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Oxidative stress: Relationship with exercise and training
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Sports Med 2006; 36 (4): 327-358
REVIEW ARTICLE 0112-1642/06/0004-0327/$39.95/0
 2006 Adis Data Information BV. All rights reserved.
Oxidative Stress
Relationship with Exercise and Training
Julien Finaud, Gérard Lac and Edith Filaire
Laboratoire Biologie Interuniversitaire des Activités Physiques et Sportives, Université Blaise
Pascal de Clermont-Ferrand, Aubière, France
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
1. Free Radicals (FR) and Activated Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
1.1 Biochemistry of Reactive Oxygen Species (ROS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
1.1.1 Dioxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
1.1.2 Superoxide Ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.1.3 Hydrogen Peroxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.1.4 Hydroxyl Radical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.2 Programmed Formation of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.3 Unprogrammed Formation of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.3.1 ROS Formation During Oxygen Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.3.2 ROS Formation During Ischaemia Reperfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
1.3.3 ROS Formation During Haemoglobin and Myoglobin Oxidation . . . . . . . . . . . . . . . . . . . . . 332
1.3.4 Other Ways of ROS Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
1.4 Biological Effects of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
1.4.1 Positive Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
1.4.2 Negative Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
2. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2.1 Enzymatic Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2.1.1 Superoxide Dismutase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2.1.2 Catalase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2.1.3 Glutathione Peroxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
2.1.4 Relationship with Exercise and Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
2.2 Non-Enzymatic Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
2.2.1 Vitamin E (Tocopherol) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
2.2.2 Vitamin C (Ascorbic Acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.2.3 β-Carotene and Vitamin A (Retinol) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.2.4 Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.2.5 Thiols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.2.6 Coenzyme Q10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.2.7 Uric Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.2.8 Heat Shock Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.2.9 Ferritin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.2.10 Albumin, Caeruloplasmin and Bilirubin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.3 Antioxidant Supplementation in Athletes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
2.3.1 Beneficial Effects of Antioxidant Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
2.3.2 Pro-Oxidant Effects of Overloaded Antioxidant Supplementation . . . . . . . . . . . . . . . . . . . 340
2.4 Summary: Exercise and the Antioxidant System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
3. Methods to Assess Oxidative Stress in Biological Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
3.1 Direct Detection of FR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
3.2 Measurement of Oxidative Damage to Lipids, Proteins and DNA Molecules . . . . . . . . . . . . . . . 341
328 Finaud et al.
3.2.1 Lipid Peroxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

3.2.2 Protein Modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
3.2.3 DNA Modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.2.4 Other Indirect Oxidative Stress Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3 Antioxidant Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3.1 Enzymatic Antioxidant Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3.2 Antioxidant Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3.3 Other Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3.4 Total Antioxidant Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
3.4 Summary: is There an Ideal Method? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
4. Oxidative Stress and Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
4.1 Oxidative Stress and Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
4.1.1 Aerobic Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
4.1.2 Anaerobic Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
4.1.3 Mixed Exercises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
4.2 Training Effects on Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
4.2.1 Aerobic Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
4.2.2 Anaerobic Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
4.2.3 Mixed Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
4.2.4 Relationship Between Training Load and Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . 350
4.2.5 Oxidative Stress and Overtraining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
4.3 Summary: Oxidative Stress, Training and Overtraining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Abstract Free radicals are reactive compounds that are naturally produced in the human
body. They can exert positive effects (e.g. on the immune system) or negative
effects (e.g. lipids, proteins or DNA oxidation). To limit these harmful effects, an
organism requires complex protection – the antioxidant system. This system
consists of antioxidant enzymes (catalase, glutathione peroxidase, superoxide
dismutase) and non-enzymatic antioxidants (e.g. vitamin E [tocopherol], vitamin
A [retinol], vitamin C [ascorbic acid], glutathione and uric acid). An imbalance
between free radical production and antioxidant defence leads to an oxidative
stress state, which may be involved in aging processes and even in some
pathology (e.g. cancer and Parkinson’s disease). Physical exercise also increases
oxidative stress and causes disruptions of the homeostasis. Training can have
positive or negative effects on oxidative stress depending on training load,
training specificity and the basal level of training. Moreover, oxidative stress
seems to be involved in muscular fatigue and may lead to overtraining.
Regular physical activity, associated with a bal- tigue, many diseases and aging.[2,3] However, they
anced diet, is known as an important factor for exert positive effects on the immune system and
health.[1] However, exhaustive and/or intense physi- essential metabolic functions.[4] Antioxidants are
cal activity can induce diseases, injuries and chronic
components that suppress FR and their harmful ef-
fatigue, which can lead to the overtraining syn-
drome, partially because of the toxicity of free radi- fects. If the production of FR is larger than antioxi-
cals (FR). FR, which are highly produced during dant activity, there is an oxidative stress state with
physical exercise,[1] are involved in muscular fa- cell damages.[5]
 2006 Adis Data Information BV. All rights reserved. Sports Med 2006; 36 (4)
Oxidative Stress and Physical Activity 329
Physical activity increases the FR production and Among FR, reactive oxygen species (ROS) are de-
the antioxidant utilisation. Nutrition provides an im- rived from oxygen. ROS contains FR and reactive
portant part of the antioxidant; however, insufficient forms of oxygen (table I). This article will focus on
micronutrient supply is often reported in athletes.[6,7] ROS, which are involved in essential physiological
It has also been shown that oxidative stress can phenomenon such as immunity or oxidative stress.
increase during periods of intensive training. There- Other FR families exist, such as reactive nitrogen
fore, oxidative stress may be one of the actors of the species (RNS) and reactive sulphur species (RSS)
overtraining syndrome.[8,9] [table I]. These species could be formed by reactions
This article presents the basis of oxidative stress with ROS or could increase ROS production.[14]
and determines the relationship between oxidative
stress, exercise, training and overtraining. 1.1 Biochemistry of Reactive Oxygen
Species (ROS)
1. Free Radicals (FR) and
Activated Species
1.1.1 Dioxygen
FR are molecules or molecule fragments with Aerobic organisms require dioxygen (O2) be-
one or more unpaired electrons in the valence cause this molecule acts as an electron acceptor
shells.[10-12] FR are very unstable and very reactive during the oxidation of energetic substrates. Para-
because they tend to catch an electron to other doxically, dioxygen is a permanent threat.[10] In-
molecules (oxidation).[5,13] Their lifetime is very deed, ROS are continually produced from exoge-
short (from milliseconds to nanoseconds [table I]). nous origins (radiation exposure, air pollutants, in-
FR are produced by an electron transfer that requires toxication by oxygen, smoke, alcohol) or from
a high energy input.[11] When reacting with other endogenous origin (oxygen metabolism).[4,11] Dur-
radicals or molecules, a FR can form new radicals.[5] ing oxygen metabolism, dioxygen receives two elec-
Table I. Classification and main effects of free radicals

Free Radical Contraction Half-life Main effects
Reactive oxygen species ROS
Superoxide ion O2•– 10–5 sec Lipid oxidation and peroxidation
Protein oxidation
DNA damage
Ozone O3 Stable
Singlet oxygen 1O2 1 µsec
Hydroxyl radical OH• 10–9 sec
Hydrogen peroxide H2O2 Stable
Hypochlorous acid HOCl Stable
Alkoxyl radical RO• 10–6 sec
Peroxyl radical ROO• 7 sec
Hydroperoxyl radical ROOH•
Reactive nitrogen species RNS
Nitric oxide NO• Lipid peroxidation
DNA damage
Proteins oxidation
Nitric dioxide NO2• 1–10 sec
Peroxynitrite ONOO•– 0.05–1 sec
Reactive sulphur species RSS
Thyil radical RS• Proteins oxidation
DNA damage
ROS production
330 Finaud et al.
trons. Dioxygen prefers to receive one electron at a tive and very toxic ROS and there is no specific
time and converts it into a superoxide ion (O2•–).[5] antioxidant against this FR. This FR causes lipid
Following this process, 2–5% of oxygen consump- peroxidation and protein oxidation.[16]
tion (V̇O2) is converted to O2•–.
1.2 Programmed Formation of ROS
1.1.2 Superoxide Ion
O2•– is created with the addition of one electron In the immune system, neutrophils and macro-
on dioxygen (equation 1) and becomes highly reac- phages are in charge of destroying foreign sub-
tive. stances (antigens). Those immunity cells produce
O 2 + e-® O 2 •- O2•– with the reduced nicotinamide-adenine
(Eq. 1) dinucleotide phosphate (NADPH)-oxidase system,
Fenton’s reaction is an iron-salt-dependent de- which is present in leukocytes.[17] During this pro-
composition of dihydrogen peroxide, generating the cess (equation 4), two O2 molecules are needed so
highly reactive hydroxyl radical. It occurs in the this reaction is called ‘oxidative burst’.
presence of ferrous ions (Fe2+) and O2•–. Iron is NADPH-oxidase
mainly present in tissues in a ferric ion state (Fe3+). 2 O 2 + NADPH → 2 O 2•- + NADP + + H +
The reaction (equation 2d) is called the Haber-Weiss (Eq. 4)
reaction. As shown in section 1.1.3, O2•– can be converted
a O 2•- + H + → O 2• H to H2O2 by SOD in Fenton’s reaction. After that,
H2O2 can be transformed into HOCL, which is very
b O 2•H + O 2•-+ H + → H 2O 2 + O 2 active for antigen degradation.[18] Thus, an impor-
tant quantity of ROS can be formed during the
c Fe 3+ + O 2•- → Fe 2+ + O 2
immunity process and plays an essential biological
• role for homeostasis control.[15,17]
d Fe 2+ + H 2O 2 → Fe 3+ + OH + OH -
(Eq. 2) 1.3 Unprogrammed Formation of ROS
1.1.3 Hydrogen Peroxide
1.3.1 ROS Formation During Oxygen Metabolism
Equation 3 summarises the first and the second
stages of Fenton’s reaction (equations 2a and 2b). It is generally considered that the oxygen metab-
This reaction forms hydrogen peroxide (H2O2) in an olism, which occurs into mitochondria, is associated
acid environment and is catalysed by the superoxide with the generation of ROS.[19] Oxidative phospho-
dismutase (SOD) enzyme. rylations result in adenosine triphosphate (ATP) for-
mation. Substrate oxidation occurs in the Krebs’
SOD
2 O 2•- + 2 H + → H 2O 2 + O 2 cycle and in the electron transport chain with oxy-
gen as the electron acceptor. In the respiratory chain,
(Eq. 3)
95–99% of oxygen consumed is reduced into water
H2O2 is not a FR because it has no unpaired
(H2O) by a tetravalent reduction (equation 5) cat-
electron, but it is considered a ROS because of its
alysed by coenzyme Q (CoQ).[17,20]
toxicity and its capacity to cause ROS formation. In
CoQ
leukocytes, myeloperoxydase (MPO) transform
O 2 + 4 e- + 4 H + → 2 H 2 O
H2O2 in hypochlorous acid (HOCL), one of the
strongest physiological oxidants and a powerful an- (Eq. 5)
timicrobial agent.[15] However, 1–5% of O2 will form O2•–.[21-23] The
ROS formation is proportional to the respiratory
1.1.4 Hydroxyl Radical chain activity, but the latter is not always propor-
Hydroxyl radical (OH•) is the end product of tional to V̇O2.[19] Two major sites of production of
Fenton’s reaction (equation 2). OH• is a very reac- ROS have been localised in the respiratory chain:
Mitochondria
Electron chain transport
NADH NAD+ Succinate Fumarate Antimycin A
Complex I Complex II Complex III

