ox idative stress

Sports Med 2006; 36 (4): 327-358REVIEW ARTICLE 0112-1642/06/0004-0327/$39.95/0

2006 Adis Data Information BV. All rights reserved.

Oxidative StressRelationship with Exercise and Training

Julien Finaud, Gerard Lac and Edith Filaire

Laboratoire Biologie Interuniversitaire des Activites Physiques et Sportives, Universite BlaisePascal de Clermont-Ferrand, Aubiere, France

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3281. Free Radicals (FR) and Activated Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329

1.1 Biochemistry of Reactive Oxygen Species (ROS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3291.1.1 Dioxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3291.1.2 Superoxide Ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3301.1.3 Hydrogen Peroxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3301.1.4 Hydroxyl Radical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

1.2 Programmed Formation of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3301.3 Unprogrammed Formation of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

1.3.1 ROS Formation During Oxygen Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3301.3.2 ROS Formation During Ischaemia Reperfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3321.3.3 ROS Formation During Haemoglobin and Myoglobin Oxidation . . . . . . . . . . . . . . . . . . . . . 3321.3.4 Other Ways of ROS Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

1.4 Biological Effects of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3331.4.1 Positive Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3331.4.2 Negative Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

2. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3352.1 Enzymatic Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

2.1.1 Superoxide Dismutase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3352.1.2 Catalase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3352.1.3 Glutathione Peroxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3362.1.4 Relationship with Exercise and Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

2.2 Non-Enzymatic Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3362.2.1 Vitamin E (Tocopherol) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3362.2.2 Vitamin C (Ascorbic Acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3382.2.3 β-Carotene and Vitamin A (Retinol) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3382.2.4 Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3382.2.5 Thiols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3382.2.6 Coenzyme Q10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3392.2.7 Uric Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3392.2.8 Heat Shock Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3392.2.9 Ferritin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3392.2.10 Albumin, Caeruloplasmin and Bilirubin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

2.3 Antioxidant Supplementation in Athletes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3402.3.1 Beneficial Effects of Antioxidant Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3402.3.2 Pro-Oxidant Effects of Overloaded Antioxidant Supplementation . . . . . . . . . . . . . . . . . . . 340

2.4 Summary: Exercise and the Antioxidant System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3403. Methods to Assess Oxidative Stress in Biological Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340

3.1 Direct Detection of FR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3403.2 Measurement of Oxidative Damage to Lipids, Proteins and DNA Molecules . . . . . . . . . . . . . . . 341

328 Finaud et al.

3.2.1 Lipid Peroxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3413.2.2 Protein Modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3413.2.3 DNA Modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423.2.4 Other Indirect Oxidative Stress Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342

3.3 Antioxidant Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423.3.1 Enzymatic Antioxidant Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423.3.2 Antioxidant Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423.3.3 Other Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423.3.4 Total Antioxidant Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

3.4 Summary: is There an Ideal Method? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3434. Oxidative Stress and Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

4.1 Oxidative Stress and Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3434.1.1 Aerobic Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3434.1.2 Anaerobic Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3454.1.3 Mixed Exercises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

4.2 Training Effects on Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3494.2.1 Aerobic Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3494.2.2 Anaerobic Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3504.2.3 Mixed Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3504.2.4 Relationship Between Training Load and Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . 3504.2.5 Oxidative Stress and Overtraining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352

4.3 Summary: Oxidative Stress, Training and Overtraining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3525. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

Free radicals are reactive compounds that are naturally produced in the humanAbstractbody. They can exert positive effects (e.g. on the immune system) or negativeeffects (e.g. lipids, proteins or DNA oxidation). To limit these harmful effects, anorganism requires complex protection – the antioxidant system. This systemconsists of antioxidant enzymes (catalase, glutathione peroxidase, superoxidedismutase) and non-enzymatic antioxidants (e.g. vitamin E [tocopherol], vitaminA [retinol], vitamin C [ascorbic acid], glutathione and uric acid). An imbalancebetween free radical production and antioxidant defence leads to an oxidativestress state, which may be involved in aging processes and even in somepathology (e.g. cancer and Parkinson’s disease). Physical exercise also increasesoxidative stress and causes disruptions of the homeostasis. Training can havepositive or negative effects on oxidative stress depending on training load,training specificity and the basal level of training. Moreover, oxidative stressseems 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, theyanced diet, is known as an important factor for exert positive effects on the immune system andhealth.[1] However, exhaustive and/or intense physi- essential metabolic functions.[4] Antioxidants arecal activity can induce diseases, injuries and chronic

components that suppress FR and their harmful ef-fatigue, which can lead to the overtraining syn-

fects. If the production of FR is larger than antioxi-drome, partially because of the toxicity of free radi-dant activity, there is an oxidative stress state withcals (FR). FR, which are highly produced during

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 reactiveportant part of the antioxidant; however, insufficient forms of oxygen (table I). This article will focus onmicronutrient supply is often reported in athletes.[6,7] ROS, which are involved in essential physiologicalIt 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 nitrogenfore, 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

with ROS or could increase ROS production.[14]This article presents the basis of oxidative stressand determines the relationship between oxidativestress, exercise, training and overtraining. 1.1 Biochemistry of Reactive Oxygen

Species (ROS)1. Free Radicals (FR) andActivated Species

1.1.1 DioxygenFR 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 acceptorshells.[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 froma 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 peroxidationProtein oxidationDNA 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 peroxidationDNA damageProteins oxidation

Nitric dioxide NO2• 1–10 sec

Peroxynitrite ONOO•– 0.05–1 sec

Reactive sulphur species RSS

Thyil radical RS• Proteins oxidationDNA damageROS production


330 Finaud et al.

trons. Dioxygen prefers to receive one electron at a tive and very toxic ROS and there is no specifictime and converts it into a superoxide ion (O2•–).[5] antioxidant against this FR. This FR causes lipidFollowing this process, 2–5% of oxygen consump- peroxidation and protein oxidation.[16]

tion (VO2) is converted to O2•–.1.2 Programmed Formation of ROS

1.1.2 Superoxide IonIn the immune system, neutrophils and macro-O2•– is created with the addition of one electron

phages are in charge of destroying foreign sub-on dioxygen (equation 1) and becomes highly reac-stances (antigens). Those immunity cells producetive.O2•– with the reduced nicotinamide-adenineO2 + e- ® O2

•-

dinucleotide phosphate (NADPH)-oxidase system,(Eq. 1)which is present in leukocytes.[17] During this pro-Fenton’s reaction is an iron-salt-dependent de-cess (equation 4), two O2 molecules are needed socomposition of dihydrogen peroxide, generating thethis reaction is called ‘oxidative burst’.highly reactive hydroxyl radical. It occurs in the

presence of ferrous ions (Fe2+) and O2•–. Iron ismainly present in tissues in a ferric ion state (Fe3+). 2 O2 + NADPH → 2 O2

•- + NADP+ + H+ NADPH-oxidase

(Eq. 4)The reaction (equation 2d) is called the Haber-Weissreaction. As shown in section 1.1.3, O2•– can be converted

to H2O2 by SOD in Fenton’s reaction. After that,H2O2 can be transformed into HOCL, which is veryactive for antigen degradation.[18] Thus, an impor-tant quantity of ROS can be formed during theimmunity process and plays an essential biologicalrole for homeostasis control.[15,17]

a O2•-

•

+ H+ → O2 H

b O2 H + O 2•- + H+ → H2O2 + O2

c Fe3+ + O2•- → Fe2+ + O2

d Fe2+ + H2O2 → Fe3+ + OH + OH -

•

•

(Eq. 2) 1.3 Unprogrammed Formation of ROS

1.1.3 Hydrogen Peroxide1.3.1 ROS Formation During Oxygen MetabolismEquation 3 summarises the first and the secondIt is generally considered that the oxygen metab-stages of Fenton’s reaction (equations 2a and 2b).

olism, which occurs into mitochondria, is associatedThis reaction forms hydrogen peroxide (H2O2) in anwith the generation of ROS.[19] Oxidative phospho-acid environment and is catalysed by the superoxiderylations result in adenosine triphosphate (ATP) for-dismutase (SOD) enzyme.mation. Substrate oxidation occurs in the Krebs’cycle and in the electron transport chain with oxy-2 O2

•- + 2 H+ → H2O2 + O2 SOD

gen as the electron acceptor. In the respiratory chain,(Eq. 3)95–99% of oxygen consumed is reduced into waterH2O2 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 itsalysed by coenzyme Q (CoQ).[17,20]

toxicity and its capacity to cause ROS formation. Inleukocytes, myeloperoxydase (MPO) transform CoQ

O2 + 4 e- + 4 H+ → 2 H2O H2O2 in hypochlorous acid (HOCL), one of the

(Eq. 5)strongest physiological oxidants and a powerful an-However, 1–5% of O2 will form O2•–.[21-23] Thetimicrobial agent.[15]

ROS formation is proportional to the respiratory1.1.4 Hydroxyl Radical chain activity, but the latter is not always propor-Hydroxyl radical (OH•) is the end product of tional to VO2.[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:



Electron chain transport

Mitochondria

Complex IIIComplex IIComplex I

b cyt.CoQ

CoQH2

Retonone Myxothiazol

NADH NAD+ Succinate Fumarate Antimycin A

O2 ® O2·-�

-

CoQ·-

FeSR

Reversede- flow

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 = reducednicotinamide-adenine dinucleotide; O2•– = superoxide ion.

complex I and complex III (see figure 1).[20,23] Dis- vealed that about 50% of O2•– production arisestribution and quantity of ROS production inside from reduced nicotinamide-adenine dinucleotidethese complexes fluctuate according to the needs of (NADH)-dehydrogenase inside complex I, betweenATP, VO2, 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] Thecontribute 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 figurewhen the ubisemiquinone anion, arising from one- 1.electron oxidation of ubiquinol, becomes accessible

The assumption that mitochondria are the majorto protons.[25]

intracellular source of ROS was essentially based onin vitro experiments with isolated mitochon-dria.[19,20,26] Artifacts due to the preparation proce-

CoQH2 + O2 ® CoQH + O2•- •

CoQH + O2 ® CoQ + H + + O2•- •

dure or inadequate measurement of ROS may lead(Eq. 6)to methodological mistakes.[26] In vivo study pro-There is a synergistic action of CoQH2 and cyto-vides direct evidence that mitochondria (in heartchrome b566 in complex III.[24] However, this hy-muscle) produce ROS during exercise.[16] So, bothpothesis is still controversial because CoQ, in itsin vitro and in vivo studies tended to affirm that thereduced form, may act as an antioxidant.[19] It wasmitochondrial respiratory chain can not only be arecently shown that ROS are not spontaneously re-major source of ROS at rest and during exercise inleased from mitochondria, but appear when the mi-the working muscle, but also in tissues such as liver,tochondrial membrane potential reaches a maximumkidneys and non-working muscles that undergo par-(state IV).[26] This fact is confirmed by other stud-tial ischaemia during physical exercise.[19] At theies.[27] The site of single-electron deviation to diox-same time, mitochondria are particularly susceptibleygen seems to be ubiquinol interacting with theto the ROS-induced oxidative damage on lipids,Rieske iron-sulphur protein and low-potential cyto-

chrome b of the complex III.[26] Another study re- proteins and DNA. In particular, damage to mito-


