khawli,

451
452   Cobley et al.

& Leis, 1994; Travaline, Sudarshan, Roy, Cordova, Methods

Leyenson, & Criner, 1997). For instance, intravenous
NAC infusion pre- and during cycling exercise-capacity Subjects
tests prolongs time to exhaustion by ~25% (McKenna
et al., 2006; Medved, Brown, Bjorksten, Murphy, et al., Using Minitab version 15.0 (Minitab Inc., USA), we
2004). Analogous results have been reported after oral estimated that a sample size of 10 would enable the
NAC supplementation (Lee et al., 2010; Matuszczak detection of a practically significant treatment effect of
et al., 2005), suggesting that the findings were not an 60 m in YIRT-L1 performance between testing Sessions
artifact of intravenous administration. Although defini- 1 and 3 with a statistical power of 90%. In accordance
tive causal mechanisms are lacking, NAC may enhance with statistical guidelines (Batterham & Atkinson, 2005),
potassium (K+) homeostasis, inhibit the oxidation of the standard deviation associated with mean test–retest
sarcoplasmic reticulum calcium ATPase, and prevent YIRT-L1 scores (24 m; Krustrup et al., 2003) was used.
the oxidation of contractile proteins to attenuate fatigue Fourteen recreationally trained male subjects were
during submaximal contractions (McKenna et al., 2006; recruited to allow for subject attrition. For this study’s
Powers & Jackson, 2008). Conversely, NAC has failed to purposes, recreationally trained was defined as participat-
enhance high-intensity intermittent-exercise performance ing in physical activity of an intermittent nature at least
in untrained humans (Matuszczak et al., 2005; Medved, three times per week for at least 12 months. During the
Brown, Bjorksten, Leppik, Sostaric, & McKenna, 2003). course of the study 2 subjects dropped out for personal
This observation could limit the use of NAC. Although reasons; hence, 12 recreationally trained men (age 24.7
the severity of the exercise may have prevented the ± 4.2 years, height 172.1 ± 4.9 cm, weight 70.1 ± 6.9 kg)
realization of treatment effects in untrained individuals, participated. Prospective subjects were excluded if they
the possibility that NAC is ineffective during this form smoked or engaged in any course of supplementation or
of contractile activity cannot be excluded. Further work medication (e.g., antioxidant supplementation) that may
with moderately trained individuals may help clarify have interfered with the study’s results. Institutional ethi-
this issue. cal approval was granted.
Contractions, especially those of an eccentric nature
(Nikolaidis, Jamurtas, Paschalis, Fatouros, Koutedakis, Experimental Design
&Kouretas, 2008), often invoke muscle damage, which In a between-subjects design, subjects were pair-matched
stimulates postexercise (48–96 hr) ROS production as according to the greatest preliminary YIRT-L1 score
a result of the respiratory burst of phagocytes (Close, (see preliminary measurements) and assigned to a treat-
Ashton, McArdle, & MacLaren, 2005; Pizza, Peterson, ment group (NAC n = 6 YIRT-L1: 1,506.7 ± 379.2 m;
Baas, & Koh, 2005). ROS generation during this period placebo n = 6 YIRT-L1: 1,466.7 ± 395.1 m) in a random
can further depress muscle function but is associated with double-blind fashion. The experimental preparation was
the long-term restoration of muscle function (Close et al., consumed in the form of a 500-ml drink that contained
2006). Acute antioxidant supplementation could prevent 375 ml H2O, 125 ml sugar-free cordial, and 2 g glucose
further decrements in muscle function during this period. dextrose powder mixed with 50 mg/kg of powdered
To our knowledge, no study has determined the affects NAC (Myprotein Inc., Manchester, UK). Blind tasting
of acute NAC supplementation on muscle function after sessions performed during pilot work with people who
repeated bouts of damaging contractions. Nevertheless, did not undertake any experimental trials revealed that
no effect of exogenous antioxidants, notably vitamin C, without added cordial and dextrose powder the NAC
on muscle function, as determined by isokinetic dyna- condition was easily detectable and unpalatable. The
mometry (IKD), has been observed at any time point placebo preparation lacked NAC but was otherwise
(0–96 hr) after damaging contractions (Close et al., identical to the experimental preparation. Because of
2006; Thompson et al. 2003; Thompson et al., 2001). the short half-life of orally ingested NAC, a 500-ml
This could reflect a need to use different antioxidants drink was consumed 1 hr before and immediately after
or markers of muscle function. It could equally reflect a each testing session (and at corresponding time points
need to perform repeated bouts of damaging contraction on the loading day) during the 6-day treatment period to
to realize treatment effects. Determining the influence of enhance NAC bioavailability (Lee et al., 2010). Analo-
acute NAC supplementation on markers of muscle func- gous treatment strategies have proven effective in arrest-
tion after repeated bouts of exercise could help resolve ing fatigue (Matuszczak et al., 2005; McKenna et al.,
some of these issues. 2006; Medved, Brown, Bjorksten, Murphy, et al., 2004).
The aim of this study was to determine the effects Side-effect prevalence was assessed using a subjective
of acute NAC supplementation on biomarkers of muscle 0–10 side-effects scale that was administered daily by
function and fatigue after repeated bouts of damaging an experimenter who was unblinded for ethical reasons.
high-intensity intermittent contractions. We hypothesized After a treatment-loading day subjects were required to
a preservation of Yo-Yo Intermittent Recovery Test Level report to the laboratory on five consecutive occasions to
1 (YIRT-L1) and IKD performance together with a reduc- complete alternate testing and sampling sessions. The
tion in creatine kinase (CK) accumulation with NAC composition of each sampling and testing session is
supplementation compared with placebo. illustrated in Figure 1. Subjects refrained from caffeine,
 N-Acetylcysteine and Fatigue   453