CoQ
Reversed b cyt.
e- flow CoQH2
CoQ·-
FeSR
Retonone O2 ® O2·- Myxothiazol

-
Fig. 1. Possible locations of mitochondrial reactive oxygen species formation inside electron chain transport (reproduced from Nohl et al.,[26]
with permission.  the Biochemical Society). b cyt. = b cytochrome; CoQ = coenzyme Q; CoQH2 = reduced coenzyme Q10; CoQ•– =
oxidised coenzyme Q10; FeSR = Rieske iron-sulphur protein; NAD+ = oxidised nicotinamide-adenine dinucleotide; NADH = reduced
nicotinamide-adenine dinucleotide; O2•– = superoxide ion.
complex I and complex III (see figure 1).[20,23] Dis- vealed that about 50% of O2•– production arises
tribution and quantity of ROS production inside from reduced nicotinamide-adenine dinucleotide
these complexes fluctuate according to the needs of (NADH)-dehydrogenase inside complex I, between
ATP, V̇O2, central temperature and other parame- a mercurial-sensitive and a retonone-sensitive com-
ters that vary with physical exercise.[19] Inside com- ponent, most likely a nonhaeme iron-sulphur func-
plexes I and III, reduced coenzyme Q10 (CoQH2) tion. This hypothesis is still controversial.[26] The
contribute to ROS formation (equation 6).[24] CoQ possible locations of ROS formation inside the mito-
may be transformed into a superoxide generator chondrial respiratory chain are represented in figure
when the ubisemiquinone anion, arising from one- 1.
electron oxidation of ubiquinol, becomes accessible
The assumption that mitochondria are the major
to protons.[25]
intracellular source of ROS was essentially based on
CoQH 2 + O 2 ® CoQH • + O 2 •-
in vitro experiments with isolated mitochon-
•
CoQH + O 2 ® CoQ + H + + O 2•- dria.[19,20,26] Artifacts due to the preparation proce-
(Eq. 6) dure or inadequate measurement of ROS may lead
There is a synergistic action of CoQH2 and cyto- to methodological mistakes.[26] In vivo study pro-
chrome b566 in complex III.[24] However, this hy- vides direct evidence that mitochondria (in heart
pothesis is still controversial because CoQ, in its muscle) produce ROS during exercise.[16] So, both
reduced form, may act as an antioxidant.[19] It was in vitro and in vivo studies tended to affirm that the
recently shown that ROS are not spontaneously re- mitochondrial respiratory chain can not only be a
leased from mitochondria, but appear when the mi- major source of ROS at rest and during exercise in
tochondrial membrane potential reaches a maximum the working muscle, but also in tissues such as liver,
(state IV).[26] This fact is confirmed by other stud- kidneys and non-working muscles that undergo par-
ies.[27] The site of single-electron deviation to diox- tial ischaemia during physical exercise.[19] At the
ygen seems to be ubiquinol interacting with the same time, mitochondria are particularly susceptible
Rieske iron-sulphur protein and low-potential cyto- to the ROS-induced oxidative damage on lipids,
chrome b of the complex III.[26] Another study re- proteins and DNA. In particular, damage to mito-
332 Finaud et al.
Intracellular space
Mitochondria:
Mn-SOD
GPX
Electron chain
transport
Membranes:
Vit E,
ROS carotenoids,
flavonoids
NADPH
Nucleus
Cytosol:
XO CAT, GPX, Cu-Zn-SOD,
Vit C, GSH
Extracellular space
Blood
Membranes, circulating
Circulating antioxidants:
ROS cells and lipoproteins:
Vit C, lipoic acid, GSH
Vit C, carotenoids, flavonoids
Fig. 2. Potential sources of reactive oxygen species (ROS) in skeletal muscle and locations of the major intracellular and extracellular
antioxidants. CAT = catalase; GPX = glutathione peroxidase; GSH = glutathione; NADPH = reduced nicotinamide-adenine dinucleotide
phosphate; SOD = superoxide dismutase; Vit = vitamin; XO = xanthine oxidase.
chondrial DNA (mtDNA) induces alterations to the [ADP] and adenosine monophosphate [AMP]). In-
polypeptides in the respiratory complexes, with con- side hypoxic tissues, XDH can be converted into
sequent decrease of electron transfer, leading to xanthine oxidase (XO).[20,32] During reperfusion,
further production of ROS. Thus, a vicious circle of O2•– can then be formed by a reaction catalysed by
oxidative stress and energetic decline is estab- XO between oxygen, hypoxanthine and xan-
lished.[28,29] However, training does not seem to thine.[1,33,34] Nevertheless, the role of XO in muscles
modify ROS release from mitochondria.[27] Never- is discussed because there is a poor amount of XO
theless, there is a lack of knowledge about the exact inside them.[19,32] Other alternative explanations
mechanisms of ROS production inside the mito- seem to be possible to explain the increased produc-
chondria, and further studies are needed. tion of FR during ischaemia reperfusion. Some stud-
ies have shown that ischaemia reperfusion increased
1.3.2 ROS Formation During Ischaemia Reperfusion
mitochondrial FR production.[19] Other studies
The second major source of ROS is ischaemia
pointed out that phagocyte infiltration, catecho-
reperfusion phenomenon, which occurs after surgi-
lamine, myoglobin and methmyoglobin auto-oxida-
cal interventions, after shocks or during physical
tion take part in FR production during ischaemia
exercise (figure 2).[17,30-32] During exhaustive or ana-
reperfusion.[35]
erobic exercise, blood flow is brought to active
territories such as skeletal muscles while other tis- 1.3.3 ROS Formation During Haemoglobin and
sues can be in an hypoxic situation.[1,19] After exer- Myoglobin Oxidation
cise, these tissues receive a great quantity of oxygen. Oxidation of haemoglobin can cause ROS forma-
This phenomenon is described as ‘ischaemia tion.[4,17,36] In the human body, 3% of the total
reperfusion’. Xanthine dehydrogenase (XDH) has haemoglobin (about 750g) is transformed by auto-
an important role in the formation of uric acid from oxidation. This reaction, which increases during ex-
purins degradation (ATP, adenosine diphosphate ercise, produces methaemoglobin and O2•–.[1,37-40]
Myoglobin can also be oxidised by auto-oxidation aract, cancers, Alzheimer’s or Parkinson’s diseases
or by FR during ischaemia reperfusion with the or in cell aging.[3]
production of H2O2.[35,38,40] Myoglobin can then in-
Lipid Oxidation
teract with H2O2 and produce other radicals such as
Lipoprotein oxidation is an important factor in
ferryl radicals or peroxyl radicals.[41-43]
the pathogenesis of atherosclerosis.[53,54] In fact,
1.3.4 Other Ways of ROS Production ROS initiate lipoprotein oxidation, in particular low-
Other processes involved in ROS production dur- density lipoprotein (LDL) oxidation.[55] This oxida-
ing exercise are increased central temperature, cat- tion is dependent on blood antioxidant capacity[56,57]
echolamine and lactic acid, which has the ability to and can increase with oxidative stress linked to
convert O2•– into OH•.[1,44] physical exercise.[58,59] However, those effects are
partially or totally compensated in athletes because
exercise decreases cardiovascular accident risk.[59]
1.4 Biological Effects of ROS
ROS also have the ability to oxide polyunsaturated
free-fatty acids (PUFFA), which take part in cell
1.4.1 Positive Effects membrane constitution.[11,21,51] This reaction initi-
ROS are involved in the immunity phenomenon, ates lipid peroxidation, a chain reaction that produc-
in particular by acting against antigens during phages other FR such as ROO• or ROOH• and sub-
ocytosis.[10,12,17] This role increases during inflam- stances such as conjugated dienes or malondi-
mation. Inflammation can be caused by physical aldehyde (MDA).[54] Lipid peroxidation changes the
exercise, particularly by intense and traumatising fluidity of cell membranes, reduces the capacity to
exercises such as eccentric exercises.[45] Although maintain an equilibrated gradient of concentration,
most studies have concentrated on the harmful ef- and also increases membrane permeability and in-
fects of FR, ROS play an important role in cellular flammation.[60] Consequently, it is possible to detect
signals or in biogenesis of cells because they can a loss of intracellular liquids, a diminution of calci-
serve as cell messengers or modify oxidation-reduc- um transport in the endoplasmic reticulum, altera-
tion (redox) status.[5,12,46-48] ROS are also known to tions of mitochondrial functions and cell alterations,
be involved in enzyme activation, in drug detoxifi- together with loss of cryptozoic proteins and en-
cation or in facilitating glycogen repletion.[10] ROS zymes.[10,31] Every type of cell can be damaged by
also play an essential role in muscular contrac- ROS, including muscular cells and erythrocytes.[61]
tion.[47-50] This role has been pointed out because
inhibition of ROS production leads to a loss of Protein Oxidation
muscular fibres contractile force. Conversely, in- ROS can also oxidise blood and structural pro-
creasing ROS leads to an increased strength contrac- teins and inhibit the proteolytic system.[62] During
tion.[47,49,50] However, an important amount of ROS oxidation, proteins can lose amino acids or can be
in muscular tissue is implicated in muscular fatigue fragmented. Those reactions lead to alteration of
and can represent one of the negative effects of structural proteins or alteration of enzyme func-
ROS. tions.[60] Protein and amino acid oxidation is accom-
panied by overall increases in the relative level of
1.4.2 Negative Effects protein carbonyl groups[11,63-65] and of oxidised
Despite some helpful effects, ROS have possible amino acids,[16,66] which are used as general indexes
harmful effects because they can alter the size and for the occurrence of oxidative damage.[16,60,67] Pro-
shape of the compounds they interact with.[1,10,51,52] tein oxidation can be the consequence of inflamma-
Consequently, ROS can induce apoptosis into tion, physical exercise or ischaemia reperfu-
healthy cells and can provoke inflammation or al- sion.[65,66] Oxidised proteins are catabolised in order
tered cellular functions. All those deteriorations take to reform amino acids but carbonyl by-products
part in some degenerative pathology such as cat- cannot enter this process. Therefore, they induce a
334 Finaud et al.
Exercise
ROS-RNS
Alteration of Increased Alteration Alteration

mitochondrial anaerobic of the action of the
functions pathways potential redox status
utilisation
Decreased Increased Pi Increased Pi