332 Finaud et al.

Extracellular space

Blood

Nucleus

Electron chaintransport

Intracellular space

Cytosol:CAT, GPX, Cu-Zn-SOD,

Vit C, GSH

Membranes:Vit E,

carotenoids,flavonoids

Mitochondria:Mn-SOD

GPX

XO

NADPH

ROS

Circulating antioxidants:Vit C, lipoic acid, GSH

Membranes, circulatingcells and lipoproteins:

Vit C, carotenoids, flavonoidsROS

Fig. 2. Potential sources of reactive oxygen species (ROS) in skeletal muscle and locations of the major intracellular and extracellularantioxidants. CAT = catalase; GPX = glutathione peroxidase; GSH = glutathione; NADPH = reduced nicotinamide-adenine dinucleotidephosphate; 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 intosequent 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 byoxidative 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 musclesmodify ROS release from mitochondria.[27] Never- is discussed because there is a poor amount of XOtheless, there is a lack of knowledge about the exact inside them.[19,32] Other alternative explanationsmechanisms 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 increased1.3.2 ROS Formation During Ischaemia Reperfusion

mitochondrial FR production.[19] Other studiesThe 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 ischaemiaexercise (figure 2).[17,30-32] During exhaustive or ana-

reperfusion.[35]

erobic exercise, blood flow is brought to activeterritories such as skeletal muscles while other tis- 1.3.3 ROS Formation During Haemoglobin and

Myoglobin Oxidationsues can be in an hypoxic situation.[1,19] After exer-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 totalreperfusion’. 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 diseasesor 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 asLipoprotein oxidation is an important factor in

ferryl radicals or peroxyl radicals.[41-43]

the pathogenesis of atherosclerosis.[53,54] In fact,ROS initiate lipoprotein oxidation, in particular low-1.3.4 Other Ways of ROS Productiondensity lipoprotein (LDL) oxidation.[55] This oxida-Other processes involved in ROS production dur-tion is dependent on blood antioxidant capacity[56,57]

ing exercise are increased central temperature, cat-and can increase with oxidative stress linked toecholamine and lactic acid, which has the ability tophysical exercise.[58,59] However, those effects areconvert O2•– into OH•.[1,44]

partially or totally compensated in athletes becauseexercise decreases cardiovascular accident risk.[59]

1.4 Biological Effects of ROSROS also have the ability to oxide polyunsaturatedfree-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 theexercise, particularly by intense and traumatising fluidity of cell membranes, reduces the capacity toexercises 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 detectsignals 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 byalso play an essential role in muscular contrac- ROS, including muscular cells and erythrocytes.[61]

tion.[47-50] This role has been pointed out becauseProtein Oxidationinhibition of ROS production leads to a loss ofROS can also oxidise blood and structural pro-muscular fibres contractile force. Conversely, in-

teins and inhibit the proteolytic system.[62] Duringcreasing ROS leads to an increased strength contrac-oxidation, proteins can lose amino acids or can betion.[47,49,50] However, an important amount of ROSfragmented. Those reactions lead to alteration ofin muscular tissue is implicated in muscular fatiguestructural proteins or alteration of enzyme func-and can represent one of the negative effects oftions.[60] Protein and amino acid oxidation is accom-ROS.panied by overall increases in the relative level of

1.4.2 Negative Effects protein carbonyl groups[11,63-65] and of oxidisedDespite 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 ordertered cellular functions. All those deteriorations take to reform amino acids but carbonyl by-productspart in some degenerative pathology such as cat- cannot enter this process. Therefore, they induce a


334 Finaud et al.

ROS-RNS

Exercise

Muscular fatigueDecreased force

Overtraining?

Alteration ofmitochondrial

functions

Increasedanaerobicpathwaysutilisation

Alterationof the

redox status

Alterationof the action

potential

Decreasedelectron transferDecreased ATP

formationIncreased ROS

formation

Increased PiAcidosis

Increased PiAcidosis

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 hypothesisgenetic transcription and cell integrity are reduced about the effects of ROS on muscular fatigue isunder 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 atime- and dose-dependent muscular fatigue increaseDNA Oxidationcan be observed.[47,72,77] Numerous factors seem toROS are also known to cause DNA strand breaksbe implicated in FR-induced muscular fatigue (fig-and base repair damage.[10,51,63,68] Every part ofure 3). The alteration of the mitochondrial functionsDNA is susceptible to attack by ROS.[69] The DNAwith exposure to ROS is considered a major factorrepair system is continual, but its capacity can be

overreached or the repair processes can be al- of muscular fatigue.[72,77] Indeed, mitochondria aretered.[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, aerobicage from mitochondria, which increased with physi- pathways become less efficient. Consequently, itcal exercise.[51,70,71]

seems that this phenomenon can induce an increaseof anaerobic pathways utilisation. This can haveImplication of FR in Muscular Fatiguenegative effects in muscle because anaerobic path-A minimal amount of ROS is necessary for mus-ways induce both an increased inorganic phosphatecular contraction.[47,49,50] Nevertheless, oxidative(Pi) level and acidosis, which are two major factorsstress, which results in muscle-increased ROS con-

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 canto redox status. Redox status is directly linked and be intracellular or extracellular antioxidants (figuremodified by ROS concentration. Thus, when ROS 2). Antioxidant enzymes include SOD, catalaseproduction is important, redox status can be altered. (CAT) and glutathione peroxidase (GPX). Non-en-Consequently, muscular contraction (contractile zymatic antioxidants include a variety of FRproteins) and muscular contraction control (calcium quenchers such as vitamin A (retinol), vitamin Cpump) 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], ubidecarenoneinactivation (particularly enzymes implicated in aer- (ubiquinone Q10), uric acid, bilirubin, ferritin) andobic 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 belease 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 efficiencyMoreover, data tend to show that the action potential is important in sport physiology because exercisefor muscle contraction can be modified by ROS.[80] increases the production of FR.Indeed, ROS causes remarkable perturbation of theinward potassium transport system in muscle. It has 2.1 Enzymatic Antioxidantsbeen shown that muscle soreness-induced decreasein maximal force generation is a result of an increase

2.1.1 Superoxide Dismutasein muscular nitric oxide (NO).[81] Indeed, NO wasSOD is the major defence upon superoxide radi-reported to decrease contractile force by inhibition

cals and is the first defence line against oxidativeof Ca21-ATPase activity in the sarcoplasmic reticu-stress. SOD represents a group of enzymes thatlum. Moreover, NO induces hyperpolarisation ofcatalyse the dismutation of O2•– and the formationmembrane potential (thereby leading to reducedof H2O2 (equation 7).force generation) and also may directly inhibit the

force-generating proteins in skeletal muscle. In sum-mary, it seems possible that ROS- and RNS-induced 2 O2

•- + 2 H+ → H2O2 + O2 SOD

(Eq. 7)decrease in maximal force generation can be a partof 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 SODdamage.[81] Moreover, repetitive muscular ROS-in- and the other part diffuse into the cytosol.[85] Induced fatigue associated with inadequate recovery is muscular cells, 65–85% of SOD activity is done insupposed 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 acofactor of the Mn-SOD form, which is present in2. Antioxidantsmitochondria 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

2.1.2 Catalaseby forming a less active radical or by quenching thedamaging FR chain reaction on substrates such as CAT is present in every cell and in particular inproteins, 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 superoxidePeroxynitrite

Cu-Zn-SOD Copper Cytosol – mitochondria (membrane) Anion superoxideZinc Peroxynitrite

CAT Iron Peroxysome, cytosol and mitochondria Hydrogen peroxide

GPX Selenium Cytosol and mitochondria Hydrogen peroxidePeroxynitrite

CAT = catalase; GPX = glutathione peroxide; SOD = superoxide dismutase.

H2O2.[86] Catalase converts H2O2 into water and 2.2 Non-Enzymatic Antioxidantsoxygen (equation 8).

2.2.1 Vitamin E (Tocopherol)O22 H ® 2 H2O + O2 CAT

(Eq. 8) Vitamin E is a fat-soluble vitamin made up ofseveral isoforms known as tocopherols. α-Tocoph-Catalase can also use H2O2 in order to detoxifyerol is the more active and abundant form.[88] Vita-some toxic substances via a peroxidase reactionmin E has been called the most important chain-(equation 9). This reaction needs a substrate such asbreaking antioxidant because of its abundance inphenol, alcohol (ethanol; A) or formic acid.cells and mitochondrial membranes and its ability toact directly on ROS.[78] Vitamin E interacts with

CAT

H2O2 + H2A (substrate) → 2 H2O + A numerous antioxidants such as vitamin C, GSH, β-(Eq. 9)carotene or lipoic acid. Those antioxidants have thecapacity to regenerate vitamin E from its oxidised

2.1.3 Glutathione Peroxidaseform.[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 waterIII). 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-dation into membranes or into blood.[53,89,90] A vita-GPX

H2O2 + 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 inH2O2 concentration.[21,86]

order to prevent exercise-induced ROS musculardamages 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 ofAntioxidant enzymes are endogenous (table II). methodological differences such as vitamin status of

However, their production can be modulated by subjects before studies, vitamin E supplementationcertain 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 – ROOHCell membranes

Vitamin C (ascorbic acid) Aqueous middle Vitamin E regeneration OH• – O2•–

Cytosol LDL protectionExtracellular 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 inhibitionVitamins C and E and cysteineregeneration

Thioredoxin Aqueous middle Mn-SOD synthesis H2O2 – ROOHVitamin C regeneration

Glutaredoxin Aqueous middle H2O2

Flavonoids Linked with glucids Pro-oxidant enzymes inhibition O2•– – OH• – ROOH – RO•Pro-oxidant ions (Fe2+, Fe3+,Cu2+)trappingLDL 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 – HOCLCu2+) ONOOHtrappingErythrocytes, 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 protectionFR 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 FRCu2+ trapping