Figure 1 — Overview of experimental design and procedures. Note that a 5-min break was allotted between the Loughborough
Intermittent Shuttle Test (LIST) and Yo-Yo Intermittent Recovery Test Level 1 (YIRT-L1; not shown for clarity). Note. Black arrows
denote capillary blood-sampling time points, white arrows denote venous blood-sampling time points, and gray arrows indicate
treatment-ingestion times. IKD = isokinetic dynamometry; NAC = N-acetylcysteine; L indicates treatment-loading day.

alcohol, recovery interventions (e.g., ice baths), and Preliminary Measurements

unprescribed exercise for the 48 hr preceding and during
the study. All experimental sessions were performed at After a standardized warm-up of 5 min at 10 km/hr on
a similar time of day and under consistent ambient a motorized treadmill (HP Cosmos, Germany) subjects
conditions to eliminate extraneous chronobiological completed a progressive shuttle protocol to estimate
and environmental effects, respectively. Dietary intake maximal oxygen uptake (VO2max; Leger & Lambert, 1982;
was recorded during the first 2 experimental days Ramsbottom, Brewer, & Williams, 1988). Saliently this
using a 48-hr food diary that was subsequently photo- ensured that running speeds during the Loughborough
copied and repeated during the remaining 4 experimental Intermittent Shuttle Test (LIST) were tailored to
days. individual VO2max values, thus ensuring that exercise
454   Cobley et al.

intensity was similar between individuals and hence Twenty-meter-sprint time was recorded on a handheld
treatment groups. Although precision is sacrificed device that measured the elapsed time between the
when estimating VO2max with this approach, it did breaking of the infrared beams separating each pair of
have the advantage of incorporating rapid accelera- timing lights. Heart rate (HR) was recorded after every
tion–deceleration actions that enabled LIST intensity sprint using wireless telemetry (Polar, Kempele, Finland).
to be more accurately prescribed. To eliminate Two 60-s and one 180-s recovery periods were allotted
learning effects, two muscle-function and YIRT-L1 at 15, 45, and 30 min, respectively. Rating of perceived
familiarization sessions were performed. The greatest exertion (RPE) on a 6–20 Borg scale was determined
YIRT-L1 familiarization score attained represented every 15 min (Borg, 1973). Water was consumed ad
each subject’s baseline score to enable the calculation libitum throughout the LIST. The amount consumed was
of the deterioration in YIRT-L1 performance during the recorded and repeated during subsequent trials. Capillary
experiment. Subjects completed a 15-min LIST block blood was extracted from a fingertip site and analyzed
only to ensure that no significant muscle damage was for lactate using a portable device (Lactate Pro, Arkary
invoked before commencement of the study. Factory Inc., Japan) pre- and post-LIST. The device was
calibrated according to the manufacturer’s instructions
Muscle Function before each testing session.