electron transfer Acidosis Acidosis
Decreased ATP
formation
Increased ROS
formation
Muscular fatigue
Decreased force
Overtraining?
Fig. 3. The different hypothesis about the effects of reactive oxygen species (ROS) on muscular fatigue. ATP = adenosine triphosphate;
redox = oxidation-reduction; RNS = reactive nitrogen species; Pi = inorganic phosphate.
proteolysis blocking and an accumulation of oxidis- ing contraction and in post-exercise muscular dam-
ed proteins.[64,65] Consequently, protein turnover, age and suffering.[1,7,31,72-76] The different hypothesis
genetic transcription and cell integrity are reduced about the effects of ROS on muscular fatigue is
under ROS actions. ROS also have the ability to summarised in figure 3. Precisely, when ROS con-
alter the lysosomal system and the proteasomes, two centration is too important or too prolonged, a time-
major pathways by which proteins are degraded.[62] and dose-dependent muscular force decrease and a
DNA Oxidation time- and dose-dependent muscular fatigue increase
ROS are also known to cause DNA strand breaks can be observed.[47,72,77] Numerous factors seem to
and base repair damage.[10,51,63,68] Every part of be implicated in FR-induced muscular fatigue (fig-
DNA is susceptible to attack by ROS.[69] The DNA ure 3). The alteration of the mitochondrial functions
repair system is continual, but its capacity can be with exposure to ROS is considered a major factor
overreached or the repair processes can be al- of muscular fatigue.[72,77] Indeed, mitochondria are
tered.[68,70] As a consequence, DNA oxidation can particularly susceptible to the ROS-induced oxida-
provoke mutagenesis and is a major contributor to tive damage on lipids, proteins and DNA, and dam-
human cancer and cell aging.[17,60,68,70,71] Different ages to mtDNA can induce alterations to the respira-
major sources of DNA damages have been found as tory complexes, with a consequent decrease of elec-
a result of: smoking, chronic inflammation and leak- tron transfer and ATP formation. Thus, aerobic
age from mitochondria, which increased with physi- pathways become less efficient. Consequently, it
cal exercise.[51,70,71] seems that this phenomenon can induce an increase
Implication of FR in Muscular Fatigue of anaerobic pathways utilisation. This can have
A minimal amount of ROS is necessary for mus- negative effects in muscle because anaerobic path-
cular contraction.[47,49,50] Nevertheless, oxidative ways induce both an increased inorganic phosphate
stress, which results in muscle-increased ROS con- (Pi) level and acidosis, which are two major factors
centration, is associated with muscular fatigue dur- of muscular fatigue.[72]
Contractile proteins (actin and myosin) and calci- enzymatic (endogenous) and non-enzymatic (main-
um pump are muscular compounds that are sensitive ly brought by food) antioxidants.[74] All of them can
to redox status. Redox status is directly linked and be intracellular or extracellular antioxidants (figure
modified by ROS concentration. Thus, when ROS 2). Antioxidant enzymes include SOD, catalase
production is important, redox status can be altered. (CAT) and glutathione peroxidase (GPX). Non-en-
Consequently, muscular contraction (contractile zymatic antioxidants include a variety of FR
proteins) and muscular contraction control (calcium quenchers such as vitamin A (retinol), vitamin C
pump) may be altered.[33] ROS can induce an intra- (ascorbic acid), vitamin E (tocopherol), flavonoids,
cellular calcium increase and intracellular enzymes thiols (including glutathione [GSH], ubidecarenone
inactivation (particularly enzymes implicated in aer- (ubiquinone Q10), uric acid, bilirubin, ferritin) and
obic and anaerobic pathways) into muscular cells, micronutrients (iron, copper, zinc, selenium, manga-
which could participate to muscular fatigue.[78] nese), which act as enzymatic cofactors. The antiox-
Moreover, during certain forms of exercise, such as idant system efficiency depends on nutritional in-
eccentric exercise, an important iron release (from takes (vitamins and micronutrients) and on endoge-
ferritin or haemoglobin) can be observed. Iron re- nous antioxidant enzyme production, which can be
lease can aggravate exercise and post-exercise oxi- modified by exercise, training, nutrition and ag-
dative stress and muscular fatigue and damages.[79] ing.[84] Moreover, the antioxidant system efficiency
Moreover, data tend to show that the action potential is important in sport physiology because exercise
for muscle contraction can be modified by ROS.[80] increases the production of FR.
Indeed, ROS causes remarkable perturbation of the
inward potassium transport system in muscle. It has 2.1 Enzymatic Antioxidants
been shown that muscle soreness-induced decrease
in maximal force generation is a result of an increase
in muscular nitric oxide (NO).[81] Indeed, NO was 2.1.1 Superoxide Dismutase
reported to decrease contractile force by inhibition SOD is the major defence upon superoxide radi-
of Ca21-ATPase activity in the sarcoplasmic reticu- cals and is the first defence line against oxidative
lum. Moreover, NO induces hyperpolarisation of stress. SOD represents a group of enzymes that
membrane potential (thereby leading to reduced catalyse the dismutation of O2•– and the formation
force generation) and also may directly inhibit the of H2O2 (equation 7).
force-generating proteins in skeletal muscle. In sum- SOD
mary, it seems possible that ROS- and RNS-induced 2 O 2•- + 2 H + → H 2O 2 + O 2
decrease in maximal force generation can be a part (Eq. 7)
of a protective mechanism by which skeletal muscle In all cells, at rest, the major part of mitochondri-
protects itself from further peak force-generated al-produced O2•– is reduced by mitochondrial SOD
damage.[81] Moreover, repetitive muscular ROS-in- and the other part diffuse into the cytosol.[85] In
duced fatigue associated with inadequate recovery is muscular cells, 65–85% of SOD activity is done in
supposed to induce overtraining syndrome.[73,82,83] the cytosol.[74] Different forms of SOD are present in
the body (see table II and figure 2). Manganese is a
2. Antioxidants cofactor of the Mn-SOD form, which is present in
mitochondria as well as copper and zinc, which are
An antioxidant can be defined as a substance that cofactors of Cu-Zn-SOD, present in cytosol.
helps to reduce the severity of oxidative stress either
by forming a less active radical or by quenching the 2.1.2 Catalase
damaging FR chain reaction on substrates such as CAT is present in every cell and in particular in
proteins, lipids, carbohydrates or DNA.[84] A range peroxysomes, cell structures that use oxygen in or-
of antioxidants are active in the body including der to detoxify toxic substances and produce
336 Finaud et al.
Table II. Localisation and actions of antioxidant enzymes

Antioxidants Cofactors Cellular localisation Targets
Mn-SOD Manganese Mitochondria Anion superoxide
Peroxynitrite
Cu-Zn-SOD Copper Cytosol – mitochondria (membrane) Anion superoxide
Zinc Peroxynitrite
CAT Iron Peroxysome, cytosol and mitochondria Hydrogen peroxide
GPX Selenium Cytosol and mitochondria Hydrogen peroxide
Peroxynitrite
CAT = catalase; GPX = glutathione peroxide; SOD = superoxide dismutase.
H2O2.[86] Catalase converts H2O2 into water and 2.2 Non-Enzymatic Antioxidants
oxygen (equation 8).
2 H 2O ®
CAT
2 H2O + O 2 2.2.1 Vitamin E (Tocopherol)
(Eq. 8) Vitamin E is a fat-soluble vitamin made up of
Catalase can also use H2O2 in order to detoxify several isoforms known as tocopherols. α-Tocoph-
some toxic substances via a peroxidase reaction erol is the more active and abundant form.[88] Vita-
(equation 9). This reaction needs a substrate such as min E has been called the most important chain-
phenol, alcohol (ethanol; A) or formic acid. breaking antioxidant because of its abundance in
CAT cells and mitochondrial membranes and its ability to
H 2O 2 + H 2A (substrate) → 2 H 2O + A act directly on ROS.[78] Vitamin E interacts with
(Eq. 9) numerous antioxidants such as vitamin C, GSH, β-
carotene or lipoic acid. Those antioxidants have the
capacity to regenerate vitamin E from its oxidised
2.1.3 Glutathione Peroxidase
form.[50] Vitamin E plays an important role in cell
The GPX present in cell cytosol and mitochon-
membranes because it stops lipid peroxidation (table
dria has the ability to transform H2O2 into water
III). The molecular structure of vitamin E enables
(equation 10). This reaction uses GSH and trans-
ROS inactivation in a lipid environment, particular-
forms it into oxidised glutathione (GSSG).
ly for peroxyl radicals, which come from LDL oxi-
®
GPX
dation into membranes or into blood.[53,89,90] A vita-
H 2O 2 + 2 GSH GSSG + 2 H2O
min E deficiency is frequent in healthy occidental
(Eq. 10) populations.[90,91] Such deficiency could increase
GPX and CAT have the same action upon H2O2, oxidative stress and fatigue associated with de-
but GPX is more efficient with high ROS concentra- creased oxidative capacity and endurance.[77,78,92,93]
tion and CAT has an important action with lower Athletes often use vitamin E supplementation in
H2O2 concentration.[21,86] order to prevent exercise-induced ROS muscular
damages and fatigue.[7,33,78,87,94,95] However, the re-
2.1.4 Relationship with Exercise and Training sults are often contradictory probably because of
Antioxidant enzymes are endogenous (table II). methodological differences such as vitamin status of
However, their production can be modulated by subjects before studies, vitamin E supplementation
certain factors. Exercise and training are well known quantity, frequency and duration, or training lev-
to be potential factors of SOD, CAT and GPX el.[6,76] Indeed, trained subjects present a higher vita-
increase as shown by numerous studies (see section min E status, whereas overreaching seems to de-
3 for more details).[16,22,74,87] crease it.[33,76]
Table III. Localisation and actions of the main non-enzymatic antioxidants