Caeruloplasmin Aqueous middle Give electron to FRCu2+, Fe2+ and Fe3+ trapping

Bilirubin Aqueous middle Give electron to FRLipid peroxidation inhibitionErythrocyte 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• = hydroxylradical; 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 antioxidanttion is more important. This phenomenon is defined properties of flavonoids.[106] Moreover, flavonoidsas 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 inforces 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 trapcopper ions, which have a powerful oxidant action. 2.2.5 ThiolsThus, vitamin C supplementation has often been Thiols are a class of molecules characterised bystudied. In athletes, its preventive effects against the presence of sulfhydryl residues (–SH) at theiroxidative stress are discussed.[32,95,98,99] A deficiency active site.[109] Thiols are synthesised from sulphurin 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 inbination with other antioxidants such as vitamin E) biological systems, e.g. protein synthesis, redox, cellhelps to maintain an adequate vitamin C level in biogenesis and immunity. They also play a majortissues.[7] role in the antioxidant defence network.[109] GSH is

the major thiol present in an organism. It acts like a2.2.3 β-Carotene and Vitamin A (Retinol)substrate for GPX in peroxidase ROS inhibition.Vitamin A is a fat-soluble vitamin present inGSH can also directly detoxify ROS and enhancesmany lipid substances. β-carotene, present in cellthe functional antioxidant capacity of vitamins Cmembranes, is converted into vitamin A when theand E.[110,111] In the presence of oxidative stress, it isbody needs it. Although the mechanism of its in vivopossible to observe a decrease of the GSH/GSSGaction is unclear, β-carotene is suggested to deacti-ratio and of the total thiol quantity.[109,112,113] Thesevate ROS (in particular singlet oxygen and lipidphenomena seem to be involved in the aetiology ofradicals) and to reduce lipid peroxidation.[74,100] Al-some neurodegenerative diseases such as Parkin-though less important than vitamin E inside theson’s or Alzheimer’s disease.[114] They are also ob-antioxidant system, β-carotene and vitamin A act inserved in aging or after physical exercise.[112,113] Atandem with vitamin C and vitamin E in order tolow GSH concentration in cells may be associatedprotect cells against ROS.[101] β-carotene supple-with cellular damage and decreased immunity effi-mentation seems to have beneficial effects againstciency, which can be compensated with a vitamin Cexercise-induced oxidative stress without enhancingand E supplementation.[115] Such results tend tophysical performance.[102,103]

show that these antioxidants have the same targets2.2.4 Flavonoids and work together against them. Lipoic acid is aFlavonoids (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 oxidisedtyrosine and malonate.[93,104] In vitro studies pointed form.[50,116,117] It can also reduce cystin (the oxidisedout the antioxidant effects of flavonoids that have form of cysteine) into cysteine in order to promotethe 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, inflammationCoenzyme 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 intracellularcially 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 haveaction by regenerating vitamins C and E.[120,121] a quick HSP liberation under stressful situationsCoQ10 also has beneficial effects, such as protection remains unchanged.[140] Given the potential of ROSagainst cardiovascular diseases, cancer and cell ag- to damage intracellular proteins during subsequenting 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-existingthesis in muscle.[48] In this case, CoQ10 acts as a pro- antioxidant pathways may be complemented by theoxidant by giving rise to O2•–, which is converted to synthesis of HSP.[141] Thus, HSP could represent anH2O2 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 Ferritinsults on oxidative stress reduction and physical per-Iron is required for normal cell growth andformance.[124,125]

proliferation and can have antioxidant effects as a2.2.7 Uric Acid cofactor of catalase. However, iron ions can haveUric 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 protectionknown 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 proteinsmuscles in order to protect them from FR oxida- of iron metabolism, plays an important part in thetion.[129] Indeed, uric acid, in plasma and in muscle, maintenance of iron balance.[143] Several studiesis 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 FRradical, peroxynitrite or ozone.[36,126,130-134] Some formation by sequestering iron in blood or instudies demonstrated that uric acid represents a great cells.[142,144,145] In addition, an increase of ferritinpart (>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 directoxidation. Another important antioxidant property links between FR and genetic expression of ferritinof uric acid is the ability to form stable complexes were shown in some studies.[142-145]

with iron ions. This process inhibits Fe3+, catalysed2.2.10 Albumin, Caeruloplasmin and Bilirubin

vitamin C oxidation and lipid peroxidation.[135,136]

Albumin, caeruloplasmin and bilirubin act asTherefore, uric acid is a vitamin C protector but isnonspecific chain-breaking antioxidants by givingalso a vitamin E protector.[56] In vivo, it is possible toelectrons to FR.[13] Albumin (a thiol protein) anddetect and measure its FR-induced oxidation prod-caeruloplasmin are implicated in copper transportuct (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 from2.2.8 Heat Shock Proteins haemoglobin, increases with oxidative stress andHeat 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 antioxidantous 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 concentrationcal exercise. and glutathione reductase activity in rats.[159] More-

over, antioxidants present in food are in a balanced2.3 Antioxidant Supplementation in Athletes biochemistry state compared with supplement anti-

oxidant compounds.[157]

2.3.1 Beneficial Effects ofAntioxidant Supplementation 2.4 Summary: Exercise and theAntioxidant supplementation among athletes is Antioxidant System

well documented. The results of these studies areBoth enzymatic and non-enzymatic antioxidantsoften contradictory because of antioxidant com-

play a vital role in protecting tissues from excessivepounds and quantity. Indeed, some studies showedoxidative damages.[44,84] The respective actions ofthat the association of several antioxidants has betterthe antioxidants are summarised in table III andeffects than single-compound supplementa-figure 2. This role is especially important duringtion.[152-154] Moreover, the subjects’ profiles (age,exercise, which is associated with FR production, innutritional status, training level and physical activityrelation to intensity, duration and training status.[87]

category) can influence the results.[33,44] In a largeThus, because of low antioxidant dietary intakes andmajority of studies, antioxidant supplementationexercise and training modifications on the antioxi-does not enhance exercise performance or physicaldant system, some antioxidant supplementation incapacity in non-deficient athletes.[7,44,78,103] In return,certain antioxidant nutrients seems to be justified.[22]

antioxidant supplementation provides protectionHowever, the theoretical basis for which antioxi-against the negative health consequences of FRdants should enhance performance is not clear.caused by exercise. Thus, antioxidant supplementa-Studies have generally found that antioxidant sup-tion helps athletes to maintain an optimal health,plements do not improve performance but improvewhich is a key condition to attaining the best per-antioxidant status.[152,154] In return, large amounts offormance. This is particularly important during peri-antioxidant in nutrition could have negative ef-ods of intensive training and/or competition, whichfects.[44,79] Therefore, it seems that antioxidant sup-cause greater needs of antioxidants.[152-155] In thisplementation must be extremely controlled for com-case, a normal diet is not always sufficient.[6,33,156]

position, duration and dose (depending on nutrition-Some antioxidants (vitamins A, E and C) can protectal intakes) in order to be efficient for athletes’ healthsubjects from FR-induced muscle damage duringand performance.exercise or can have anabolic effects.[76,102] Results

tend to show that antioxidant supplementation can 3. Methods to Assess Oxidative Stress inhave beneficial effects in athletes by preventing Biological Systemsagainst antioxidant deficiencies and FR harmful ef-

Oxidative stress can be estimated according tofects on tissues, particularly muscular tissues.[152,154]

the measurement of: (i) FR; (ii) radical-mediated2.3.2 Pro-Oxidant Effects of Overloaded

damages on lipids, proteins or DNA molecules; andAntioxidant Supplementation(iii) antioxidant enzymatic activity or concentra-Every antioxidant is a redox agent that can pro-tions. Results must be interpreted with caution be-tect against FR in some circumstances and promotecause of possible contradictions.[44,160,161]

FR production in others.[157] Therefore, some pre-cautions must be taken because antioxidants can

3.1 Direct Detection of FRhave 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 resonancewas 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 inducesparamagnetic properties.[12,97,162] Measurements can MDA overestimation), this method is accepted as abe made in vitro, in vivo or ex vivo. However, the general marker of lipid peroxidation but results aremost 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 methoducts 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 lipidtrappers, which are ROS stabilisers. After centrifu- peroxidation is the analysis of volatile hydrocarbongation, the serum is analysed by a spectroscopic end products such as pentane, hexane and ethane inmethod. However, the results are to be interpreted expired air. Such a method is non-invasive but is notwith caution because of the short half-life of the precise because these gases can be formed by otherROS, 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-isoprostanesbetter understanding of the ROS reactions, and re- are produced by FR catalysed peroxidation ofagents used can also quantify ROS.[12] Realised ex arachidonic acid.[18] Numerous recent studies havevivo, 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 endogenousples. lipid peroxidation and oxidant injury assessment as

well as some other recent markers such as blood3.2 Measurement of Oxidative Damage to oxidised LDL or antibodies against oxidisedLipids, Proteins and DNA Molecules LDL.[59,93,163]

3.2.2 Protein Modification3.2.1 Lipid PeroxidationFR-induced modification of proteins causes theA basic approach to study oxidative stress would

formation of carbonyl groups into amino acid sidebe to measure the rate of peroxidation of membranechains. An increase of carbonyl is present in everylipids or fatty acids. Lipid peroxidation leads to thephenomenon linked to oxidative stress.[66] Thus, thebreakdown of lipids and to the formation of a widemeasurement of carbonyl formation is the most usu-array of primary oxidation products such as conju-al method for determination of FR-damaged pro-gated dienes or lipid hydroperoxides, and secondaryteins.[65,66] Total proteins are often measured in orderoxidation products including MDA, F2-isoprostaneto use the carbonyl/protein ratio, which is a moreor expired pentane, ethane or hexane.precise index of protein oxidation.[164] This methodMeasurement of conjugated dienes is interestingis particularly interesting because the half-life ofbecause it detects molecular reorganisation of poly-carbonyl is long. Thus, a high amount of carbonylunsaturated fatty acids during the initial phase ofcan show cumulative effects of oxidative stress,lipid peroxidation. Because of this specificity, thiswhich is essential in some studies (e.g. longitudinalmethod is often used to assess oxidative stress.[18,44]

following of athletes).Lipid hydroperoxide is another marker of the initialreaction 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) anddary 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 oxidisedwith thiobarbituric acid, which generates thiobarbi- amino acid kinetics, which limits the interpretationturic 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 isROS induce several types of DNA damage in- important or long (utilisation).

cluding strand breaks, DNA-protein cross-links and3.3.2 Antioxidant Vitaminsbase modifications. Nowadays, numerous methodsPlasmatic quantification of antioxidant vitaminsare used for DNA modification quantification.[69]

(vitamin A, C and E) is a common method to assessThe most used marker is the nucleotide 8-hy-antioxidant protection and to detect vitamin defi-droxy-2′-deoxyguanosine (8-OHdG), which is pro-ciency.[12,13] As well as antioxidant enzymes, antiox-duced by FR-induced guanine oxidation. The ox-idant vitamin concentrations are modified in theidised DNA is continually repaired, and oxidisedpresence of oxidative stress and can be indirectnucleotides such as 8-OHdG are excreted via bloodmarkers of oxidative stress.[12] However, some pre-and urine. Thus, invasive or non-invasive methodscautions must be taken, especially for vitamin C. Aare possible.[12] However, there have been doubtsstabiliser must be added in samples in order toabout the precision of this method because of thestabilise this vitamin.[98] Vitamin E, in blood, ispossible artefactural production of 8-OHdG by auto-transported linked to blood lipids. Therefore, cho-oxidation during and after sample extraction.[69,165]

lesterol is often measured in order to obtain thevitamin E/cholesterol ratio, which is a good marker3.2.4 Other Indirect Oxidative Stress Markersof vitamin E status.[59] Caution is recommendedCreatine kinase (CK) and myoglobin are markerswhen interpreting plasma antioxidant concentrationsof muscular cellular damage.[9,166] These parametersbecause variations, during exercise or training, maycan also be considered indirect markers of oxidativerepresent a redistribution between tissue and plas-stress because lipid peroxidation induces damage ofma.[87]cellular membranes.[9,12] Thus, they are more perme-

able and allow the release of these intracellular 3.3.3 Other Antioxidantssubstances.[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 isathletes 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 theof 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. Theinducing 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 intoletes.[167]

GSSG.[112,113]