After a standardized warm-up, the dominant-limb con- YIRT-L1

centric quadriceps was determined using an IKD (Biodex
Medical Systems, Shirley, NY). Once the subject was A YIRT-L1 was performed to obtain a valid, reliable,
seated, his lateral femoral condyle was aligned to the and intermittent sport-specific marker of the ability to
axis of rotation of the dynamometer, and the actuator was perform repeated bouts of high-intensity exercise (see
attached proximal to the lateral malleolus. The chair set- Krustrup et al., 2003). Briefly, the YIRT-L1 involves the
tings required to produce this position were recorded and performance of consecutive 2 × 20-m shuttles separated
repeated in subsequent trials. Range-of-motion assess- by 10-s recovery intervals. Running velocity is dictated
ments were performed to minimize injury risk. Gravity by audio beeps and increased by 0.5 km/hr throughout
corrections were conducted to negate the extraneous the test until volitional exhaustion ensues (demarcated
influence of limb mass on torque development. Concentric by an inability to run in time with the audio beeps).
quadriceps torque was determined at 60, 180, and 300 rad/s). Blood lactate and RPE were determined immediately
Three maximal repetitions were performed at each speed, post-YIRT-L1.
with the greatest value attained being recorded. Subjects
received no quantitative performance feedback, but strong Blood Sampling
verbal encouragement was provided throughout. IKD tests
were performed daily to provide a baseline measure of Duplicate venous blood samples were drawn from a
the decline in muscle function between testing days. They prominent superficial forearm vein pre- and postexercise
were conducted postexercise on testing days to deter- on testing days and preexercise only on sampling days.
mine the impact of exercise on muscle function. Muscle After sterilization of the skin surface with an alcoholic
soreness was determined using the previously validated swab a tourniquet was applied to induce vasodilation. A
sample of 6 ml of venous blood was drawn into a lithium
Visual Analog Scale (VAS; Price, McGrath, Rafii, &
heparin Vacutainer using a butterfly needle. Samples
Buckingham, 1983). The VAS consists of a 12-cm line
were analyzed for hemoglobin and hematocrit using an
that has two end points labeled no pain and intolerable
automated system (Hemocue AB, Änglehom, Sweden)
pain. Subjects were required to mark a point on the VAS
and a Hawksley reader (Gelman Hawksley Ltd., Lansing,
scale that corresponded to their perception of total muscle
UK), respectively. This basic hematological analysis
soreness after performing a 90° squat. The VAS score
was performed to correct for changes in plasma volume
was the distance in centimeters from the no-pain mark.
postexercise according to the method of Dill and Costill
(1974). Samples were centrifuged immediately at 3,000
Intermittent-Exercise Bout repetitions/min for 15 min at 4° C. Plasma was dispensed
into three 2-ml aliquots and stored at –80° C for subse-
A 60-min LIST was completed in a well-ventilated quent biochemical analysis. Plasma CK concentration
indoor runway. The LIST test was selected to provide was determined using a commercially available kit (Day-
an intermittent exercise stimulus capable of inducing tona RX, Randox Laboratories Ltd., Crumlin, UK). This
muscle damage (Thompson, Nicholas, & Williams, CK-NAC kit involves spectrophotometric measurement
1999; Nicholas, Nutall, & Williams, 2000). The LIST of nicotinamide adenine dinucleotide phosphate and uses
consists of successive cycles of cruising at 95% VO2max NAC as a reducing agent to optimize the assay.
(60 m), jogging at 55% VO2max (60 m), walking (60 m),
and maximally sprinting (20 m) between two pairs of
timing lights (TC timing system, Brower Timing Sys- Statistical Analysis
tems, Draper, USA) placed 20 m apart in time with audio A mixed general linear model was employed to statisti-
beeps for 15 min (Nicholas, Nutall, & Williams, 2000). cally determine the efficacy of NAC treatment. The
 N-Acetylcysteine and Fatigue   455

between-subjects factor was treatment group and the Plasma CK

within-subject factor was dependent variables (e.g., YIRT-L1
scores) across time. If Mauchly’s test of sphericity indicated Plasma CK significantly increased across time (p = .002)
a minimum level of violation, as assessed by a Greenhouse– in both groups, confirming the damaging nature of the
Geisser epsilon (ε) of ≥.75, data were corrected using the experimental protocol. CK values were significantly
Huynh–Feldt ε. If Mauchly’s test of sphericity was violated greater (p = .029) in NAC-treated than placebo-treated
(Greenhouse–Geisser ε of ≤.75) data were corrected using subjects at 24, 50, and 72 hr postexercise. Although not
the Greenhouse–Geisser ε (Close et al., 2006). If any sig- statistically significant, a trend toward greater CK levels
nificant F values were observed, least-significant-difference at 48 and 96 hr was also observed in NAC-treated com-
tests were performed post hoc to determine where any pared with placebo-treated subjects (Figure 3).
significant differences occurred (Close et al., 2006). An
alpha value of p ≤ .05 was used for all tests. All statisti- VAS
cal analysis was performed with the Statistical Package VAS scores increased significantly across time (p ≤ .0005)
for Social Sciences version 17.0 (SPSS, Woking, Surrey, irrespective of treatment group (p = .651; see Figure 4).
UK). Data are presented as M and SD.
Side Effects
Results Acute oral NAC supplementation produced mild gastro-
YIRT-L1 Performance intestinal side effects (Table 2).