Antioxidant Localisation Actions Targets
Direct antioxidants
Vitamin E (tocopherol) Lipids Lipid peroxidation inhibition ROOH – 1O2
Cell/mitochondria membranes Membrane stabilisation
Vitamin A (retinol) Lipids Lipid peroxidation reduction 1O2 – ROOH
Cell membranes
Vitamin C (ascorbic acid) Aqueous middle Vitamin E regeneration OH• – O2•–
Cytosol LDL protection
Extracellular liquids
Glutathione Aqueous middle Substrate for GPX 1O2 – OH•
Vitamins E and C regeneration
Cysteine Intracellular middle Glutathione precursor
Lipoic acid Aqueous middle Lipid peroxidation inhibition
Vitamins C and E and cysteine
regeneration
Thioredoxin Aqueous middle Mn-SOD synthesis H2O2 – ROOH
Vitamin C regeneration
Glutaredoxin Aqueous middle H2O2
Flavonoids Linked with glucids Pro-oxidant enzymes inhibition O2•– – OH• – ROOH – RO•
Pro-oxidant ions (Fe2+, Fe3+,
Cu2+)
trapping
LDL protection
Coenzyme Q10 Internal membrane of Vitamin C and E regeneration ROO•
mitochondria LDL protection
Uric acid Aqueous middle Pro-oxidant ions (Fe2+, Fe3+, ROOH – OH• – O3 – HOCL
Cu2+) ONOOH
trapping
Erythrocytes, haemoglobin, DNA,
lipids protection
Indirect antioxidants
HSP Aqueous middle Protection of proteins (cells)
Iron Aqueous middle Catalase cofactor
Ferritin Aqueous middle Free iron trapping
Zinc Aqueous middle SOD cofactor (Cu-Zn-SOD)
LDL and thiols protection
FR production inhibition
Copper Aqueous middle SOD cofactor (Cu-Zn-SOD)
Selenium Aqueous middle GPX cofactor
Manganese Aqueous middle SOD cofactor (Mn-SOD)
Albumin Aqueous middle Give electron to FR
Cu2+ trapping
Caeruloplasmin Aqueous middle Give electron to FR
Cu2+, Fe2+ and Fe3+ trapping
Bilirubin Aqueous middle Give electron to FR
Lipid peroxidation inhibition
Erythrocyte protection
1O2 = singlet oxygen; FR = free radicals; GPX = glutathione peroxidase; H2O2 = hydrogen peroxide; HOCL = hypochlorous acid; HSP =
heat shock proteins; LDL = low-density lipoprotein; O2•– = superoxide ion; ONOOH = peroxynitrous acid; O3 = ozone; OH• = hydroxyl
radical; RO• = alkoxyl radical; ROO• = alkylperoxyl radical; ROOH = hydroperoxyl radical; SOD = superoxide dismutase.
338 Finaud et al.
2.2.2 Vitamin C (Ascorbic Acid) upon some ROS by direct hydrogen atom donation.
Vitamin C is a water-soluble vitamin and is prob- Despite increasing evidence for the in vitro antioxi-
ably the most important antioxidant in extracellular dant effects of flavonoids, there is a lack of knowl-
fluids, but is also effective in cytosol.[82,96] Vitamin edge on their in vivo actions.[52,104,105] However,
C is more abundant in tissues in which ROS produc- some studies tend to confirm the in vivo antioxidant
tion is more important. This phenomenon is defined properties of flavonoids.[106] Moreover, flavonoids
as an adaptation against oxidative stress.[96] In seem to have a sparing effect on vitamin E and β-
fluids, vitamin C has the ability to neutralise ROS carotene.[52,106] The in vivo effects of flavonoids are
(OH•, O2•–, fatty acid peroxyl radical (LOO•), al- discussed because some of them can have pro-oxi-
koxyl radical [RO•]).[82] Inside cells, vitamin C rein- dant effects and because flavonoids are present in
forces the action of vitamin E and GSH by regener- the body as metabolite forms that have poor antioxi-
ating their active form after they have reacted with dant effects.[105,107,108]
ROS.[56,78,97] Vitamin C also has the ability to trap
copper ions, which have a powerful oxidant action. 2.2.5 Thiols
Thus, vitamin C supplementation has often been Thiols are a class of molecules characterised by
studied. In athletes, its preventive effects against the presence of sulfhydryl residues (–SH) at their
oxidative stress are discussed.[32,95,98,99] A deficiency active site.[109] Thiols are synthesised from sulphur
in vitamin C has negative effects on performance amino acids: cysteine or methionin, which is a cyste-
and vitamin C supplementation (especially in com- ine precursor. They have numerous functions in
bination with other antioxidants such as vitamin E) biological systems, e.g. protein synthesis, redox, cell
helps to maintain an adequate vitamin C level in biogenesis and immunity. They also play a major
tissues.[7] role in the antioxidant defence network.[109] GSH is
2.2.3 β-Carotene and Vitamin A (Retinol)
the major thiol present in an organism. It acts like a
substrate for GPX in peroxidase ROS inhibition.
Vitamin A is a fat-soluble vitamin present in
GSH can also directly detoxify ROS and enhances
many lipid substances. β-carotene, present in cell
the functional antioxidant capacity of vitamins C
membranes, is converted into vitamin A when the
and E.[110,111] In the presence of oxidative stress, it is
body needs it. Although the mechanism of its in vivo
possible to observe a decrease of the GSH/GSSG
action is unclear, β-carotene is suggested to deacti-
ratio and of the total thiol quantity.[109,112,113] These
vate ROS (in particular singlet oxygen and lipid
phenomena seem to be involved in the aetiology of
radicals) and to reduce lipid peroxidation.[74,100] Al-
some neurodegenerative diseases such as Parkin-
though less important than vitamin E inside the
son’s or Alzheimer’s disease.[114] They are also ob-
antioxidant system, β-carotene and vitamin A act in
served in aging or after physical exercise.[112,113] A
tandem with vitamin C and vitamin E in order to
low GSH concentration in cells may be associated
protect cells against ROS.[101] β-carotene supple-
with cellular damage and decreased immunity effi-
mentation seems to have beneficial effects against
ciency, which can be compensated with a vitamin C
exercise-induced oxidative stress without enhancing
and E supplementation.[115] Such results tend to
physical performance.[102,103]
show that these antioxidants have the same targets
2.2.4 Flavonoids and work together against them. Lipoic acid is a
Flavonoids (Fl-OH) are phenolic substances thiol that inhibits lipid peroxidation and helps to
formed in plants from amino acids phenylalanine, reduce vitamins C and E from their oxidised
tyrosine and malonate.[93,104] In vitro studies pointed form.[50,116,117] It can also reduce cystin (the oxidised
out the antioxidant effects of flavonoids that have form of cysteine) into cysteine in order to promote
the ability to inhibit pro-oxidant enzymes or to form thiol genesis.[109,114,118] Therefore, lipoic acid sup-
complexes with pro-oxidant ions such as Fe2+, Fe3+ plementation helps to increase antioxidant protec-
or Cu2+. Flavonoids also have direct trapping action tion and may have some therapeutic effects.[50,109]
2.2.6 Coenzyme Q10 ly with body temperature variations, inflammation

Coenzyme Q10 (CoQ10) is an endogenous mole- and oxidative stress.[139-141] HSP are considered anti-
cule that is essential for ATP synthesis and is espe- oxidants because they protect cells and intracellular
cially present in mitochondrial membrane.[48,119] proteins against FR-induced damage.[17,139,140] Phys-
CoQ10 is known to act as an antioxidant with a direct ical training and antioxidant supplementation pro-
action upon peroxyl radicals or with an indirect mote a lower HSP basal level but the ability to have
action by regenerating vitamins C and E.[120,121] a quick HSP liberation under stressful situations
CoQ10 also has beneficial effects, such as protection remains unchanged.[140] Given the potential of ROS
against cardiovascular diseases, cancer and cell ag- to damage intracellular proteins during subsequent
ing or apoptosis.[48,119,122,123] However, CoQ10 acts bouts of muscle contractions, data suggested that,
as a mediator for gene expression and protein syn- under oxidative stress conditions, the pre-existing
thesis in muscle.[48] In this case, CoQ10 acts as a pro- antioxidant pathways may be complemented by the
oxidant by giving rise to O2•–, which is converted to synthesis of HSP.[141] Thus, HSP could represent an
H2O2 by SOD. H2O2 then acts as a second messen- important protection mechanism against exercise-
ger for genetic expression. CoQ10 supplementation induced damage to muscle.[139-141]
has been tested in sporting groups with limited re-
2.2.9 Ferritin
sults on oxidative stress reduction and physical per-
formance.[124,125] Iron is required for normal cell growth and
proliferation and can have antioxidant effects as a
2.2.7 Uric Acid cofactor of catalase. However, iron ions can have
Uric acid is an end-product of purine metabolism pro-oxidant effects in Fenton’s reaction or can oxi-
in humans.[113,126,127] Intense physical exercise is dise vitamin C and reduce antioxidant protection
known to increase plasmatic concentrations of uric against FR.[136,142] Therefore, excess iron is poten-
acid.[90,128] Plasmatic uric acid can then diffuse into tially harmful and ferritin, one of the major proteins
muscles in order to protect them from FR oxida- of iron metabolism, plays an important part in the
tion.[129] Indeed, uric acid, in plasma and in muscle, maintenance of iron balance.[143] Several studies
is also one of the more important antioxidants with support a protective role of ferritin against FR-
direct effects on singlet oxygen, HOCL, peroxyl mediated damage because ferritin minimises FR
radical, peroxynitrite or ozone.[36,126,130-134] Some formation by sequestering iron in blood or in
studies demonstrated that uric acid represents a great cells.[142,144,145] In addition, an increase of ferritin
part (>50%) of the plasmatic antioxidant capaci- synthesis is observed in response to physical exer-
ty.[131] Thus, uric acid helps to protect erythrocytes, cise, cellular damage and inflammation, which pro-
cell membranes, hyaluronic acid and DNA from FR mote oxidative stress.[144-148] Indirect and direct
oxidation. Another important antioxidant property links between FR and genetic expression of ferritin
of uric acid is the ability to form stable complexes were shown in some studies.[142-145]
with iron ions. This process inhibits Fe3+, catalysed
2.2.10 Albumin, Caeruloplasmin and Bilirubin
vitamin C oxidation and lipid peroxidation.[135,136]
Albumin, caeruloplasmin and bilirubin act as
Therefore, uric acid is a vitamin C protector but is
nonspecific chain-breaking antioxidants by giving
also a vitamin E protector.[56] In vivo, it is possible to
electrons to FR.[13] Albumin (a thiol protein) and
detect and measure its FR-induced oxidation prod-
caeruloplasmin are implicated in copper transport
uct (allantoin) in body fluids after episodes of oxida-
and so they reduce FR generation by Fenton’s reac-
tive stress, such as physical exercise.[113,127,137,138]
tion.[12,149] Bilirubin, a biliary protein coming from
2.2.8 Heat Shock Proteins haemoglobin, increases with oxidative stress and
Heat shock proteins (HSP) are a variety of pro- has antioxidant effects in body fluids.[147,150,151]
teins known to have protective effects against vari- However, these proteins have a limited antioxidant
ous stresses. HSP increase with exercise, particular- action because their action is indirect and is effec-
340 Finaud et al.
tive in body fluids such as blood, far from the major effects because long-term administration of querce-
FR production localisation, especially during physi- tin significantly decreases glutathione concentration
cal exercise. and glutathione reductase activity in rats.[159] More-
over, antioxidants present in food are in a balanced
2.3 Antioxidant Supplementation in Athletes biochemistry state compared with supplement anti-
oxidant compounds.[157]
2.3.1 Beneficial Effects of
Antioxidant Supplementation 2.4 Summary: Exercise and the
Antioxidant supplementation among athletes is Antioxidant System
well documented. The results of these studies are
often contradictory because of antioxidant com- Both enzymatic and non-enzymatic antioxidants
pounds and quantity. Indeed, some studies showed play a vital role in protecting tissues from excessive
that the association of several antioxidants has better oxidative damages.[44,84] The respective actions of
effects than single-compound supplementa- the antioxidants are summarised in table III and
tion.[152-154] Moreover, the subjects’ profiles (age, figure 2. This role is especially important during
nutritional status, training level and physical activity exercise, which is associated with FR production, in
category) can influence the results.[33,44] In a large relation to intensity, duration and training status.[87]
majority of studies, antioxidant supplementation Thus, because of low antioxidant dietary intakes and
does not enhance exercise performance or physical exercise and training modifications on the antioxi-
capacity in non-deficient athletes.[7,44,78,103] In return, dant system, some antioxidant supplementation in
antioxidant supplementation provides protection certain antioxidant nutrients seems to be justified.[22]
against the negative health consequences of FR However, the theoretical basis for which antioxi-
caused by exercise. Thus, antioxidant supplementa- dants should enhance performance is not clear.
tion helps athletes to maintain an optimal health, Studies have generally found that antioxidant sup-
which is a key condition to attaining the best per- plements do not improve performance but improve
formance. This is particularly important during peri- antioxidant status.[152,154] In return, large amounts of
ods of intensive training and/or competition, which antioxidant in nutrition could have negative ef-
cause greater needs of antioxidants.[152-155] In this fects.[44,79] Therefore, it seems that antioxidant sup-
case, a normal diet is not always sufficient.[6,33,156] plementation must be extremely controlled for com-
Some antioxidants (vitamins A, E and C) can protect position, duration and dose (depending on nutrition-
subjects from FR-induced muscle damage during al intakes) in order to be efficient for athletes’ health
exercise or can have anabolic effects.[76,102] Results and performance.
tend to show that antioxidant supplementation can
3. Methods to Assess Oxidative Stress in
have beneficial effects in athletes by preventing
Biological Systems
against antioxidant deficiencies and FR harmful ef-
fects on tissues, particularly muscular tissues.[152,154] Oxidative stress can be estimated according to
the measurement of: (i) FR; (ii) radical-mediated
2.3.2 Pro-Oxidant Effects of Overloaded
Antioxidant Supplementation damages on lipids, proteins or DNA molecules; and
Every antioxidant is a redox agent that can pro- (iii) antioxidant enzymatic activity or concentra-
tect against FR in some circumstances and promote tions. Results must be interpreted with caution be-
FR production in others.[157] Therefore, some pre- cause of possible contradictions.[44,160,161]
cautions must be taken because antioxidants can
3.1 Direct Detection of FR
have pro-oxidant effects, especially when mega-
doses are used.[44,79] Such findings were demonstrat- The production of ROS can be revealed accord-
ed for vitamin C,[79] β-carotene[6,7] and CoQ10.[158] It ing to direct methods. The electron spin resonance
was also shown that quercetin can have pro-oxidant technique is a direct spectroscopic method that al-
lows the direct measurement of ROS from their TBARS assay is not specific to MDA (this induces
paramagnetic properties.[12,97,162] Measurements can MDA overestimation), this method is accepted as a
be made in vitro, in vivo or ex vivo. However, the general marker of lipid peroxidation but results are
most precise measurements (in vivo) are not practi- subject to caution.[12,44,111,161] In addition, some stud-
cable in humans because of the toxicity of the prod- ies tend to show that MDA is not an adapted method
ucts used for such methods.[12,44] Blood samples can to assess oxidative stress after exercise.[111]
be collected in tubes containing a solution with spin A further technique for the measurement of lipid
trappers, which are ROS stabilisers. After centrifu- peroxidation is the analysis of volatile hydrocarbon
gation, the serum is analysed by a spectroscopic end products such as pentane, hexane and ethane in
method. However, the results are to be interpreted expired air. Such a method is non-invasive but is not
with caution because of the short half-life of the precise because these gases can be formed by other
ROS, their strong ability to react and their weak ways than FR oxidation.[12]
concentration.[1,97,161] This direct method allows a More recently, it was found that F2-isoprostanes
better understanding of the ROS reactions, and re- are produced by FR catalysed peroxidation of
agents used can also quantify ROS.[12] Realised ex arachidonic acid.[18] Numerous recent studies have
vivo, it raises the problem of the short ROS half-life, shown that quantification of F2-isoprostane com-
these being stabilised in the serum after blood sam- pounds could be a reliable method for endogenous
ples. lipid peroxidation and oxidant injury assessment as
well as some other recent markers such as blood
3.2 Measurement of Oxidative Damage to oxidised LDL or antibodies against oxidised
Lipids, Proteins and DNA Molecules LDL.[59,93,163]
3.2.1 Lipid Peroxidation 3.2.2 Protein Modification