Uric acid is an important plasmatic and muscular3.3 Antioxidant Measures antioxidant.[131,137] However, uric acid concentration

can vary because of oxidative stress, purins cycle3.3.1 Enzymatic Antioxidant Activity and renal excretions. Uric acid alone, therefore, canEnzymatic 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 uricThis 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 beof 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 absenttion 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 tableand 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 VO2, which may increase FRstress.[137] activity. Aerobic exercise increases VO2, which, in

turn, may increase FR production. Therefore, many3.3.4 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 haveHowever, this phenomenon cannot occur with

been developed to measure the total antioxidantlow exercise intensity (<50% maximum oxygen

capacity (TAC) of a biological sample.[162] The useconsumption [VO2max]). In such a case, antioxidant

of a pro-oxidant in order to quantify the oxygencapacity is not overreached and FR-induced damage

radical absorbance capacity is one of the most useddoes not appear.[174] Moreover, the more intense the

techniques.[13,170] The TAC gave an overall valueexercise 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 isHowever, the interpretation of the changes in the

confirmed by some studies that show a correlationantioxidant capacity is difficult because it can in-

between VO2 and oxidative stress.[162] However,crease as a result of nutritional effects or because of

other studies show that oxidative stress does notan adaptation of oxidative stress. Furthermore, some

increase after intense aerobic exercise.[53,76,179] Suchantioxidant 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 trainedendurance athletes who are adapted to exercise ef-In general, every method has its interests and itsfects such as FR production.[53,76,179] However,limits, and because of this complexity, no singletrained subjects can exhibit oxidative stress as wellmeasurement of oxidative stress or of antioxidantas sedentary subjects.[59,153] Moreover, some differ-status is going to be sufficient. Indeed, the interpre-ences can be explained by the methods used for thetation of the values coming from a single markermeasurement of oxidative stress as shown in thecould be a source of error. Therefore, a battery ofparagraph above.measurements, including TAC, isolated antioxidant

and markers of FR-induced damage on lipids, pro-Effects on Antioxidantsteins and DNA seems to be a reliable method toEndurance exercise also causes some modifica-assess oxidative stress.[13]

tions in the non-enzymatic antioxidant concentra-tions or enzymatic antioxidant activity. Numerous4. Oxidative Stress and Physical Activitystudies, both in animals and in humans, have shownthat antioxidant enzyme activity increases (SOD,

4.1 Oxidative Stress and ExerciseGPX, CAT) in blood or in tissues after aerobicexercise.[16,22,178,180] This adaptation may occur very

4.1.1 Aerobic Exercisequickly (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 exercisecise 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% VO2max 6 UT MDA (at 40% VO2max) ↓MDA (at 70% VO2max) ↔MDA (at 100% VO2max) ↑

Margaritis et al.[177] (1997) Triathlon (long distance) 18 VT TBARS – GSSG ↔Marzatico et al.[168] (1997) Running (half-marathon) 6 T MDA ↑

CD ↔SOD – GPX ↑CAT ↔

Vasankari et al.[53] (1997) Running (marathon) 22 VT Tocopherol – TRAP ↑CD ↑Retinol – CoQ10 ↔

Ashton et al.[162] (1998) VO2max 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% 8 T Allantoin ↑VO2max (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) VO2max test (ergocycle) 9 UT TBARS – neutrophil FR ↑

production ↔Protein carbonyls ↔SOD – GPX – CAT

Vider et al.[176] (2001) VO2max 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) 8 T 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 reactivesubstances; TEAC = trolox equivalent antioxidant capacity; TRAP = total radical antioxidant potential; UA = uric acid; UT = untrained; vit =vitamin; VT = very trained; VO2max = 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 radicaluric acid tend to increase after endurance generator in muscle during exercise is lacking. Instrain.[58,90,96] Vitamins E and C seem to be mo- ischaemic tissues, it has been proposed that thebilised 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 itsacid increases can not be considered as a specific electron acceptor.[33,34] It is known that xanthineadaptation 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 thatantioxidant 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 oxidaseand its requisite substrates would be present in high4.1.2 Anaerobic Exerciseconcentrations in reperfused tissue and consequent-

Effects on FR Production ly would result in oxygen FR generation uponAnaerobic 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 cellularsprints, 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 cellularcise.[111] However, these studies generally show andamage, which often happen after traumatising ex-increase of the oxidative stress after supramaximalercise such as impact sports and clinometric or ec-exercise such as intermittent running, sprints, jumpscentric exercises.[79,94,166,186,187] An iron liberation,or sets of jumps, resistance exercise (eccentric orfrom haemoglobin or ferritin, may amplify the in-concentric) or Wingate tests on an ergocycle (tableflammatory answer and the oxidative stress.[79] Fur-V).[94,111,163,164,182-185]

thermore, a positive link between the increase ofThe increase of FR production, specific to anaer-lactic acid and the rise of oxidative stress markersobic exercise, may be mediated through varioushas been evidenced.[22,183] This would lead to a de-pathways in addition to electron leakage, such ascline in the concentration of NADH and NADPHduring aerobic exercise.[94,111,186] Xanthine oxidaseand then to the reduction of the antioxidant actionproduction, ischaemia reperfusion and phagocyticand the increase of the FR production.[22]

respiratory burst activity seem to be implicated inFR production during anaerobic exercise.[186] More-

Effects on Antioxidantsover, the important increases of lactic acid, acidosis,Studies about the effects of anaerobic exercise oncatecholamine and post-exercise inflammation,

antioxidants are scarce compared with those con-characteristic in supramaximal exercises, are othercerning submaximal exercise. Some studies show anfactors that can increase the production of FR.[183,186]

increase of the enzymatic antioxidant activity inIt seems possible that ischaemic reperfusion ofplasma or in muscle after anaerobic exer-the active muscle is greatly involved in oxidativecise.[79,168,178] In turn, a Wingate test provokes astress during and after anaerobic exercise.[186] Pre-decline of SOD activity without any GPX activitycisely, this type of exercise significantly enhanceschange.[111] According to the authors, the decline ofthe catabolism of purins and provokes a fast deox-the SOD activity would result from an increase ofygenation (phenomenon of ischaemia reperfusion).FR production. Those differences could be ex-These two phenomena are known to increase theplained by the differences in exercise intensity.activity of xanthine oxidase, which accelerates FR


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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 6 T 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 9 T CAT – GPX ↑GSH ↓

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

Groussard et al.[111] (2003) Cycling – Wingate tests (30 sec) 8 T ESR signals ↑TBARS ↓SOD – GSH ↓GPX ↔

Ramel et al.[185] (2004) Resistance programme (10 exercises – max of 7 T 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 ↑GSH ↓

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 7 T 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; ↑ indicatesincrease; ↔ indicates no change (stable).

There are few data on the effects of anaerobic reported after an intermittent running session andexercise 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 modifycentrations 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 exerciseGSH 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 studiesE.[188] In turn, a recent study shows that fat-soluble suggest that non-enzymatic antioxidants may haveplasma antioxidants (vitamins A and E) increase the same evolution after mixed exercise comparedafter acute resistance exercise.[185] Therefore, further with aerobic and anaerobic exercise: an increase ofstudies 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 aboutcise. other non-enzymatic antioxidant responses (vita-

mins A, E and C).4.1.3 Mixed Exercises

General Findings about Mixed Exercise Summary: Oxidative Stress and ExerciseA 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 samelism in a balanced ratio. Team sports such as foot- way, humans have an adaptive reaction with anball, rugby and basketball are some examples of this increased mobilisation of a variety of enzymatic andtype 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, antioxidantobic 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 becausethe source of few investigations and are more cen- exercise intensity and duration are high and becausetred on training effects.[156,188]

subjects have low training levels and inadequatenutritional status. Some differences can be notedMixed Exercise Effects on FR Production

and Antioxidants between aerobic exercise and mixed or anaerobicThe 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 FRobic exercise on FR production. Such results were production location in anaerobic and in mixed exer-


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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% VO2max – 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% VO2max 4 × week – 9 T 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% VO2max 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 VTBlood samples at rest or after a duathlon)

At rest

GSH – SOD ↔CK – myoglobin – TBARS ↔GPX ↑TAC ↓

Post-exercise

CK – myoglobin – TBARS ↑TAC ↓

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 reactivesubstances; TRAP = total radical antioxidant potential; UA = uric acid; UT = untrained; vit = vitamin; VT = very trained; VO2max = maximum oxygen consumption; ↓ indicatesdecrease; ↑ indicates increase; ↔ indicates no change (stable).


Effects on Antioxidantscise. Ischaemia reperfusion, acidosis and catecho-The effects of aerobic training on antioxidantlamine oxidation are other phenomenon that are

enzymes are situated at the muscular, plasmatic,implicated in oxidative stress during supramaximalhepatic and cardiac levels.[179,194] In muscle, someexercise. However, there is a lack of knowledge andstudies suggest that a specific antioxidant enzymefurther studies are needed to understand oxidativeadaptation exists in muscle having a strong oxida-stress during this kind of exercise, which is probablytive power, thus a strong percentage of type 1 fib-more difficult to investigate.res.[16,178,195] In plasma and other tissues, an increasein 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-aptation is not correlated with the increase of4.2.1 Aerobic TrainingVO2max observed during these studies and that SODand GPX increase more than CAT.[16,169,191,195,197]

Effects on Oxidative Stress and FR ProductionThe results concerning the effects of enduranceThe majority of studies show that endurance

training on the non-enzymatic antioxidants are moretraining reduces post-exercise oxidative stress and

controversial with studies showing an improvementmuscular damage (table VII).[16,22,53,60,112,169,190]

or a reduction of the total antioxidant capacity or ofThese findings agree with the general thinking that an isolated antioxidant in trained subjects comparedregular aerobic exercise permits fighting against cell with sedentary subjects.[22,58,112,197] Some studiesaging and the apparition of some cancers. This re- have also shown that the antioxidant adaptation canduction can be so important that oxidative stress did be correlated with the training volume or withnot increase in highly trained triathletes despite an VO2max.[177,198] However, it seems that the trainingimportant triathlon-induced inflammation.[177] How- protocol must be sufficiently long and intense inever, 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 VO2max without in-from a decrease of FR production during exercise or creasing the antioxidant potential, whereas afrom an increase of the antioxidant system efficien- 10-week protocol (longer and more intensive) in-cy. creases VO2max 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 reactivesubstances; 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 oxidativenutritional antioxidant contribution is essential be- stress at rest than sedentary subjects (tablecause 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 a4.2.2 Anaerobic Training lower fitness level.[189] Thus, the training level

seems to have an important influence on oxidativeEffects on Oxidative Stress and FR Productionstress in this type of activity.Few data about the effect of anaerobic training on

oxidative stress are available. However, it has been Effects on Antioxidantsshown that anaerobic-trained subjects have a lower Studies showed that football or rugby playersoxidative 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 topsubjects.[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 totaltrained 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 deleteriouslations’ characteristics, training protocols, biologi- effects of oxidative stress. However, the increase ofcal measurements) can explain some of these dis- the training and competitive load can induce thecrepancies (table VIII). opposite effect as shown with basketball players.[156]

Contrary results have been obtained with high-levelEffects on Antioxidantsfootball players.[202] Differences could be explainedAccording to some studies, the anaerobic-trainedby nutritional status. The football players had suffi-subjects have a better antioxidant enzyme activity incient nutritional antioxidant contributions, whereasblood, in tissues and especially in working musclethe basketball players’ diet was not controlled.(table VIII);[166,168,200,201] however, this improvement

was not found in every study.[196] The differences 4.2.4 Relationship Between Training Load andbetween the results can be explained by the location Oxidative Stressof dosages and by the training protocol. Indeed, as The markers of the oxidative stress and of thefor aerobic training, it seems that the length of the antioxidant status might be important parameters inprotocol 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-uppractice.[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 cycliststation would be a result of the repeated FR produc- shows a significant increase of the GPX activitytion during ischaemia reperfusion and inflammation during the training periods and a reduction duringprovoked by this type of exercise at muscular level. the recovery periods.[192] Besides, it is important to

note that the authors noticed a decrease in the GPX4.2.3 Mixed Trainingactivity and in selenium plasmatic concentrations

Effects on Oxidative Stress and FR Production during the periods of intensive training. In the sameLittle 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


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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 ↓

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).