Maximal HR (~190 beats/min) and RPE (~20) were

observed at volitional exhaustion, confirming the maxi- Discussion
mal nature of the YIRT-L1. Maximal HR and RPE values
were not influenced by treatment group (HR p = .058, The main finding of this study was that acute oral NAC
RPE p = .661). Blood lactate concentration significantly supplementation prevents the deterioration in YIRT-L1
increased postexercise (p = .006) irrespective of treatment performance of repeated bouts of damaging intermit-
group (p = .133). A divergence in YIRT-L1 performance tent exercise. Indeed, YIRT-L1 performance diverged
occurred between testing Sessions 1 and 3 in NAC- and between the two groups over time, culminating in an
placebo-treated subjects, with performance being sig- enhancement and depression in YIRT-L1 performance
nificantly increased across time in NAC-treated subjects during testing Session 3 in NAC- and placebo-treated
and decreased in placebo-treated subjects (p ≤ .0005). subjects, respectively.
YIRT-L1 performance was ~50% greater in NAC- than Previous work has reported that acute intravenous
in placebo-treated subjects by testing Session 3. Analo- NAC treatment pre- (125 mg/kg) and during (25 mg/
gous results were obtained when YIRT-L1 scores were kg) nondamaging high-intensity intermittent cycling
expressed absolutely (see Figure 2). exercise fails to prolong time to fatigue at 130% VO2max
in untrained humans (Medved et al., 2003). Disparate
LIST Performance protocols, treatment regimens, and subject training status
confound any direct comparisons between the findings
The physiologically demanding nature of the LIST was of the current study and that of Medved et al. (2003).
confirmed by blood lactate values’ increasing from pre- Nevertheless, it is interesting to note that only trained
exercise values of ~0.8 mmol/L to ~4.0 mmol/L postex- individuals have consistently demonstrated performance
ercise (time effect: p ≤ .0005). NAC supplementation did enhancements after NAC treatment (McKenna et al.,
not influence blood lactate supplementation (p = 8.25; 2006; Medved, Brown, Bjorksten, Murphy, et al.,
data not shown). HR values significantly increased across 2004). A commonality of these studies, the current
time (p = .002; data not shown) irrespective of treatment one included, is the incorporation of a fatiguing sub-
group (p = .618). RPE increased across time, but values
maximal exercise protocol before the maximal work
were significantly lower in the NAC group (p = .038).
bout (Lee et al., 2010; McKenna et al., 2006; Medved,
Brown, Bjorksten, Murphy, et al., 2004). It could be that
IKD Performance submaximal fatiguing exercise is needed to precipitate
Absolute muscle torque significantly decreased across treatment effects in trained individuals. Future stud-
time at 60 rad/s (p = .000), 180 rad/s (p = .000), and 300 ies are encouraged to address the question of whether
rad/s (p = .003). This depression in muscle function was submaximal fatiguing exercise is required to precipitate
not influenced by treatment group 60 rad/s (p = .246), treatment effects.
180 rad/s (p = .520), and 300 rad/s (p = .898). Analogous We hypothesized that the efficacy of NAC in
results were obtained when muscle torque was observed preserving muscle function would, in part, be contingent
when IKD scores were expressed relative to preexer- on arresting muscle damage. The fact that NAC
cise (testing Session 1 scores). Table 1 illustrates the significantly increased plasma CK levels is discordant
depression in absolute and relative IKD scores across with this hypothesis. Indeed, other groups have
time. documented increased CK values after short-term
456   Cobley et al.