A basic approach to study oxidative stress would FR-induced modification of proteins causes the
be to measure the rate of peroxidation of membrane formation of carbonyl groups into amino acid side
lipids or fatty acids. Lipid peroxidation leads to the chains. An increase of carbonyl is present in every
breakdown of lipids and to the formation of a wide phenomenon linked to oxidative stress.[66] Thus, the
array of primary oxidation products such as conju- measurement of carbonyl formation is the most usu-
gated dienes or lipid hydroperoxides, and secondary al method for determination of FR-damaged pro-
oxidation products including MDA, F2-isoprostane teins.[65,66] Total proteins are often measured in order
or expired pentane, ethane or hexane. to use the carbonyl/protein ratio, which is a more
Measurement of conjugated dienes is interesting precise index of protein oxidation.[164] This method
because it detects molecular reorganisation of poly- is particularly interesting because the half-life of
unsaturated fatty acids during the initial phase of carbonyl is long. Thus, a high amount of carbonyl
lipid peroxidation. Because of this specificity, this can show cumulative effects of oxidative stress,
method is often used to assess oxidative stress.[18,44] which is essential in some studies (e.g. longitudinal
Lipid hydroperoxide is another marker of the initial following of athletes).
reaction of FR and is a specific marker of cellular Oxidised amino-acid (e.g. o-o′-dityrosine) quan-
membrane damage.[12,97] tification is an alternative method for oxidised prote-
Other products are often used to measure oxida- in measurement.[16] This method can be non-inva-
tive stress but have the disadvantage of being secon- sive (with the possibility of using urine samples) and
dary oxidation products. One of them, MDA, is presents a methodological interest (high concentra-
produced during fatty acid auto-oxidation. This sub- tions and stability of measured compounds). Never-
stance is most commonly measured by its reaction theless, there is a lack of knowledge in oxidised
with thiobarbituric acid, which generates thiobarbi- amino acid kinetics, which limits the interpretation
turic acid reactive substances (TBARS). Although of the results.[12,16]
342 Finaud et al.
3.2.3 DNA Modification at first (adaptation) or decrease if oxidative stress is