352 Finaud et al.

to the training load and competition.[208] Thus, biological variables in athletes in order to detect andthrough a sport season, a decrease of the efficiency prevent overtraining.[209] Oxidative stress markersof the antioxidant system and an increase of oxida- could be interesting, complementary with biologicaltive stress can be observed. However, these two variables, because of the possible links betweenstudies 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 arerelationship between training load and oxidative complex and there are divergent hypotheses basedstress. 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, animproves antioxidant status (see sections increase of the ROS production and a proportional4.2.1–4.2.3); however, in the study by Pincemail et increase of oxidative stress.[204] Although there is noal.,[59] half of the subjects (high-level football and direct evidence, the increase of oxidative stress canbasketball players) presented with a low antioxidant be implied in the appearance of the overtrainingstatus 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 cellstition 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) inpopulations.[156,193,204,206] Recently, it was also order to repair damaged tissues. Inflammation candemonstrated that overloaded training compromises induce an enhanced oxidative stress caused by thethe antioxidant defences, leading to an increase of increase of the FR production by neutrophils andthe exercise-induced oxidative stress.[153,155] macrophages.[73,82]

4.2.5 Oxidative Stress and Overtraining 4.3 Summary: Oxidative Stress, TrainingThe training programme aims to optimise indi- and Overtraining

vidual and collective performance. However, it isAerobic, anaerobic or mixed training provokes adifficult to know whether the programme applied to

decrease of oxidative stress, which is caused by anthe athletes is well adapted or leads to persistentincrease if the efficiency of the antioxidant systemfatigue known as overtraining.[209] This overtrainingin response to the supplementary production of FRsyndrome is characterised by excessive fatigue,during exercise. Nevertheless, the training pro-drops in performance, physical changes, moodinessgramme must be sufficiently long and intense toand biological modifications that can be detected bytrigger a consequent adaptive response of the antiox-a biological check-ups.[209,210] Prolonged periods ofidant system and a decrease of oxidative stress.intense exercise training and/or intense competitionMoreover, this adaptation is more important whenare associated with a large variety of hormonal,the training level of the subjects is low at the begin-immunological, haematological and biochemicalning of the protocol.changes.[210,211] However, the different studies on

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 aretraining 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 antioxidanttraining.[9,83,209,210] It is therefore necessary to imple- system efficiency, particularly in high-level athletesment a longitudinal follow-up that includes selected subjected to an important training and competitive



work is dedicated to the late Prof. Robert (2004) and the lateload with an inappropriate diet. These studies sug-Prof. Bedo (2006).gest a limit beyond which oxidative stress can in-

crease in excess and cause overtraining. Indeed, theReferencesFR produced during exercise play an important role

1. Cooper CE, Vollaard NBJ, Choueiri T, et al. Exercise, freein the induction of muscular lesions but also in theradicals and oxidative stress. Biochem Soc Trans 2002; 30 (2):

induction and propagation of post-exercise inflam- 280-52. Lachance PA, Nakat Z, Jeong WS. Antioxidants: an integrativemation, which can increase cellular lesions. Al-

approach. Nutrition 2001; 17: 835-8though this hypothesis is discussed, the set of these3. Golden TR, Hinerfeld DA, Melov S. Oxidative stress and aging:

phenomena can disrupt muscular functions and lead beyond correlation. Aging Cell 2002; 1: 117-234. Thomas MJ. The role of free radicals and antioxidants. Nutritionto the overtraining syndrome.

2000; 16 (7-8): 716-85. Sen CK. Antioxidant and redox regulation of cellular signaling:

5. Conclusions introduction. Med Sci Sports Exerc 2001; 33 (3): 368-706. Guilland JC, Penaranda T, Gallet C, et al. Vitamin status of

young athletes including the effects of supplementation. MedFR and especially ROS are formed during normalSci Sports Exerc 1989; 21 (4): 441-9physiological processes by nonenzymatic and enzy-

7. Laursen PB. Free radicals and antioxidant vitamins: optimizingmatic sources and continuously cause damage to the health of the athlete. Strength Cond J 2001; 23 (2): 17-25

8. McKenzie DC. Markers of excessive exercise. Can J Appllipids, proteins and nucleic acids. AntioxidantPhysiol 1999; 24 (1): 66-73defences (both enzymatic and non-enzymatic) can

9. Petibois C, Cazorla G, Poortmans JR, et al. Biochemical aspectstemper the negative influence of FR and associated of overtraining in endurance sports. Sports Med 2002; 32 (13):

867-78reactions.10. Jenkins RR. Free radical chemistry: relationship to exercise.

Physical exercise provokes intracellular homeo- Sports Med 1988; 5: 156-7011. Cheeseman KH, Slater TF. An introduction to free radicalstasis disruptions with an unbalance between pro-

biochemistry. Br Med Bull 1993; 49 (3): 481-93oxidants and antioxidants. The mitochondrial respir-12. Rimbach G, Hohler D, Fischer A, et al. Methods to assess free

atory chain, the ischaemia reperfusion phenomenon radicals and oxidative stress in biological systems. Arch Tier-ernahr 1999; 52 (3): 203-22and the inflammatory reaction have been identified

13. Prior RL, Cao G. In vivo total antioxidant capacity: comparisonas the main sources of FR during and after exer-of different analytical methods. Free Radic Biol Med 1999; 27

cise.[21] Oxidative stress is especially important after (11-12): 1173-8114. Giles GI, Jacob C. Reactive sulfur species: an emerging conceptintensive or traumatic exercise and in athletes with a

in oxidative stress. Biol Chem 2002; 383: 375-88low training level and low nutritional antioxidant 15. Hampton MB, Kettle AJ, Winterbourn CC. Inside the neutrophilintakes.[2,78] phagosome: oxidants, myeloperoxidase, and bacterial killing.

Blood 1998; 92: 3007-17Although a training-induced oxidative stress re-16. Leewenburgh C, Hansen PA, Holloszy JO, et al. Hydroxyl

duction caused by an adaptation of the antioxidant radical generation during exercise increases mitochondrialprotein oxidation and levels of urinary dityrosine. Free Radicsystem has been observed in several studies, dataBiol Med 1999; 27 (1-2): 186-92suggest that an accumulation of intense exercise

17. Fehrenbach E, Northoff H. Free radicals, exercise, apoptosis,(intense period of training and/or competition) can and heat shock proteins. Exerc Immunol Rev 2001; 7: 66-89

18. Aruoma OI. Free radicals, antioxidants and international nutri-provoke an increase in oxidative stress.[153] This cantion. Asia Pac J Clin Nutr 1999; 8 (1): 53-63be the origin of muscular fatigue and injuries.[73] If

19. Di Meo S, Venditti P. Mitochondria in exercise-induced oxida-the individual recovery capacity is overreached, tive stress. Biol Signals Recept 2001; 10: 125-40

20. Sjodin B, Hellsten Westing Y, et al. Biochemical mechanism forthese changes can contribute to the appearance ofoxygen free radical formation during exercise. Sports Medovertraining, which in turn may aggravate the oxida- 1990; 10: 236-54

tive stress.[8] 21. Jenkins RR, Goldfarb A. Introduction: oxidant stress, aging andexercise. Med Sci Sport Exerc 1993; 25 (2): 210-2

22. Clarkson PM. Antioxidants and physical performance. Crit RevAcknowledgements Food Sci Nutr 1995; 35: 131-4123. Lenaz G. Role of mitochondria in oxidative stress and ageing.

No sources of funding were used to assist in the prepara- Biochim Biophys Acta 1998; 1366 (1-2): 53-67tion of this review. The authors have no conflicts of interest 24. Nohl H, Jordan W. The mitochondrial site of superoxide forma-

tion. Biochem Biophys Res Commun 1986; 138 (2): 533-9that are directly relevant to the content of this review. This


354 Finaud et al.

25. Lenaz G, D’Aurelio M, Merlo Pich M, et al. Mitochondrial 45. Malm C. Exercise-induced muscle damage and inflammation:bioenergetics in aging. Biochim Biophys Acta 2000; 1459: fact or fiction. Acta Physiol Scand 2001; 171: 233-9397-404 46. Sen CK, Packer L. Antioxidant and redox regulation of gene

transcription. FASEB J 1996; 10: 709-2026. Nohl H, Kozlov AV, Gille L, et al. Cell respiration and forma-tion of reactive oxygen species: facts and artifacts. Biochem 47. Reid MB. Plasticity in skeletal, cardiac, and smooth muscle.Soc Trans 2003; 31 (6): 1308-11 Invited review: redox modulation of skeletal muscle contrac-

tion: what we know and what we don’t. J Appl Physiol 2001;27. Servais S, Couturier K, Koubi H, et al. Effect of voluntary90: 724-31exercise on H2O2 release by subsarcolemmal and intermy-

48. Linnane AW, Zhang C, Yarovaya N, et al. Human aging andofibrillar mitochondria. Free Radic Biol Med 2003; 35 (1):global function of coenzyme Q10. Ann N Y Acad Sci 2002;25-32959: 396-41128. Turrens JF, Boveris A. Generation of superoxide anion by the

49. Andrade FH, Reid MB, Allen DG, et al. Effect of hydrogenNADH dehydrogenase of bovine heart mitochondria. Biochemperoxide and dithiothreitol on contractile function of singleJ 1980; 191: 421-7skeletal muscle fibres from the mouse. J Physiol 1998; 509 (2):29. Genova ML, Pich MM, Bernacchia A, et al. The mitochondrial565-75production of reactive oxygen species in relation to aging and

50. Coombes JS, Powers SK, Rowell B, et al. Effects of vitamin Epathologies. Ann N Y Acad Sci 2004; 1011: 86-100and α-lipoic acid on skeletal muscle contractile properties. J30. Thompson-Gorman SL, Zweier JL. Evaluation of the role ofAppl Physiol 2001; 90: 1424-30xanthine oxidase in myocardial reperfusion injury. J Biol

51. Alessio HM. Exercise-induced oxidative stress. Med Sci SportsChem 1990; 265 (12): 6656-63Exerc 1993; 25 (2): 218-2431. Jackson MJ, O’Farrell S. Free radicals and muscle damage. Br

52. Pietta PG. Flavonoids as antioxidants. J Nat Prod 2000; 63:Med Bull 1993; 49 (3): 630-411035-4232. Frederiks WM, Bosch KS. The role of xanthine oxidase in