Figure 2 — A: Mean (SD) relative Yo-Yo Intermittent Recovery Test Level 1 (YIRT-L1) performance across time. B: Mean (SD)
absolute YIRT-L1 performance across time. Note. NAC = N-acetylcysteine. *Denotes a significant treatment effect.

antioxidant (vitamin C and NAC) supplementation signal to limit ROS toxicity (Reid, 2008). According to
in humans (Childs, Jacobs, Kaminski, Halliwell, & this hypothesis, attenuating ROS-mediated fatigue would
Leewenburgh, 2001). The physiological relevance of this be expected to increase the susceptibility of muscle to
finding is unclear because Childs et al. did not determine contraction-induced damage (Reid, 2008). It should,
muscle function. In the current instance, it is conceivable however, be noted that this increased susceptibility to
that elevated CK levels with NAC were the biochemical exercise-induced muscle damage was not accompanied
manifestation of an ability to perform more work with by a corresponding increase in the perception of muscle
NAC and hence induce greater muscle damage. Our soreness and decrease in muscle-force production (IKD
results are compatible with the redox-brake hypothesis of tests) in NAC-treated subjects. The results of the current
Reid (2008), which postulates that the fatiguing actions study, along with those of previous investigations,
of ROS during contractions act as a negative feedback indicate that NAC treatment increases the susceptibility
 N-Acetylcysteine and Fatigue   457

Table 1  Side-Effect Incidence and Severity by to contraction-induced damage but that this does not
Treatment Group impair short-term muscle function. It is apparent that
future work employing histological techniques and
No Mild Severe measures of oxidative stress that are influenced by NAC
incidence incidence incidence administration such as 3-methylhistidine is required
Side effect (0) (1–5) (6–10)
to further elucidate the relationship between NAC
Sweating supplementation and muscle damage.
  NAC 6 0 0 The fact that acute NAC supplementation reverses
  placebo 6 0 0 fatigue implicates ROS in the etiology of muscle fatigue
during contractions (Ferreira & Reid, 2008; Matuszczak
Light-headedness et al., 2005; McKenna et al., 2006; Medved, Brown,
  NAC 6 0 0 Bjorksten, Murphy, et al., 2004; Powers & Jackson, 2008;
  placebo 6 0 0 Reid et al., 1994; Travaline et al., 1997). The applied
Diarrhea
nature of the current investigation means we are unable to
link improvements in intermittent-exercise performance
  NAC 0 5 1 with acute NAC supplementation to a physiological
  placebo 6 0 0 mechanism. It should, however, be noted that taking serial
Indigestion muscle biopsies to reveal mechanistic insights would
have been prohibitive in the current instance because of
  NAC 2 4 0
the confounding influence of the inflammatory response
  placebo 5 1 0 that accompanies serial biopsies. This reasoning does not
Conjunctivitis apply to blood-borne redox markers; hence, the lack of
  NAC 6 0 0 these measurements represents a limitation of the current
study. Nevertheless, in terms of potential mechanisms,
  placebo 6 0 0
recent work suggests that ROS oxidize sodium (Na+),K+
Other pumps to accelerate K+ loss, which is associated with
  NAC 6 0 0 impaired membrane potential and reduced contractil-
  placebo 6 0 0 ity (McKenna et al., 2006). Consistent with this, NAC
treatment can salvage Na+,K+ activity (McKenna et al.,
Note. Incidence reflects number of cases. Severity reflects subject 2006). Sarcoplasmic reticulum calcium ATPase is another
perception of the side effect on a 0–10 Likert scale with 0 indicating
no incidence and 10 severe incidence. redox-sensitive protein important to force production
(Powers & Jackson, 2008). Specifically, ROS exposure

Figure 3 — Mean (SD) plasma CK activity across time by treatment group. Note. NAC = N-acetylcysteine; CK = creatine kinase.
*Denotes a significant treatment–time interaction effect.
458   Cobley et al.

Figure 4 — Mean (SD) scores on the visual analogue scale (VAS) across time by treatment group. Note. NAC = N-acetylcysteine.