ROS induce several types of DNA damage in- important or long (utilisation).
cluding strand breaks, DNA-protein cross-links and
3.3.2 Antioxidant Vitamins
base modifications. Nowadays, numerous methods
are used for DNA modification quantification.[69] Plasmatic quantification of antioxidant vitamins
The most used marker is the nucleotide 8-hy- (vitamin A, C and E) is a common method to assess
droxy-2′-deoxyguanosine (8-OHdG), which is pro- antioxidant protection and to detect vitamin defi-
duced by FR-induced guanine oxidation. The ox- ciency.[12,13] As well as antioxidant enzymes, antiox-
idised DNA is continually repaired, and oxidised idant vitamin concentrations are modified in the
nucleotides such as 8-OHdG are excreted via blood presence of oxidative stress and can be indirect
and urine. Thus, invasive or non-invasive methods markers of oxidative stress.[12] However, some pre-
are possible.[12] However, there have been doubts cautions must be taken, especially for vitamin C. A
about the precision of this method because of the stabiliser must be added in samples in order to
possible artefactural production of 8-OHdG by auto- stabilise this vitamin.[98] Vitamin E, in blood, is
oxidation during and after sample extraction.[69,165] transported linked to blood lipids. Therefore, cho-
lesterol is often measured in order to obtain the
3.2.4 Other Indirect Oxidative Stress Markers vitamin E/cholesterol ratio, which is a good marker
Creatine kinase (CK) and myoglobin are markers of vitamin E status.[59] Caution is recommended
of muscular cellular damage.[9,166] These parameters when interpreting plasma antioxidant concentrations
can also be considered indirect markers of oxidative because variations, during exercise or training, may
stress because lipid peroxidation induces damage of represent a redistribution between tissue and plas-
cellular membranes.[9,12] Thus, they are more perme- ma.[87]
able and allow the release of these intracellular 3.3.3 Other Antioxidants
substances.[76] However, CK and myoglobin are not A further technique for the measurement of anti-
specific markers of oxidative stress, especially in oxidant capacity of the body and oxidative stress is
athletes who can have high plasmatic CK and my- the measurement of thiol proteins. Like other anti-
oglobin values because of sports characteristics oxidants, a loss of thiol proteins can appear during a
(shocks, contacts), which induce cellular damage.[9] long period of oxidative stress. However, the quanti-
Moreover, trained athletes have higher basal values fication of GSH, the most important thiol in the
of CK and myoglobin.[76] Another effect on the human body, and GSSG (the oxidised form of GSH)
cellular membrane is an alteration of its pliability, is a popular technique to assess oxidative stress. The
inducing a modification of blood rheology, which GSH/GSSG ratio is an interesting marker of oxida-
has been used to evaluate states of fitness in ath- tive stress because FR oxidise GSH into
letes.[167] GSSG.[112,113]
Uric acid is an important plasmatic and muscular
3.3 Antioxidant Measures antioxidant.[131,137] However, uric acid concentration
can vary because of oxidative stress, purins cycle
3.3.1 Enzymatic Antioxidant Activity and renal excretions. Uric acid alone, therefore, can
Enzymatic antioxidant activity (SOD, CAT and not represent a reliable marker of antioxidant capac-
GPX) is quantified in a large majority of studies. ity and oxidative stress; however, allantoin, a uric
This method can evaluate the quality of antioxidant acid oxidation product, may be a valuable endoge-
protection at rest but can also show the importance nous marker of oxidative stress. Thus, it could be
of oxidative stress, especially after physical activity. considered as a good parameter to quantify oxida-
After exercise, their evolution represents an adaptative stress because allantoin is theoretically absent
tion upon FR production.[168,169] Antioxidant en- from human body fluids under normal circum-
zyme activity can be modified differently: increase stances. Nevertheless, some results suggest that al-
lantoin alone may have limited value as a marker of out with methods including aerobic exercise (run-
oxidative stress because allantoin can be oxidised ning, cycling and swimming [see table
and degraded by FR in blood samples. Thus, al- IV]).[51,53,58,90,96,162,173-175] Aerobic exercise is accom-
lantoin quantity can underestimate oxidative panied by an increased V̇O2, which may increase FR
stress.[137] activity. Aerobic exercise increases V̇O2, which, in
turn, may increase FR production. Therefore, many
3.3.4 Total Antioxidant Capacity
studies suggested that such physical activity en-
The large number of antioxidants in human fluids
hanced FR production both in animals and in
or in tissue makes it difficult to measure each antiox-
humans.[51,53,58,90,96,173-176]
idant separately. Therefore, several methods have
However, this phenomenon cannot occur with
been developed to measure the total antioxidant
low exercise intensity (<50% maximum oxygen
capacity (TAC) of a biological sample.[162] The use
consumption [V̇O2max]). In such a case, antioxidant
of a pro-oxidant in order to quantify the oxygen
capacity is not overreached and FR-induced damage
radical absorbance capacity is one of the most used
does not appear.[174] Moreover, the more intense the
techniques.[13,170] The TAC gave an overall value
exercise intensity is, the more important the FR
corresponding to the sum of all antioxidants.[13,170]
production and the oxidative stress are.[96,174] This is
However, the interpretation of the changes in the
confirmed by some studies that show a correlation
antioxidant capacity is difficult because it can in-
between V̇O2 and oxidative stress.[162] However,
crease as a result of nutritional effects or because of
other studies show that oxidative stress does not
an adaptation of oxidative stress. Furthermore, some
increase after intense aerobic exercise.[53,76,179] Such
antioxidant concentrations can be modified without
contradictory results can be explained by antioxi-
any evolution of the TAC.[171]
dant nutritional status (which is not always con-
trolled in studies), exercise intensity or training lev-
3.4 Summary: is There an Ideal Method?
el. Effectively, these studies are done with trained
In general, every method has its interests and its endurance athletes who are adapted to exercise ef-
limits, and because of this complexity, no single fects such as FR production.[53,76,179] However,
measurement of oxidative stress or of antioxidant trained subjects can exhibit oxidative stress as well
status is going to be sufficient. Indeed, the interpre- as sedentary subjects.[59,153] Moreover, some differ-
tation of the values coming from a single marker ences can be explained by the methods used for the
could be a source of error. Therefore, a battery of measurement of oxidative stress as shown in the
measurements, including TAC, isolated antioxidant paragraph above.
and markers of FR-induced damage on lipids, pro-
teins and DNA seems to be a reliable method to Effects on Antioxidants
assess oxidative stress.[13] Endurance exercise also causes some modifica-
tions in the non-enzymatic antioxidant concentra-
4. Oxidative Stress and Physical Activity tions or enzymatic antioxidant activity. Numerous
studies, both in animals and in humans, have shown
that antioxidant enzyme activity increases (SOD,
4.1 Oxidative Stress and Exercise
GPX, CAT) in blood or in tissues after aerobic
exercise.[16,22,178,180] This adaptation may occur very
4.1.1 Aerobic Exercise
quickly (about 5 minutes) after FR production and
Effects on FR Production seems to be specific to oxidative muscular fibres,
In 1982, Davies et al.[172] were the first to show which is the main FR production location during
that exercise increases FR production. Since then, a exercise.[74,87,180] However, the increase of antioxi-
lot of studies have investigated the effects of exer- dant enzyme activity is not proportional to exercise
cise on oxidative stress. Most of them were carried intensity.[181]
344 Finaud et al.
Table IV. Human studies on the effects of aerobic exercise on markers of oxidative stress
Study (year) Activity Subjects Markers Effect
Lovlin et al.[174] (1987) Cycling at 40%, 70% and 100% V̇O2max 6 UT MDA (at 40% V̇O2max) ↓
MDA (at 70% V̇O2max) ↔
MDA (at 100% V̇O2max) ↑
Margaritis et al.[177] (1997) Triathlon (long distance) 18 VT TBARS – GSSG ↔
Marzatico et al.[168] (1997) Running (half-marathon) 6T MDA ↑
CD ↔
SOD – GPX ↑
CAT ↔
Vasankari et al.[53] (1997) Running (marathon) 22 VT Tocopherol – TRAP ↑
CD ↑
Retinol – CoQ10 ↔
Ashton et al.[162] (1998) V̇O2max test (ergocycle) 12 T TAC ↑
FR (ESR) – MDA – LH ↑
Child et al.[173] (1998) Running (half-marathon) 17 T MDA ↑
CK ↑
TEAC – UA ↑
Liu et al.[58] (1999) Running (marathon) 11 VT Oxidised LDL ↑
10 UT TRAP – UA ↑
Thiols ↓
Tocopherol – vit C – vit A ↔
Hellsten et al.[138] (2001) Two exercises to exhaustion at 90% 8T Allantoin ↑
V̇O2max (cycling) UA (muscle) ↑
GSH – cysteine – UA (plasma) ↔
Inal et al.[178] (2001) Swimming (800m) 10 T CAT – GPX ↑
GSH ↓
Mastaloudis et al.[90] (2001) Running (50km) 11 T Isoprostane ↑
UA – tocopherol – vit C ↑
Miyazaki et al.[169] (2001) V̇O2max test (ergocycle) 9 UT TBARS – neutrophil FR ↑
production ↔
Protein carbonyls ↔
SOD – GPX – CAT
Vider et al.[176] (2001) V̇O2max test (treadmill) 19 T TBARS – CD ↑
TAC – GSH – CAT ↑
GPX – SOD ↔
Dawson et al.[76] (2002) Running (21km) 15 T MDA ↑
CK – myoglobin ↑
Chevion et al.[179] (2003) Walking (50km) 29 T CK ↑
Walking (80km) 16 T Protein carbonyls ↓
UA ↑
Palmer et al.[96] (2003) Ultra-marathon (80km) 28 T LH – F2-isoprostane ↑
Vit C ↑
Aguilo et al.[175] (2005) Cycling (171km) 8T GSSG ↑
UA – tocopherol ↑
GPX ↓
CAT = catalase; CD = conjugated dienes; CK = creatine kinase; CoQ10 = coenzyme Q10; ESR = electron spin resonance; FR = free radical;
GPX = glutathione peroxidase; GSH = glutathione; GSSG = oxidised glutathione; LDL = low-density lipoprotein; LH = lipid hydroperoxide;
MDA = malondialdehyde; SOD = superoxide dismutase; T = trained; TAC = total antioxidant capacity; TBARS = thiobarbituric reactive
substances; TEAC = trolox equivalent antioxidant capacity; TRAP = total radical antioxidant potential; UA = uric acid; UT = untrained; vit =
vitamin; VT = very trained; V̇O2max = maximum oxygen consumption; ↓ indicates decrease; ↑ indicates increase; ↔ indicates no change
(stable).
Aerobic exercise effects are not limited to antiox- trations (in plasma, urine or in tissues) are modified,
idant enzymes. Non-enzymatic antioxidant concen- but results are often contradictory. For example,
some studies suggest that GSH or GSH/GSSG de- production.[33,34] Xanthine oxidase has been demon-
creases during exercise because of its utilisation strated to generate FR during ischaemia reperfusion,
against FR.[58,74,112,178] In turn, vitamins E and C and but direct evidence for xanthine oxidase as a radical
uric acid tend to increase after endurance generator in muscle during exercise is lacking. In
strain.[58,90,96] Vitamins E and C seem to be mo- ischaemic tissues, it has been proposed that the
bilised from their respective reserve in order to xanthine dehydrogenase undergoes proteolytic con-
preserve the body against FR harmful effects. Uric version to the oxidase form, which uses O2 as its
acid increases can not be considered as a specific electron acceptor.[33,34] It is known that xanthine
adaptation against oxidative stress because it is an oxidase in the presence of the substrates hypoxan-
end product of the purins cycle.[90,95] Together, all thine or xanthine reduces molecular oxygen to O2•–
these modifications provoke an increase in the total and H2O2. Recently, it has been demonstrated that
antioxidant capacity as can be observed in several the enzyme can further reduce H2O2 to OH•.[34]
studies.[58,172] Thus, it has been hypothesised that xanthine oxidase
4.1.2 Anaerobic Exercise and its requisite substrates would be present in high
concentrations in reperfused tissue and consequent-
Effects on FR Production ly would result in oxygen FR generation upon
Anaerobic exercise is a type of exercise that reperfusion. The OH• and O2•– radicals generated
includes a large variety of sport activities (e.g. by the enzyme could in turn react with cellular
sprints, jumps or resistance exercise). Information proteins and membranes causing cellular injury.[34]
on the production of FR as a result of acute anaerob-
Another source of FR production during anaerob-
ic exercise is lacking compared with aerobic exer-
ic exercise arises from inflammation and cellular
cise.[111] However, these studies generally show an
damage, which often happen after traumatising ex-
increase of the oxidative stress after supramaximal
ercise such as impact sports and clinometric or ec-
exercise such as intermittent running, sprints, jumps
centric exercises.[79,94,166,186,187] An iron liberation,
or sets of jumps, resistance exercise (eccentric or
concentric) or Wingate tests on an ergocycle (table from haemoglobin or ferritin, may amplify the in-
V).[94,111,163,164,182-185] flammatory answer and the oxidative stress.[79] Fur-
thermore, a positive link between the increase of
The increase of FR production, specific to anaer-
lactic acid and the rise of oxidative stress markers
obic exercise, may be mediated through various
has been evidenced.[22,183] This would lead to a de-
pathways in addition to electron leakage, such as
during aerobic exercise.[94,111,186] Xanthine oxidase cline in the concentration of NADH and NADPH
production, ischaemia reperfusion and phagocytic and then to the reduction of the antioxidant action
respiratory burst activity seem to be implicated in and the increase of the FR production.[22]
FR production during anaerobic exercise.[186] More-
Effects on Antioxidants
over, the important increases of lactic acid, acidosis,
catecholamine and post-exercise inflammation, Studies about the effects of anaerobic exercise on
characteristic in supramaximal exercises, are other antioxidants are scarce compared with those con-
factors that can increase the production of FR.[183,186] cerning submaximal exercise. Some studies show an
It seems possible that ischaemic reperfusion of increase of the enzymatic antioxidant activity in
the active muscle is greatly involved in oxidative plasma or in muscle after anaerobic exer-
stress during and after anaerobic exercise.[186] Pre- cise.[79,168,178] In turn, a Wingate test provokes a
cisely, this type of exercise significantly enhances decline of SOD activity without any GPX activity
the catabolism of purins and provokes a fast deox- change.[111] According to the authors, the decline of
ygenation (phenomenon of ischaemia reperfusion). the SOD activity would result from an increase of
These two phenomena are known to increase the FR production. Those differences could be ex-
activity of xanthine oxidase, which accelerates FR plained by the differences in exercise intensity.
346
Table V. Human studies on the effects of anaerobic exercise on markers of oxidative stress

Sahlin et al.[186] (1992) Isometric knee extension at 60% 1RM 7 UT MDA ↔
intermittent – 80 min GSH (blood) ↑
GSH (muscle) ↔
GSSG (blood and muscle) ↔
Saxton et al.[187] (1994) Elbow flexion – 70 max eccentric or concentric 14 NRT TBARS – CD – MDA ↔
actions Protein carbonyls ↑
Marzatico et al.[168] (1997) 6 × 150m sprints 6T MDA – CD ↑

SOD – GPX ↑
CAT ↔
Ortenblad et al.[166] (1997) 6 bouts of jumping – 30 sec each bout 8 JT MDA ↔

8 UT
McBride et al.[94] (1998) Resistance training programme (8 exercises, 3 12 T MDA ↑

sets of each failure)
Childs et al.[79] (2001) Eccentric arm flexion (cybex) 14 UT LH – isoprostane ↑

3 × 10 reps at 80% RM CK – LDH – myoglobin ↑
SOD ↑
GPX ↔
Inal et al.[178] (2001) 100m swim 9T CAT – GPX ↑

GSH ↓
Groussard et al.[188] (2003) Cycling – Wingate tests (30 sec) 7T UA – vit C ↑

Tocopherol – vit A ↓
Groussard et al.[111] (2003) Cycling – Wingate tests (30 sec) 8T ESR signals ↑
TBARS ↓
SOD – GSH ↓
GPX ↔
Ramel et al.[185] (2004) Resistance programme (10 exercises – max of 7T MDA ↔

reps at 75% 1RM) 10 UT CD (trained group) ↔
CD (untrained group) ↑
Vit A – tocopherol ↑
Goldfarb et al.[184] (2005) Eccentric resistance exercise 18 UT Protein carbonyls – MDA ↑