53. Vasankari TJ, Kujala UM, Vasankari TM, et al. Effects of acuteischemia/reperfusion damage of rat liver. Histol Histopatholprolonged exercise on serum and LDL oxidation and antioxi-1995; 10: 111-6dants defenses. Free Radic Biol Med 1997; 22 (3): 509-13

33. Goldfarb AH. Nutritional antioxidants as therapeutic and pre-54. Young IS, McEneny J. Lipoprotein oxidation and atherosclero-ventive modalities in exercise-induced muscle damage. Can J

sis. Biochem Soc Trans 2001; 29 (2): 358-62Appl Physiol 1999; 24 (3): 249-6655. Morel DW, Hessler JR, Chisolm GM. Low density lipoprotein34. Heunks LMA, Vina J, Van Herwaarden AV, et al. Xanthine

cytotoxicity induced by free radical peroxidation of lipid. Joxidase is involved in exercise-induced oxidative stress inLipid Res 1983; 24: 1070-6chronic obstrutive pulmonary disease. Am J Physiol 1999;

56. Ma YS, Stone WL, Leclair IO. The effects of vitamin C and277: R1697-704urate on the oxidation kinetics of human low-density lipoprote-

35. Gunther MR, Sampath V, Caughey WS. Potential roles of in. Proc Soc Exp Biol Med 1994; 206: 53-9myoglobin autoxidation in myocardial ischemia-reperfusion

57. Terentis AC, Thomas SR, Burr JA, et al. Vitamin E oxidation ininjury. Free Radic Biol Med 1999; 26 (11-12): 1388-95human atherosclerotic lesions. Circ Res 2002; 90 (3): 333-9

36. Ames BN, Catchcart R, Schwiers E, et al. Uric acid provides an58. Liu ML, Bergholm R, Makimattila S, et al. A marathon run

antioxidant defense in humans against oxidant and radical-increases the susceptibility of LDL to oxidation in vitro and

caused aging and cancer: a hypothesis. Proc Natl Acad Sci U Smodifies plasma antioxidants. Am J Physiol 1999; 276 (6):

A 1981; 78 (11): 6858-62E1083-91

37. Misra HP, Fridovich I. The generation of superoxide radical 59. Pincemail J, Lecomte J, Castiau J, et al. Evaluation of autoan-during the autoxidation of hemoglobin. J Biol Chem 1972; 21: tibodies against oxidized LDL and antioxidant status in top6960-2 soccer and basketball players after 4 months of competition.

38. Wallace JW, Houtchens RA, Maxwell JC, et al. Mechanism of Free Radic Biol Med 2000; 28 (4): 559-65autoxidation for hemoglobins and myoglobins: promotion of 60. Radak Z, Kaneko T, Tahara S, et al. The effect of exercisesuperoxide production by protons and anions. J Biol Chem training on oxidative damage of lipids, proteins, and DNA in1982; 257 (9): 4966-77 rat skeletal muscle: evidence for beneficial outcomes. Free

39. Gohil K, Viguie C, Stanley W, et al. Blood glutathion oxidation Radic Biol Med 1999; 27 (1-2): 69-74during human exercise. J Appl Physiol 1988; 64 (1): 115-9 61. Tavazzi B, Di Pierro D, Amorini AM, et al. et al. Energy

40. Brantley RE, Smerdon SJ, Wilkinson AJ, et al. The mechanism metabolism and lipid peroxidation of human erythrocytes as aof autoxidation of myoglobin. J Biol Chem 1993; 268 (10): function of increased oxidative stress. Eur J Biochem 2000;6995-7010 267: 684-9

41. Harel S, Kanner J. The generation of ferryl or hydroxyl radicals 62. Szweda PA, Friguet B, Szweda LI. Proteolysis, free radicals,during interaction of haemproteins with hydrogen peroxide. and aging. Free Radic Biol Med 2002; 33 (1): 29-36Free Radic Res Commun 1988; 5 (1): 21-33 63. Packer L. Oxidants, antioxidant nutrients and the athlete. J

42. Giulivi C, Cadenas E. Heme protein radicals: formation, fate, Sports Sci 1997; 15 (3): 353-63and biological consequences. Free Radic Biol Med 1998; 24 64. Renke J, Popadiuk S, Korzon M, et al. Protein carbonyl groups’(2): 269-79 content as a useful clinical marker of antioxidant barrier im-

pairment in plasma of children with juvenile chronic arthrisis.43. Kelman DJ, DeGray JA, Mason RP. Reaction of myoglobinFree Radic Biol Med 2000; 29 (2): 101-4with hydrogen peroxide forms a peroxyl radical which oxi-

dizes substrates. J Biol Chem 1994; 269 (10): 7458-63 65. Levine RL. Carbonyl modified proteins in cellular regulation,aging and disease. Free Radic Biol Med 2002; 32 (9): 790-644. Clarkson PM, Thompson HS. Antioxidants: what role do they

play in physical activity and health? Am J Clin Nutr 2000; 72 66. Stadtman ER, Levine RL. Protein oxidation. Ann N Y Acad Sci(S): 637-46 2000; 899: 191-208



67. Berlett BS, Stadtman ER. Protein oxidation in aging, disease, ma dose and free radical scavenging activity. Free Radic Bioland oxidative stress. J Biol Chem 1997; 272 (33): 20313-6 Med 2003; 34 (3): 330-6

68. Wallace SS. Biological consequences of free radical-damaged 89. Liebler DC, Kling DS, Reed DJ. Antioxidant protection of lipidDNA bases. Free Radic Biol Med 2002; 33 (1): 1-14 balayers by α-tocopherol: control of α-tocopherol status and

lipid peroxidation by ascorbic acid and glutathione. J Biol69. Dizdaroglu M, Jaruga P, Birincioglu M, et al. Free radical-Chem 1986; 261: 12144-9induced damage to DNA: mechanisms and measurement. Free

Radic Biol Med 2002; 32 (11): 1102-15 90. Mastaloudis A, Leonard SW, Traber MG. Oxidative stress in70. Beckman KB, Ames BN. Oxidative decay of DNA. J Biol Chem athletes during extreme endurance exercise. Free Radic Biol

1997; 272 (32): 19633-6 Med 2001; 31 (7): 911-2271. Kasai H. Chemistry-based studies on oxidative DNA damage: 91. Mitmesser SH, Giraud DW, Driskell JA. Dietary and plasma

formation, repair, and mutagenesis. Free Radic Biol Med level of carotenoids, vitamin E, vitamin C in a group of young2002; 33 (4): 450-6 and middle-aged nonsupplemented women and men. Nutr Res

2000; 20 (11): 1537-4672. Reid MB, Haack KE, Franchek KM, et al. Reactive oxygen inskeletal muscle I: intracellular oxidant kinetics and fatigue in- 92. Goldfard AH. Antioxidant: role of supplementation to preventvitro. J Appl Physiol 1992; 73 (5): 1797-804 exercise-induced oxidative stress. Med Sci Sports Exerc 1993;

73. Tiidus PM. Radical species in inflammation and overtraining. 25: 232-6Can J Physiol Pharmacol 1998; 76: 533-8 93. Willcox JK, Catignani GL, Roberts LJ. Dietary flavonoids fail

74. Powers SK, Lennon SL. Analysis of cellular responses to free to suppress F2-isoprostane formation in-vivo. Free Radic Biolradicals: focus on exercise and skeletal muscle. Proc Nutr Soc Med 2002; 34 (7): 795-92000; 58: 1025-33 94. McBride JM, Kraemer WJ, Triplett-McBride T, et al. Effect of

75. McArdle A, Pattwell D, Vasilaki A, et al. Contractile activity- resistance exercise on free radical production. Med Sci Sportsinduced oxidative stress: cellular origin and adaptative re- Exerc 1998; 30 (1): 67-72sponses. Am J Physiol 2001; 280: C621-7 95. Takanami Y, Iwane H, Kawai Y, et al. Vitamin E, supplementa-

76. Dawson B, Henry GJ, Goodman C, et al. Effect of vitamin C and tion and endurance exercise. Sports Med 2000; 29 (2): 73-83E supplementation on biochemical and ultrastructural indices 96. Palmer FM, Nieman DC, Henson DA, et al. Influence of vitaminof muscle damage after 21 km run. Int J Sports Med 2002; 23: C supplementation on oxidative and salivary IgA changes10-5 following an ultramarathon. Eur J Appl Physiol 2003; 89:

77. Coombes JS, Rowell B, Dodd SL, et al. Effects of vitamin E 100-7deficiency on fatigue and muscle contractile properties. Eur J 97. Ashton T, Young IS, Peters JR, et al. Electron spin resonanceAppl Physiol 2002; 87: 272-7 spectroscopy, exercise, and oxidative stress: an ascorbic acid

78. Evans WJ. Vitamin E, vitamin C, and exercise. Am J Clin Nutr intervention study. J Appl Physiol 1999; 87 (6): 2032-62000; 72 (S): 647-52

98. Chung WY, Chung JKO, Szeto YT, et al. Plasma ascorbic acid:79. Childs A, Jacobs C, Kaminski T, et al. Supplementation with measurement, stability and clinical utility revisited. Clin Bi-

vitamin C and N-acetyl-cysteine increases oxidative stress in ochem 2001; 34: 623-7humans after an acute muscle injury induced by eccentric

99. Thompson D, Williams C, Garcia-Roves P, et al. Post-exerciseexercise. Free Radic Biol Med 2001; 31 (6): 745-53vitamin C supplementation and recovery from demanding

80. Sen CK, Kolosova I, Hanninen O, et al. Inward potassium exercise. Eur J Appl Physiol 2003; 89: 393-400transport systems in skeletal muscle derived cells are highly

100. Ozhogina OA, Kasaikina OT. β-carotene as an interceptor ofsensitive to oxidant exposure. Free Radic Biol Med 1995; 18free radicals. Free Radic Biol Med 1995; 19 (5): 575-81(4): 795-800

101. Livrea MA, Tesoriere L, Bongiorno A, et al. Contribution of81. Radak Z, Pucsok J, Mecseki S, et al. Muscle soreness-inducedvitamin A to the oxidation resistance of human low densityreduction in force generation is accompanied by increasedlipoproteins. Free Radic Biol Med 1995; 18 (3): 401-9nitric oxide content and DNA damage in human skeletal

102. Schroder H, Navarro E, Mora J, et al. Effects of α-tocopherol, β-muscle. Free Radic Biol Med 1999; 26 (7-8): 1059-63carotene and ascorbic acid on oxidative, hormonal and enzy-82. Bigard AX. Lesions musculaires induites par l’exercice etmatic exercise stress markers in habitual training activity ofsurentrainement. Sci Sports 2001; 16: 204-15professional basketball players. Eur J Nutr 2001; 40: 178-8483. Petibois C, Cazorla G, Poortmans JR, et al. Biochemical aspects

103. Singh A, Moses FM, Deuster PA. Chronic multivitamin-mineralof overtraining in endurance sports: the metabolism alterationsupplementation does not enhance physical performance. Medprocess syndrome. Sports Med 2003; 33 (2): 83-94Sci Sports Exerc 2001; 24 (6): 726-3284. Dekkers JC, van Doornen LJ, Kemper HC. The role of antioxi-