can inhibit the function of sarcoplasmic reticulum cal- Reid, 2011). It will be necessary to confirm the findings
cium ATPase by disrupting ATP binding and calcium of the current study with further titration studies and to
uptake after ATP hydrolysis (Powers & Jackson, 2008; conduct pharmacokinetic studies on high-dose oral NAC
Scherer & Deamer, 1986; Xu, Zweier, & Becker, 1997). supplementation before this nutritional strategy can be
ROS may also interfere with calcium sensitivity during recommended as a safe and effective means of enhancing
contractions via several mechanisms, notably through athletic performance.
altering cross-bridge kinetics (reviewed in Smith & Reid,
2006). Fascinating insights may be derived from further
research focusing on how NAC is able to attenuate muscle Conclusion
fatigue during contractions. It has been demonstrated for the first time that acute oral
In an exercise setting, Matuszczak et al. (2005) were NAC supplementation preserves YIRT-L1 performance
the first to adopt an oral NAC supplementation strategy in after repeated bouts of intermittent damaging contrac-
humans. They observed a 32% increase in time to fatigue tions at the expense of inducing mild gastrointestinal side
during submaximal handgrip exercise after acute oral effects. This novel finding supports the efficacy of acute
NAC ingestion (150 mg/kg dissolved in 100 ml saline). oral NAC supplementation for performance preservation
This supplementation strategy induced several mild side during demanding short-term (≤14-day) athletic events
effects including erythema, conjunctivitis, puritis, light- where adaptation is inconsequential. In light of the role
headedness, drowsiness, dysphoria, nausea, dyspepsia, of ROS in stimulating adaptive responses, chronic NAC
and diarrhea (Matuszczak et al., 2005). The fact that supplementation may be ill advised. It is recommended
none of these side effects were evident in placebo-treated that titration studies be performed to elucidate a supple-
subjects who ingested 100 ml saline (Matuszczak et mentation strategy that enhances performance without
al., 2005) supports the notion that reduced side-effect inducing side effects.
incidence in the current study was attributable to a
decreased treatment dose that was consumed twice Acknowledgments
daily. Nevertheless, our strategy did induce mild
gastrointestinal side effects. Despite the performance We would like to thank all subjects for their sterling efforts
benefits of NAC, the occurrence of gastrointestinal side during data collection. Christopher Thompson and Rebecca
effects may limit its use in practical settings (Ferreira & Lockhart are thanked for their valued assistance during data
Reid, 2008). Recent work by Mike Reid’s group indicates collection. Dr. Gordon Lowe is thanked for advice regarding
that a 70-mg/kg dose of orally ingested NAC does not laboratory analysis. Dr. Stuart Galloway is thanked for his
cause significant adverse reactions (Ferreira, Campbell, & critical reading of the manuscript.
 Table 2  Twenty-Meter-Sprint Time, Heart Rate (HR), and Rating of Perceived Exertion (RPE) by Day, Block of the Loughborough
Intermittent Shuttle Test (LISTB), and Treatment Group, M (SD)
Day 1 Day 3 Day 5
LISTB 1 LISTB 2 LISTB 3 LISTB 4 LISTB 1 LISTB 2 LISTB 3 LISTB 4 LISTB 1 LISTB 2 LISTB 3 LISTB 4
20-m-sprint time, s
  placebo 3.44* 3.45* 3.51* 3.61* 3.59* 3.68* 3.71* 3.71* 3.64* 3.62* 3.61* 3.66*
(0.26) (0.25) (0.22) (0.18) (0.28) (0.28) (0.23) (0.23) (0.24) (0.26) (0.28) (0.25)
  NAC 3.27* 3.23* 3.24* 3.20* 3.34* 3.30* 3.34* 3.41* 3.31* 3.33* 3.37* 3.36*
(0.15) (0.15) (0.14) (0.21) (0.13) (0.08) (0.14) (0.15) (0.12) (0.09) (0.16) (0.16)

HR, beats/min
  placebo 147.4 154.6 156.7 162.0 144.4 153.0 156.5 160.1 147.0 151.0 154.0 158.5
(4.5) (7.1) (5.2) (6.0) (10.8) (10.9) (8.9) (10.2) (10.3) (7.6) (6.3) (7.3)

  NAC 149.7 156.3 158.4 162.8 148.2 155.5 158.8 161.5 149.9 155.3 154.9 156.8
(4.5) (7.3) (5.8) (7.8) (7.4) (5.9) (6.6) (6.4) (7.0) (5.5) (5.8) (5.2)

RPE
  placebo 14.0 15.7 16.5 17.8 14.5 15.8 16.5 17.2 14.7 16.1 17.0 17.7
(1.1) (1.0) (0.8) (1.7) (2.4) (2.3) (1.9) (1.6) (1.2) (2.2) (2.1) (1.4)
  NAC 12.7 14.8 15.7 16.5 12.8 14.3 15.7 16.5 12.0 13.5 14.5 15.5
(0.5) (2.4) (2.0) (2.0) (0.8) (1.0) (1.0) (1.6) (0.6) (0.8) (0.8) (1.4)

Note. NAC = N-acetylcysteine.

*Significant treatment effect, p = .029.

459
460   Cobley et al.

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