GSSG ↑
Sports Med 2006; 36 (4)
GSH ↓
Finaud et al.
CAT = catalase; CD = conjugated dienes; CK = creatine kinase; ESR = electron spin resonance; GPX = glutathione peroxidase; GSH = glutathione; GSSG = oxidised glutathione;
JT = jump trained; LDH = lactate dehydrogenase; LH = lipid hydroperoxide; max = maximum; MDA = malondialdehyde; NRT = non-resistance trained; reps = repetitions; RM =
repetition maximum; SOD = superoxide dismutase; T = trained; TBARS = thiobarbituric reactive substances; UA = uric acid; UT = untrained; vit = vitamin; ↓ indicates decrease; ↑
indicates increase; ↔ indicates no change (stable).
Table VI. Human studies on the effects of mixed exercise on markers of oxidative stress
Hellsten et al.[129] (1998) 100 min of intermittent exercise 7T UA (blood) ↑
on legs and arms UA (muscle) ↓
Chang et al.[189] (2002) Rugby match (2 × 40 min) 15 VT vs 6 T and 10 UT TBARS ↑
CD ↔
GPX – SOD ↔
Svensson et al.[113] (2002) 50 min of aerobic exercise and 15 T GSH ↓
intermittent 10–20 sec anaerobic UA ↑
exercise (ergocycle)
Thompson et al.[99] (2003) Running shuttle (20m) during 90 16 T MDA ↑
min (intermittent) UA ↑
CD = conjugated dienes; GPX = glutathione peroxidase; GSH = glutathione; MDA = malondialdehyde; SOD = superoxide dismutase; T =
trained; TBARS = thiobarbituric reactive substances; UA = uric acid; UT = untrained; VT = very trained; ↓ indicates decrease; ↑ indicates
increase; ↔ indicates no change (stable).
There are few data on the effects of anaerobic reported after an intermittent running session and
exercise on non-enzymatic antioxidants. Neverthe- after a rugby match (table VI).[99,189]
less, it was shown that a Wingate test induced an In turn, the effects on antioxidants are more con-
increase in plasmatic uric acid and vitamin C contradictory. Indeed, a rugby match does not modify
centrations and a drop of the plasmatic vitamin A enzymatic antioxidant activity.[189] This result is sur-
and E concentrations.[188] In this study, a decline of prising in regard to aerobic and anaerobic exercise
GSH was also observed, which could be explained effects on SOD, GPX and CAT, and must be con-
by its use in the regeneration of vitamins C and firmed by further study. In contrast, some studies
E.[188] In turn, a recent study shows that fat-soluble suggest that non-enzymatic antioxidants may have
plasma antioxidants (vitamins A and E) increase the same evolution after mixed exercise compared
after acute resistance exercise.[185] Therefore, further with aerobic and anaerobic exercise: an increase of
studies are needed for a better understanding of non- uric acid and a decrease of GSH.[99,113,129,138] How-
enzymatic antioxidant response to anaerobic exer- ever, there is an important lack of knowledge about
cise. other non-enzymatic antioxidant responses (vita-
4.1.3 Mixed Exercises mins A, E and C).
General Findings about Mixed Exercise Summary: Oxidative Stress and Exercise
A mixed activity can be defined as an activity In summary, aerobic, anaerobic or mixed exer-
that involves both aerobic and anaerobic metabo- cise causes an enhanced FR production. In the same
lism in a balanced ratio. Team sports such as foot- way, humans have an adaptive reaction with an
ball, rugby and basketball are some examples of this increased mobilisation of a variety of enzymatic and
type of exercise, which include aerobic phases (in- non-enzymatic antioxidants in cells or in plasma.
termittent running at different intensity) and anaer- However, in a large majority of cases, antioxidant
obic phases (jumps, sprints). Therefore, the effects capacities are overreached, which lead to an oxida-
of this type of exercise on oxidative stress have been tive stress situation, all the more important because
the source of few investigations and are more cen- exercise intensity and duration are high and because
tred on training effects.[156,188] subjects have low training levels and inadequate
Mixed Exercise Effects on FR Production nutritional status. Some differences can be noted
and Antioxidants between aerobic exercise and mixed or anaerobic
The literature tends to show that mixed exercise exercise. Indeed, contrary to endurance exercise, the
has logically the same effects as aerobic and anaer- mitochondrial respiratory chain is not the main FR
obic exercise on FR production. Such results were production location in anaerobic and in mixed exer-
348
Table VII. Human studies on effects of aerobic training on markers of oxidative stress

Ohno et al.[191] (1988) Running >5km – 6 × wk – 10wk 7 UT GSH – GPX – SOD ↔
GR – CAT ↑
Accominotti et al.[192] (1991) Cycling (follow up) 12 T GSH (after intensive training) ↑
GSH (after long-term intensive training) ↓
Tessier et al.[112] (1995) Running <80% V̇O2max – 3 × wk – 10wk 24 T GSH – GSSG ↓

GPX ↑
Marzatico et al.[168] (1997) Running (half-marathon) 6 T vs 6 UT MDA – CD ↑

Blood samples at rest SOD – GPX – CAT ↑
Bergholm et al.[193] (1999) Running 60 min at 70–80% V̇O2max 4 × week – 9T TRAP – vit C ↑
3mo UA – thiols – tocopherol – vit A ↓
Liu et al.[58] (1999) Running (marathon) 11 VT vs 10 UT LDL oxidation ↓

Post-exercise blood samples TRAP ↑
UA – vit E – vit C – vit A ↔
Miyazaki et al.[169] (2001) Running 9 UT TBARS ↓

60 min at 80% V̇O2max Protein carbonyls ↔
5 × wk – 12wk SOD – GPX ↑
CAT ↔
Elosua et al.[190] (2003) Running 17 UT LDL oxidation ↓

50 min – 5 × wk – 16wk LP ↑
Blood samples after 30 min aerobic exercise SOD – GSH ↑
Palazzetti et al.[153] (2003) Triathlon – overload training (4wk) 9 VT

Blood samples at rest or after a duathlon)
At rest
GSH – SOD ↔
CK – myoglobin – TBARS ↔
GPX ↑
TAC ↓
Post-exercise
CK – myoglobin – TBARS ↑
Sports Med 2006; 36 (4)
TAC ↓
Finaud et al.
CAT = catalase; CD = conjugated dienes; CK = creatine kinase; GPX = glutathione peroxidase; GR = glutathione reductase; GSH = glutathione; GSSG = oxidised glutathione; LDL
= low-density lipoprotein; LP = lag phase; MDA = malondialdehyde; SOD = superoxide dismutase; T = trained; TAC = total antioxidant capacity; TBARS = thiobarbituric reactive
substances; TRAP = total radical antioxidant potential; UA = uric acid; UT = untrained; vit = vitamin; VT = very trained; V̇O2max = maximum oxygen consumption; ↓ indicates
decrease; ↑ indicates increase; ↔ indicates no change (stable).
cise. Ischaemia reperfusion, acidosis and catecho- Effects on Antioxidants

lamine oxidation are other phenomenon that are The effects of aerobic training on antioxidant
implicated in oxidative stress during supramaximal enzymes are situated at the muscular, plasmatic,
exercise. However, there is a lack of knowledge and hepatic and cardiac levels.[179,194] In muscle, some
further studies are needed to understand oxidative studies suggest that a specific antioxidant enzyme
stress during this kind of exercise, which is probably adaptation exists in muscle having a strong oxida-
more difficult to investigate. tive power, thus a strong percentage of type 1 fib-
res.[16,178,195] In plasma and other tissues, an increase
in antioxidant enzyme activity was observed follow-
4.2 Training Effects on Oxidative Stress ing a controlled protocol of endurance train-
ing.[110,168,169,190,196] However, it seems that this ad-
4.2.1 Aerobic Training aptation is not correlated with the increase of
V̇O2max observed during these studies and that SOD
Effects on Oxidative Stress and FR Production and GPX increase more than CAT.[16,169,191,195,197]
The results concerning the effects of endurance
The majority of studies show that endurance
training on the non-enzymatic antioxidants are more
training reduces post-exercise oxidative stress and
controversial with studies showing an improvement
muscular damage (table VII).[16,22,53,60,112,169,190]
or a reduction of the total antioxidant capacity or of
These findings agree with the general thinking that
an isolated antioxidant in trained subjects compared
regular aerobic exercise permits fighting against cell with sedentary subjects.[22,58,112,197] Some studies
aging and the apparition of some cancers. This re- have also shown that the antioxidant adaptation can
duction can be so important that oxidative stress did be correlated with the training volume or with
not increase in highly trained triathletes despite an V̇O2max.[177,198] However, it seems that the training
important triathlon-induced inflammation.[177] How- protocol must be sufficiently long and intense in
ever, from these results, it has not been determined order to create an adaptive answer.[169] For example,
yet whether this decrease of oxidative stress comes an 8-week protocol increases V̇O2max without in-
from a decrease of FR production during exercise or creasing the antioxidant potential, whereas a
from an increase of the antioxidant system efficien- 10-week protocol (longer and more intensive) in-
cy. creases V̇O2max and the activity of some antioxi-
Table VIII. Human studies on effects of anaerobic training on markers of oxidative stress
Hellsten et al.[201] (1996) 15 × 10 sec of anaerobic exercise 11 UT GPX – CAT ↑
(50 sec rest) 3 × wk – 7wk SOD ↔
Ortenblad et al.[166] (1997) Jump training: blood samples at 8 T vs 8 UT CK (after exercise) ↓
rest and after 6 × 30 sec jumping MDA (after exercise) ↔
SOD – GPX (at rest) ↑
CAT (at rest) ↔
Marzatico et al.[168] (1997) Running (sprint): blood samples 6 T vs 6 UT MDA ↑
at rest CD ↔
SOD – GPX ↑
CAT ↓
Rall et al.[199] (2000) Progressive resistance strength 8 UT elderly, 8 T and 8 UT 8-OHdG (in both groups) ↔
training 12wk with rheumatoid arthritis
Vincent et al.[200] (2002) Muscular exercise (50–80% 1RM) 84 UT elderly TBARS – LH ↓
3 × wk – 6mo Thiols ↑
8-OHdG = 8-hydroxy-2′-deoxyguanosine; CAT = catalase; CK = creatine kinase; GPX = glutathione peroxidase; LH = lipid hydroperoxide;
MDA = malondialdehyde; RM = repetition maximum; SOD = superoxide dismutase; T = trained; TBARS = thiobarbituric reactive
substances; UT = untrained; ↓ indicates decrease; ↑ indicates increase; ↔ indicates no change (stable).
350 Finaud et al.
dants.[73,112] During such studies, the measure of the football or rugby players have a lower oxidative
nutritional antioxidant contribution is essential be- stress at rest than sedentary subjects (table
cause the efficiency of the antioxidant system large- IX).[189,202,203] Moreover, after a rugby match, play-
ly depends on it. ers with a high fitness level have a lower oxidative
stress elevation when compared with players with a
4.2.2 Anaerobic Training
lower fitness level.[189] Thus, the training level
Effects on Oxidative Stress and FR Production seems to have an important influence on oxidative
Few data about the effect of anaerobic training on stress in this type of activity.
oxidative stress are available. However, it has been Effects on Antioxidants
shown that anaerobic-trained subjects have a lower Studies showed that football or rugby players
oxidative stress and lower muscular damage at rest have an increased enzymatic antioxidant sys-
or after exercise when compared with non-trained tem.[189,202,203,205,207] These results are verified in top
subjects.[166,196] Moreover, these improvements are athletes as well as in subjects with a lower lev-
comparable with those observed in endurance- el.[202,205] Mixed training also increases the total
trained sportsmen.[196] These results are controver- antioxidant capacity and some non-enzymatic anti-
sial because other studies did not show a diminished oxidants such as vitamin C, vitamin E or uric ac-
oxidative stress following an anaerobic training pro- id.[202,205,207] Thus, the improvement of the antioxi-
tocol.[199,200] The methodological differences (popu- dant system protects players from the deleterious
lations’ characteristics, training protocols, biologi- effects of oxidative stress. However, the increase of
cal measurements) can explain some of these dis- the training and competitive load can induce the
crepancies (table VIII). opposite effect as shown with basketball players.[156]
Effects on Antioxidants Contrary results have been obtained with high-level
According to some studies, the anaerobic-trained football players.[202] Differences could be explained
subjects have a better antioxidant enzyme activity in by nutritional status. The football players had suffi-
blood, in tissues and especially in working muscle cient nutritional antioxidant contributions, whereas
(table VIII);[166,168,200,201] however, this improvement the basketball players’ diet was not controlled.
was not found in every study.[196] The differences 4.2.4 Relationship Between Training Load and
between the results can be explained by the location Oxidative Stress
of dosages and by the training protocol. Indeed, as The markers of the oxidative stress and of the
for aerobic training, it seems that the length of the antioxidant status might be important parameters in
protocol is important because the adaptation phe- the biological follow-up. However, although numer-
nomenon only appears after several weeks of intense ous data concerning a classical biological check-up
practice.[201] of sportsmen are available, few studies have been
For non-enzymatic antioxidants, it seems that the done concerning the longitudinal follow-up of oxi-
anaerobic practice increases their concentra- dative stress markers and antioxidant status.
tions.[202] According to Cazzola et al.,[202] this adap- A longitudinal follow-up of high-level cyclists
tation would be a result of the repeated FR produc- shows a significant increase of the GPX activity
tion during ischaemia reperfusion and inflammation during the training periods and a reduction during
provoked by this type of exercise at muscular level. the recovery periods.[192] Besides, it is important to
4.2.3 Mixed Training
note that the authors noticed a decrease in the GPX
activity and in selenium plasmatic concentrations
Effects on Oxidative Stress and FR Production during the periods of intensive training. In the same
Little research has been carried out on the influ- way, a recent study with professional American
ence of mixed training effects on oxidative stress. footballers suggests that antioxidant status and oxi-
Nevertheless, recent studies suggest that trained dative stress evolve during a sport season according
Oxidative Stress and Physical Activity