104. Wedworth SM, Lynch S. Dietary flavonoids in atherosclerosisdant vitamins and enzymes in the prevention of exercise-prevention. Ann Pharmacother 1995; 29 (6): 627-8induced muscle damage. Sports Med 1996; 21 (3): 213-38

105. Depeint F, Gee JM, Williamson G, et al. Evidence for consistent85. Das KC, Lewis-Molock Y, White CW. Elevation of manganesepatterns between flavonoids structures and cellular activities.superoxide dismutase gene expression by thioredoxin. Am JProc Nutr Soc 2002; 61 (1): 97-103Respir Cell Mol Biol 1997; 17: 713-26

106. Morand C, Crespy V, Manach C, et al. Plasma metabolites of86. Antunes F, Derick H, Cadenas E. Relative contributions of heartquercetin and their antioxidant properties. Am J Physiol 1998;mitochondria glutathione peroxidase and catalase to H2O2275 (44): R212-9detoxification in in vivo conditions. Free Radic Biol Med

2002; 33 (9): 1260-7 107. Cotelle N. Role of flavonoids in oxidative stress. Curr Top MedChem 2001; 1 (6): 569-9087. Ji LL. Oxidative stress during exercise: implication of antioxi-

dant nutrients. Free Radic Biol Med 1995; 18 (6): 1079-86 108. Arts MJTJ, Haenen GRMM, Wilms LC, et al. Interactions88. Fuchs J, Weber S, Podda M, et al. HPLC analysis of vitamin E between flavonoids and proteins: effect on the total antioxidant

isoforms in human epidermis: correlation with minimal erythe- capacity. J Agric Food Chem 2002; 50: 1184-7


356 Finaud et al.

109. Sen CK, Packer L. Thiol homeostasis and supplements in physi- 129. Hellsten Y, Sjodin B, Richter EA, et al. Urate uptake andcal exercise. Am J Clin Nutr 2000; 72: 653S-69S lowered ATP levels in human muscle after high-intensity

intermittent exercise. Am J Physiol 1998; 274: E600-6110. May JM, Qu Z, Whitesell RR, et al. Ascorbate recycling inhuman erythrocytes: role of GSH in reducing dehydroas- 130. Kaur H, Halliwell B. Action of biologically-relevant oxidizingcorbate. Free Radic Biol Med 1996; 20 (4): 543-51 species upon uric acid: identification of uric acid oxidation

111. Groussard C, Rannou-Bekono F, Machefer G, et al. Changes in products. Chem-Biol Interactions 1990; 73: 235-47blood lipid peroxidation markers and antioxidants after a sin- 131. Wayner DDM, Burton GW, Ingold KU, et al. The relativegle sprint anaerobic exercise. Eur J Appl Physiol 2003; 89: contributions of vitamin E, urate, ascorbate and proteins to the14-20 total peroxyl radical-trapping antioxidant activity of human

112. Tessier F, Margaritis I, Richard MJ, et al. Selenium and training blood plasma. Biochim Biophys Acta 1987; 924: 408-19effects on the glutathione system and aerobic performance. 132. Hooper DC, Spitsin S, Kean RB, et al. Uric acid, a naturalMed Sci Sports Exerc 1995; 27 (3): 390-6 scavenger of peroxynitrite, in experimental allergic encephalo-

113. Svensson M, Ekblom B, Cotgreave I, et al. Adaptative stress myelitis and multiple sclerosis. Proc Natl Acad Sci U S Aresponse of glutathione and acid uric metabolism in man 1998; 95: 675-80following controlled exercise and diet. Acta Physiol Scand

133. Hooper DC, Scott GS, Zborek A, et al. Uric acid, a peroxynitrite2002; 176: 43-56scavenger, inhibits CNS inflammation, blood-CNS barrier per-

114. Schulz JB, Lindenau J, Seyfried J, et al. Glutathione, oxidative meability changes and tissue damage in a mouse model ofstress and neurodegeneration. Eur J Biochem 2000; 267: multiple sclerosis. FASEB J 2000; 14: 691-84904-11

134. Kean RB, Spitsin SV, Mikheeva T, et al. The peroxynitrite115. Shang F, Lu M, Dudek E, et al. Vitamin C and vitamin E restorescavenger uric acid prevents inflammatory cell invasion intothe resistance of GSH-depleted lens cells to H2O2. Free Radicthe central nervous system in experimental allergic encephalo-Biol Med 2003; 34 (5): 521-30myelitis through maintenance of blood-central nervous system

116. Serbinova E, Reznick SKAZ, Packer L. Thioctic acid protects barrier integrity. J Immunol 2000; 165: 6511-8against ischemia-reperfusion injury in the isolated langendorff

135. Davies KJA, Sevanian A, Muakkassah-Kelly SF, et al. Uricheart. Free Radic Res Commun 1992; 17: 49-58acid-iron ion complexes: a new aspect of the antioxidant117. Scott BC, Aruoma OI, Evans PJ, et al. Lipoic and dihydrolipoicfunctions of uric acid. Biochem J 1986; 235: 747-54acids as antioxidants: a critical evaluation. Free Radic Res

136. Sevanian A, Davies KJA, Hochstein P. Serum urate as an1994; 20: 119-30antioxidant for ascorbic acid. Am J Clin Nutr 1991; 54:118. Khanna S, Atalay M, Laaksonen DE, et al. α-lipoic acid supple-1129S-34Smentation: tissue glutathione homeostasis at rest and after

137. Marklund N, Ostman B, Nalmo L, et al. Hypoxanthine, uric acidexercise. J Appl Physiol 1999; 86 (4): 1191-6and allantoin as indicators of in vivo free radical reactions:119. Maulik N, Yoshida T, Engelman RM, et al. Dietary coenzymedescription of a HPLC method and human brain microdialysisQ10 supplement renders swine hearts resistant to ischemia-data. Acta Neurochir (Wien) 2000; 142: 1135-42reperfusion injury. Am J Physiol 2000; 278: H1084-90

138. Hellsten Y, Svensson M, Sjodin B, et al. Allantoin formation120. Witt EH, Reznick AZ, Viguie CA, et al. Exercise, oxidativeand urate and glutathione exchange in human muscle duringdamage and effects of antioxidant manipulation. J Nutr 1992;submaximal exercise. Free Radic Biol Med 2001; 31 (11):122 (3 Suppl.): 766-731313-22121. Crane FL. Biochemical functions of coenzyme Q10. J Am Coll

Nutr 2001; 20 (6): 591-8 139. Nishizawa J, Nakai A, Matsuda K, et al. Reactive oxygenspecies play an important role in the activation of heat shock122. Crestanello JA, Doliba NM, Babsky AM, et al. Effects offactor 1 in ischemic-reperfused heart. Circulation 1999; 99:coenzyme Q10 supplementation on mitochondrial function934-41after myocardial ischemia reperfusion. J Surg Res 2002; 102

(2): 221-8 140. Hamilton KL, Staib JL, Phillips T, et al. Exercise, antioxidants,123. Rosenfelt FL, Pepe S, Linnane A, et al. Coenzyme Q10 protects and HSP72: protection against myocardial ischemia/reperfu-

the aging heart against stress: studies in rats, human tissues, sion. Free Radic Biol Med 2003; 34 (7): 800-9and patients. Ann N Y Acad Sci 2002; 959: 355-9 141. Smolka MB, Zoppi CC, Alves AA, et al. HSP72 as a comple-

124. Braun B, Clarkson PM, Freedson PS, et al. Effects of coenzyme mentary protection against oxidative stress induced by exer-Q10 supplementation on exercise performance, VO2 max, and cise in the soleus muscle of rats. Am J Physiol Regul Integrlipid peroxidation in trained cyclists. Int J Sport Nutr 1991; 1 Comp Physiol 2000; 279: R1539-45(4): 353-65 142. Meneghini R. Iron homeostasis, oxidative stress, and DNA

125. Svensson M, Malm C, Tonkonogi M, et al. Effect of Q10 damage. Free Radic Biol Med 1997; 23 (5): 783-92supplementation on tissue Q10 levels and adenine nucleotide

143. Cairo G, Recalcati S, Pietrangelo A, et al. The iron regulatorycatabolism during high-intensity exercise. Int J Sport Nutrproteins: targets and modulators of free radical reactions and1999; 9 (2): 166-80oxidative damage. Free Radic Biol Med 2002; 32 (12):126. Grootveld M, Halliwell B. Measurement of allantoin and uric1237-43acid in human body fluids: a potential index of free-radical

144. Orino K, Lehman L, Tsuji Y, et al. Ferritin and the response toreactions in vivo. Biochem J 1987; 243: 803-8oxidative stress. Biochem J 2001; 357: 241-7127. Hellsten Y, Tullson PC, Richter EA, et al. Oxidation of urate in

145. Arosio P, Levi S. Ferritin, iron homeostasis, and oxidativehuman skeletal muscle during exercise. Free Radic Biol Meddamage. Free Radic Biol Med 2002; 33 (4): 457-631997; 22 (1-2): 169-74

128. Green HJ, Fraser IG. Differential effects of exercise intensity on 146. Applegate LA, Scaletta C, Panizzon R, et al. Evidence thatserum uric acid concentration. Med Sci Sports Exerc 1988; 20 ferritin is UV inducible in human skin: part of putative defense(2): 55-9 mechanism. J Invest Dermatol 1998; 111: 159-63



147. Erario MA, Gonzales S, Noriega GO, et al. Bilirubin and ferritin 167. Varlet-Marie E, Maso F, Lac G, et al. Hemorheological distur-as protectors against hemin-induced oxidative stress in liver. bances in the overtraining syndrome. Clin HemorheolCell Mol Biol 2002; 48 (8): 877-84 Microcirc 2004; 30: 211-8

148. Nikolaidis MG, Michailidis Y, Mougios V. Variation of soluble 168. Marzatico F, Pansarasa O, Bertorelli L, et al. Blood free radicaltransferring receptor and ferritin concentrations in human se- antioxidant enzymes and lipid peroxides following long-dis-rum during recovery and exercise. Eur J Appl Physiol 2003; tance and lactacidemic performances in highly trained aerobic89: 500-2 and sprint athletes. J Sports Med Phys Fitness 1997; 37: 235-9

149. Atanasiu RL, Stea D, Mateescu MA, et al. Direct evidence of 169. Miyazaki H, Oh-ishi S, Ookawara T, et al. Strenuous endurancecaeruloplasmin antioxidant properties. Moll Cell Biochem training in humans reduces oxidative stress following exhaus-1998; 189: 127-35 tive exercise. Eur J Appl Physiol 2001; 84: 1-6

150. Yesikaya A, Yegin A, Ozdem S, et al. The effect of bilirubin on 170. Cao G, Prior RL. Postprandrial increases in serum antioxidantlipid peroxidation and antioxidant enzymes in cumene capacity in older women. J Appl Physiol 2000; 89: 877-83hydroperoxide-treated erythrocytes. Int J Clin Lab Res 1998; 171. Kohen R, Vellaichamy E, Hrbac J, et al. Quantification of the28 (4): 230-4 overall reactive oxygen species scavenging capacity of biolog-