Table IX. Human studies on effects of mixed training on markers of oxidative stress

Balakrishnan and Anuradha[204] Football (6 × wk), hockey 26 T vs 27 UT TBARS – CD ↑
(1998) (20 h/wk), running (2–3y) Tocopherol – CAT ↔
Blood samples at rest Vit C – GSH – GPX ↓
SOD ↑
Brites et al.[205] (1999) Football – regular training 30 T vs 12 UT TEAC – vit C – UA – vit E ↑

Blood samples at rest SOD ↑
Pincemail et al.[59] (2000) Football – regular training 21 T (top soccer players) Autoantibodies against oxidised ↑
Basketball – regular training 9 T (basketball players) LDL ↓
Blood samples at rest Vit C (results in half the players)
Subudhi et al.[206] (2001) Alpine ski 12 VT TEAC ↓

Blood samples before and after a MDA – LH – protein carbonyls ↔
10d training camp
Svensson et al.[113] (2002) 3d of aerobic and anaerobic 15 T GSH ↑

training on ergocycle UA ↓
Chang et al.[189] (2002) Rugby – regular training 15 VT vs 6 T and 10 S TBARS – CD ↓

Blood samples after a rugby match SOD – GPX ↑
(2 × 40 min)
Evelson et al.[207] (2002) Rugby – regular training 15 T vs 15 UT TRAP – SOD – vit C – tocopherol ↑
Blood samples at rest
Schippinger et al.[208] (2002) American football – regular training 8 VT LH ↑

Blood samples at rest (follow-up – LP ↓
before and during competitive Tocopherol – vit A ↓
season) Vit C ↑
Cazzola et al.[202] (2003) Football – regular training 20 VT vs 20 UT Tocopherol – vit C – UA – SOD ↑

Blood samples at rest LP ↑
LH ↓
Metin et al.[203] (2003) Football – regular training 25 VT vs 25 UT Zinc ↔

Blood samples at rest Copper ↓
↑
Sports Med 2006; 36 (4)
SOD
MDA ↓
CAT = catalase; CD = conjugated dienes; GPX = glutathione peroxidase; GSH = glutathione; LDL = low-density lipoprotein; LH = lipid hydroperoxide; LP = lag phase; MDA =
malondialdehyde; S = sedentary; SOD = superoxide dismutase; T = trained; TBARS = thiobarbituric reactive substances; TEAC = trolox equivalent antioxidant capacity; TRAP =
total radical antioxidant potential; UA = uric acid; UT = untrained; vit = vitamin; VT = very trained; ↓ indicates decrease; ↑ indicates increase; ↔ indicates no change (stable).
351
352 Finaud et al.
to the training load and competition.[208] Thus, biological variables in athletes in order to detect and
through a sport season, a decrease of the efficiency prevent overtraining.[209] Oxidative stress markers
of the antioxidant system and an increase of oxida- could be interesting, complementary with biological
tive stress can be observed. However, these two variables, because of the possible links between
studies should be completed by other investigations oxidative stress and overtraining.[9,82]
in order to provide a better understanding of the The causes of the overtraining syndrome are
relationship between training load and oxidative complex and there are divergent hypotheses based
stress. Although they are not based on longitudinal on structural, metabolic, immunological or inflam-
follow-up, other studies tend to prove that oxidative matory phenomenon.[9,82] A period of intense train-
stress can increase during an intense period of training, as described in the previous paragraphs, is asso-
ing. Numerous studies have shown that training ciated with a decrease of the antioxidant status, an
improves antioxidant status (see sections increase of the ROS production and a proportional
4.2.1–4.2.3); however, in the study by Pincemail et increase of oxidative stress.[204] Although there is no
al.,[59] half of the subjects (high-level football and direct evidence, the increase of oxidative stress can
basketball players) presented with a low antioxidant be implied in the appearance of the overtraining
status and an important oxidative stress. These re- syndrome.[8,9] Cell damage, in particular at the mus-
sults can be explained by individual low antioxidant cular level, could be an important explanatory ele-
intakes and by the frequency of training and compe- ment of overtraining by reducing the muscular cells
tition that lead to an important mobilisation and metabolic capacities.[8,73,82] Besides, the accumula-
utilisation of antioxidant compounds. These results tion of muscular lesions is associated with inflam-
are confirmed by other studies in various sports and mation (increase of cytokines and neutrophils) in
populations.[156,193,204,206] Recently, it was also order to repair damaged tissues. Inflammation can
demonstrated that overloaded training compromises induce an enhanced oxidative stress caused by the
the antioxidant defences, leading to an increase of increase of the FR production by neutrophils and
the exercise-induced oxidative stress.[153,155] macrophages.[73,82]
4.2.5 Oxidative Stress and Overtraining 4.3 Summary: Oxidative Stress, Training
The training programme aims to optimise indi- and Overtraining
vidual and collective performance. However, it is
difficult to know whether the programme applied to Aerobic, anaerobic or mixed training provokes a
the athletes is well adapted or leads to persistent decrease of oxidative stress, which is caused by an
fatigue known as overtraining.[209] This overtraining increase if the efficiency of the antioxidant system
syndrome is characterised by excessive fatigue, in response to the supplementary production of FR
drops in performance, physical changes, moodiness during exercise. Nevertheless, the training pro-
and biological modifications that can be detected by gramme must be sufficiently long and intense to
a biological check-ups.[209,210] Prolonged periods of trigger a consequent adaptive response of the antiox-
intense exercise training and/or intense competition idant system and a decrease of oxidative stress.
are associated with a large variety of hormonal, Moreover, this adaptation is more important when
immunological, haematological and biochemical the training level of the subjects is low at the begin-
changes.[210,211] However, the different studies on ning of the protocol.
this subject are often contradictory.[210] Therefore, This training-induced improvement of the anti-
no single reliable diagnostic element of the over- oxidant status and decrease of oxidative stress are
training syndrome is currently available except the extensively documented in the literature. However,
decrease of the performance with the same load of some studies report a decrease of the antioxidant
training.[9,83,209,210] It is therefore necessary to imple- system efficiency, particularly in high-level athletes
ment a longitudinal follow-up that includes selected subjected to an important training and competitive
load with an inappropriate diet. These studies sug- work is dedicated to the late Prof. Robert (2004) and the late
gest a limit beyond which oxidative stress can in- Prof. Bedo (2006).
crease in excess and cause overtraining. Indeed, the
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Oxidative stress: Relationship with exercise and training

Article in Sports Medicine · February 2006

Julien Finaud Gérard Lac

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3.2.1 Lipid Peroxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

Table I. Classification and main effects of free radicals

Electron chain transport

NADH NAD+ Succinate Fumarate Antimycin A

Complex I Complex II Complex III

Retonone O2 ® O2·- Myxothiazol

Alteration of Increased Alteration Alteration

Decreased Increased Pi Increased Pi

Table II. Localisation and actions of antioxidant enzymes

Table III. Localisation and actions of the main non-enzymatic antioxidants

2.2.6 Coenzyme Q10 ly with body temperature variations, inflammation

3.2.1 Lipid Peroxidation 3.2.2 Protein Modification

3.2.3 DNA Modification at first (adaptation) or decrease if oxidative stress is

Study (year) Activity Subjects Markers Effect

Marzatico et al.[168] (1997) 6 × 150m sprints 6T MDA – CD ↑

Ortenblad et al.[166] (1997) 6 bouts of jumping – 30 sec each bout 8 JT MDA ↔

McBride et al.[94] (1998) Resistance training programme (8 exercises, 3 12 T MDA ↑

Childs et al.[79] (2001) Eccentric arm flexion (cybex) 14 UT LH – isoprostane ↑

Inal et al.[178] (2001) 100m swim 9T CAT – GPX ↑

Groussard et al.[188] (2003) Cycling – Wingate tests (30 sec) 7T UA – vit C ↑

Ramel et al.[185] (2004) Resistance programme (10 exercises – max of 7T MDA ↔

Goldfarb et al.[184] (2005) Eccentric resistance exercise 18 UT Protein carbonyls – MDA ↑

Study (year) Activity Subjects Markers Effect

Tessier et al.[112] (1995) Running <80% V̇O2max – 3 × wk – 10wk 24 T GSH – GSSG ↓

Marzatico et al.[168] (1997) Running (half-marathon) 6 T vs 6 UT MDA – CD ↑

Liu et al.[58] (1999) Running (marathon) 11 VT vs 10 UT LDL oxidation ↓

Miyazaki et al.[169] (2001) Running 9 UT TBARS ↓

Elosua et al.[190] (2003) Running 17 UT LDL oxidation ↓

Palazzetti et al.[153] (2003) Triathlon – overload training (4wk) 9 VT

cise. Ischaemia reperfusion, acidosis and catecho- Effects on Antioxidants

Oxidative Stress and Physical Activity

Study (year) Activity Subjects Markers Effect

Brites et al.[205] (1999) Football – regular training 30 T vs 12 UT TEAC – vit C – UA – vit E ↑

Subudhi et al.[206] (2001) Alpine ski 12 VT TEAC ↓

Svensson et al.[113] (2002) 3d of aerobic and anaerobic 15 T GSH ↑

Chang et al.[189] (2002) Rugby – regular training 15 VT vs 6 T and 10 S TBARS – CD ↓

Schippinger et al.[208] (2002) American football – regular training 8 VT LH ↑

Cazzola et al.[202] (2003) Football – regular training 20 VT vs 20 UT Tocopherol – vit C – UA – SOD ↑

Metin et al.[203] (2003) Football – regular training 25 VT vs 25 UT Zinc ↔

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