151. Kaur H, Hugues MN, Green CJ, et al. Interaction of bilirubin ical fluids and tissues. Free Radic Biol Med 2000; 28 (6):and biliverdin with reactive nitrogen species. FEBS Lett 2003; 871-9543 (1-3): 113-9 172. Davies KJ, Quintanilha AT, Brooks GA, et al. Free radicals and

152. Margaritis I, Palazzetti S, Rousseau AS, et al. Antioxidant tissue damage produced by exercise. Biochem Biophys Ressupplementation and tapering exercise improve exercise-in- Commun 1982; 107: 1198-205duced antioxidant response. J Am Coll Nutr 2003; 22 (2): 173. Child RB, Wilkinson DM, Fallowfield JL, et al. Elevated serum147-56 antioxidant capacity and plasma malondialdehyde concentra-

153. Palazzetti S, Richard MJ, Favier A, et al. Overload training tion in response to a simulated half-marathon run. Med Sciincreases exercise-induced oxidative stress and damage. Can J Sports Exerc 1998; 30 (11): 1603-7Appl Physiol 2003; 28 (4): 588-604 174. Lovlin R, Cottle W, Pyke I, et al. Are indices of radical damage

154. Palazzetti S, Rousseau AS, Richard MJ, et al. Antioxidant related to exercise intensity? Eur J Appl Physiol 1987; 56:supplementation preserves antioxidant response in physical 313-6training and low antioxidant intake. Br J Nutr 2004; 91: 91-100

175. Aguilo A, Tauler P, Fuentespina E, et al. Antioxidant response155. Finaud J, Scislowski V, Lac G, et al. Antioxidant status and to oxidative stress induced by exhaustive exercise. Physiol

oxidative stress in professional rugby players: evolution Behav 2005; 84 (1): 1-7throughout a season. Int J Sports Med 2006; 27: 87-93

176. Vider J, Lehtmaa J, Kullisaar T, et al. Acute immune response in156. Schroder H, Navarro E, Tramullas A, et al. Nutrition antioxidant respect to exercise-induced oxidative stress. Pathophysiology

status and oxidative stress in professional basketball players: 2001; 7: 263-70effects of a three compound antioxidative supplement. Int J

177. Margaritis I, Tessier F, Richard MJ, et al. No evidence ofSports Med 2000; 21 (2): 146-50oxidative stress after a triathlon race in highly trained competi-

157. Herbert V. Symposium: prooxidant effects of antioxidant vita-tors. Int J Sports Med 1997; 18 (3): 186-90

mins. J Nutr 1996; 126: 1197-200178. Inal M, Akyuz F, Turgut A, et al. Effect of aerobic and anaerob-158. Choi EJ, Chee KM, Lee BH. Anti- and prooxidant effects of

ic metabolism on free radical generation swimmers. Med Scichronic quercitin administration in rats. Eur J Pharmacol 2003;Sports Exerc 2001; 33 (4): 564-7482: 281-5

179. Chevion S, Moran DS, Heled Y, et al. Plasma antioxidant status159. James AM, Smith RAJ, Murphy MP. Antioxidant and prooxi-and cell injury after severe physical exercise. Proc Natl Acaddant properties of mitochondrial coenzyme Q. Arch BiochemSci U S A 2003; 100 (9): 5119-23Biophys 2004; 423: 47-56

180. Ji LL, Fu R. Antioxidant enzyme response to exercise and aging.160. Duthie GG. Determination of activity of antioxidants in humanMed Sci Sport Exerc 1993; 25 (2): 225-31subjects. Proc Nutr Soc 1999; 58 (4): 1015-24

181. Criswell D, Powers S, Dodd S, et al. High intensity training-161. Jenkins RR. Exercise and oxidative stress methodology: a cri-induced changes in skeletal muscle anti-oxidant enzyme activ-tique. Am J Clin Nutr 2000; 72 (2- Suppl.): 670-4ity. Med Sci Sports Exerc 1993; 25 (10): 1135-40162. Ashton T, Rowlands CC, Jones E, et al. Electron spin resonance

182. Radak Z, Nakamura A, Nakamoto H, et al. A period of anaerob-spectroscopic detection of oxygen-centred radicals in humanic exercise increases the accumulation of reactive carbonylserum following exhaustive exercise. Eur J Appl Physiol 1998;derivatives in the lungs of rats. Plugers Arch 1998; 435:77 (6): 498-502439-41163. Frank J, Pompella A, Biesalski HK. Histochemical visualization

183. Kayatekin BM, Gonenc S, Acikgoz O, et al. Effects of sprintof oxidant stress. Free Radic Biol Med 2000; 29 (11):exercise on oxidative stress in skeletal muscle and liver. Eur J1096-105Appl Physiol 2002; 87: 141-4164. Chen SS, Chang LS, Wei YH. Oxidative damage to proteins and

184. Goldfarb AH, Bloomer RJ, McKenzie MJ. Combined antioxi-decrease of antioxidant capacity in patients with varicocele.dant treatment effects on blood oxidative stress after eccentricFree Radic Biol Med 2001; 30 (11): 1328-34exercise. Med Sci Sports Exerc 2005; 37 (2): 234-9165. Hofer T, Moller L. Optimization of the workup procedure for

185. Ramel A, Wagner KH, Elmadfa I. Plasma antioxidants and lipidthe analysis of 8-oxo-7,8-dihydro-2′-deoxyguanosine withoxidation after submaximal resistance exercise in men. Eur Jelectrochemical detection. Chem Res Toxicol 2002; 15:Nutr 2004; 43: 2-6426-32

166. Ortenblad N, Madsen K, Djurhuus MS. Antioxidant status and 186. Sahlin K, Cizinsky S, Warholm M, et al. Repetitive staticlipid peroxidation after short-term maximal exercise in trained muscle contractions in humans: a trigger of metabolic andand untrained humans. Am J Physiol 1997; 272 (4): R1258-63 oxidative stress? Eur J Appl Physiol 1992; 64: 228-36


358 Finaud et al.

187. Saxton JM, Donnelly AE, Roper HP. Indices of free-radical- 201. Hellsten Y, Apple FS, Sjodin B. Effect of sprint cycle trainingmediated damage following maximum voluntary eccentric and on activities of antioxidant enzymes in human skeletal muscle.concentric muscular work. Eur J Appl Physiol 1994; 68: J Appl Physiol 1996; 81 (4): 1484-7189-93

202. Cazzola R, Russo-Volpe S, Cervato G, et al. Biochemical as-188. Groussard C, Machefer G, Rannou F, et al. Physical fitness and

sessments of oxidative stress, erythrocyte membrane fluidityplasma non-enzymatic antioxidant status at rest and after aand antioxidant status in professional soccer players and sed-Wingate test. Can J Appl Physiol 2003; 28 (1): 79-92entary controls. Eur J Clin Invest 2003; 33 (10): 924-30189. Chang CK, Tseng HF, Hsuuw YD, et al. Higher LDL oxidation

at rest and after a rugby game in weekend warriors. Ann Nutr 203. Metin G, Gumustas MK, Uslu E, et al. Effect of regular trainingMetab 2002; 46: 103-7 on plasma thiols, malondialdehyde and carnitine concentra-

190. Elosua R, Molina L, Fito M, et al. Response of oxidative stress tions in young soccer players. Chin J Physiol 2003; 46 (1):biomarkers to a 16-week aerobic physical activity program, 35-9and to acute physical activity, in healthy young men and

204. Balakrishnan SD, Anuradha CV. Exercise, depletion of antioxi-women. Atherosclerosis 2003; 167: 327-34dants and antioxidant manipulation. Cell Biochem Funct 1998;191. Ohno H, Yahata T, Sato Y, et al. Physical training and fasting16 (4): 269-75erythrocyte activities of free radical scavenging enzyme sys-

tems in sedentary men. Eur J Appl Physiol 1988; 57 (2): 173-6 205. Brites FD, Evelson PA, Christiansen MG, et al. Soccer players192. Accominotti M, Dutey P, Lahet C, et al. Evolution des taux de under regular training show oxidative stress but an improved

selenium et de glutathion peroxydase sanguins de sportifs de plasma antioxidant status. Clin Sci 1999; 96 (4): 381-5haut niveau. Sci Sports 1991; 6: 165-72

206. Subudhi AW, Davis SL, Kipp RW, et al. Antioxidant status and193. Bergholm R, Makimattila S, Valkonen M, et al. Intense physical

oxidative stress in elite alpine ski racers. Int J Sport Nutr Exerctraining decreases circulating antioxidants and endothelium-Metab 2001; 11 (1): 32-41dependant vasodilatation in-vivo. Atherosclerosis 1999; 145

(2): 341-9 207. Evelson P, Gambino G, Travacio M, et al. Higher antioxidant194. Venditti P, Di Meo S. Effect of training on antioxidant capacity, defences in plasma and low density lipoproteins from rugby

tissue damage, and endurance of adult male rats. Int J Sports players. Eur J Clin Invest 2002; 32 (11): 818-25Med 1997; 18: 497-502

208. Schippinger G, Wonisch W, Abuja PM, et al. Lipid peroxidation195. Hollander J, Fiebig R, Gore M, et al. Superoxide dismutase gene and antioxidant status in professional American football play-

expression in skeletal muscle: fiber-specific adaptation to en-ers during competition. Eur J Clin Invest 2002; 32 (9): 686-92durance training. Am J Physiol 1999; 277 (46): R856-62

209. Fry RW, Morton AR, Keast D. Overtraining in athletes: an196. Selamoglu S, Turgay F, Kayatekin BM, et al. Aerobic andupdate. Sports Med 1991; 12 (1): 32-65anaerobic training effects on the antioxidant enzymes in the

blood. Acta Physiol Hung 2000; 87 (3): 267-73 210. Rowbottom DG, Keast D, Goodman C, et al. The haematologi-197. Powers SK, Ji LL, Leewenburgh C. Exercise training-induced cal, biochemical and immunological profile of athletes suffer-

alterations in skeletal muscle antioxidant capacity: a brief ing from the overtraining syndrome. Eur J Appl Physiol 1995;review. Med Sci Sports Exerc 1999; 31 (7): 987-97

70: 502-9198. Child RB, Wilkinson DM, Fallowfield JL. Resting serum anti-

211. Urhausen A, Kindermann W. Diagnosis of overtraining: whatoxidant status is positively correlated with peak oxygen uptaketools do we have? Sports Med 2002; 32 (2): 95-102in endurance trained runners. J Sports Med Phys Fitness 1999;

39 (4): 282-4

199. Rall LC, Roubenoff R, Meydani SN, et al. Urinary 8-hy-Correspondence and offprints: Julien Finaud, Laboratoiredroxy-2′-deoxyguanosine (8-OHdG) as a marker of oxidative

stress in rheumatoid arthritis and aging: effect of progressive Biologie Interuniversitaire des Activites Physiques et Spor-resistance training. J Nutr Biochem 2000; 11: 581-4

tives, Bat Biologie B. Campus des Cezeaux. 63177, Aubiere200. Vincent KR, Vincent HK, Braith RW, et al. Resistance exercise

Cedex, France.training attenuates exercise-induced lipid peroxidation in theE-mail: [email protected]. Eur J Appl Physiol 2002; 87: 416-23


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