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), is
formed in mitochondria and in the cytosol. A small
amount of molecular oxygen passing through the
electron transport chain in mitochondria is prema-
turely released as O
2
or
H
2
O
2
reacts with metal ions such as iron or copper
(Valko et al., 2004). The fourth radical, nitric oxide
(NO
reacts with NO
OH are able to
acquire the protons adjacent to double bonds
in unsaturated fatty acids, such as those in cell
membranes. This begins a chain reaction of deforma-
tion to these fatty acids forming lipid peroxides. This
process, called lipid peroxidation, results in poorly
functioning (i.e. leaky) cell membranes (Kellogg &
Fridovich, 1975; Lai & Piette, 1977; Valko et al.,
2004). Similarly,
OH, NO
, and ONOO
can
oxidize nucleotides causing damage to DNA, which
can lead to tumours (Valko, Rhodes, Moncol,
Izakovic, & Mazur, 2006). Nitric oxide is able to
bind to the cysteine groups on proteins, called
S-nitrosylation, changing the proteins tertiary
structure and altering their function (Stamler
et al., 2008), and ONOO
is able to irreversibly
denature proteins in a similar manner, rendering
them non-functional (Koppenol, Moreno, Pryor,
Ischiropoulos, & Beckman, 1992). Nitric oxide has
also been suggested to have a direct inhibitory effect
on contractility in muscle fibres (Kobzik, Reid,
Bredt, & Stamler, 1994).
Important biological functions of free radicals
Although free radicals have traditionally been con-
sidered purely a threat to cells, such one-sided
thinking is beginning to be challenged. There is
increasing evidence to suggest that free radicals play
an important role in modulating redox-sensitive
signalling pathways on the way to muscular adapta-
tions (Jackson, 2009). Results from several recent
studies on animals as well as some involving athletes
present the framework for a functional role of
reactive oxygen species, including O
2
, H
2
O
2
, and
NO
by SOD3
in the extracellular space acts as a vasodilator, which
can acutely optimize blood flow. Nitric oxide pro-
duced in endothelial cells by eNOS also in
duces vasodilation in feeding and resistance arteries
(Clifford & Hellsten, 2004), leading to an increase in
blood-flow velocity (Kayar et al., 1992). The result-
ing increase in shear stress in the microvasculature of
28 M. Gross et al.
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muscle fibres is an important stimulus for angiogen-
esis in muscle (Baum et al., 2004). Endogenous
oxidant-defence is also upregulated by negative
feedback from reactive oxygen species, especially
O
2
, H
2
O
2
, and
NO
to H
2
O
2
. In the cytosol, H
2
O
2
can there-
after be converted to water by glutathione peroxidase
(Gpx), which oxidizes glutathione (GSH), or one of
several peroxiredoxins with the help of thioredoxin,
or to water and molecular oxygen by catalase (Valko
et al., 2007). The dipeptides carnosine and anserine
also act as antioxidants by scavenging O
2
and
OH
(Chan & Decker, 1994).
Other non-enzymatic antioxidants, which are not
synthesized in humans, must be obtained exogen-
ously, and include the vitamins A (b-carotene), C
(ascorbic acid), and E (a-tocopherol). These sub-
stances are able to scavenge various free radicals by
proton donation (Sies & Stahl, 1995). Vitamin C
may help strengthen immune defence (Kreider et al.,
2004; Valko et al., 2006), while vitamin E could
enhance energy balance at high altitude (Simon-
Schnass & Pabst, 1988). Furthermore, the two
function together to protect against lipid peroxida-
tion. Beta-carotene is particularly well-suited for
scavenging O
2
,
OH, and peroxyl radicals such as
ONOO
release from
eNOS is blocked (Baum et al., 2004; Hudlicka,
Brown, & Silgram, 2000).
Data such as these suggest that over-dominant
radical scavenging can actually reduce training
stimuli and effectiveness by suppressing the radical-
dependent signal for adaptation. Indeed, where
training-induced changes in aerobic and endurance
capacity were measured, daily vitamin C supple-
mentation appeared to have greatly inhibited the
peripheral adaptations (i.e. capillarization and mito-
chondrial genesis). Mean improvement in maximal
oxygen uptake was about twice as great in humans
and in rats who received a placebo than in those who
received vitamin C (1 g day
1
in humans) and
improvement of endurance capacity (measured only
in rats) was seven-fold greater (Gomez-Cabrera
et al., 2008a), supposedly because this parameter is
more specifically related to peripheral adaptations.
Another instance of antioxidant supplementation
interfering with training is when muscle injury
occurs, such as after intense, unaccustomed, and
especially eccentric exercise. Vitamins C and E have
been shown to delay healing and recovery of
strength, and increase oxidative stress after such
muscle-damaging exercise (Beaton et al., 2002;
Childs et al., 2001; Close et al., 2006; Teixeira,
Valente, Casal, Marques, & Moreira, 2009).
Such findings are intriguing from the standpoint of
athletes and coaches who wish to improve perfor-
mance capacity through training. Could it be that
many are unknowingly counteracting training effec-
tiveness through banal practices such as consuming
an antioxidant-rich recovery drink after an endurance
training session or taking a daily multivitamin?
Conclusions
With the above discussion, we wish to spark
a generally more critical analysis of the radical-
antioxidant situation. Certainly, it is too early to
condemn all forms of antioxidant supplementation.
Also, we recognize that there are certain circum-
stances in which supplementation is probably advan-
tageous, such as high-altitude training camps, since
radical production is intensified and endogenous
defence weakened in hypoxia (Pialoux et al., 2006,
2009a, 2009b), or around important competitions,
where only (eventual) benefits remain relevant.
Also, in the case of a diagnosed deficient anti-
oxidant capacity, supplementation could be called
for, although this is seldom the case in healthy
endurance athletes eating a balanced diet (Knez
et al., 2007; Margaritis & Rousseau, 2008).
Anyway, it is clear, based on the positive and
negative effects of free radicals, that the right balance
between these and antioxidants is necessary for
health and optimal training effectiveness. For the
time being, identifying the optimal balance remains
elusive, making the area of free radicals, antiox-
idants, and training a ripe one for further research,
especially in athletes. Specifically, questions regard-
ing the effects of dose (if possible, based on
individual needs), timing, and setting (e.g. hypoxia)
of antioxidant supplementation on radical signalling
during endurance training remain to be answered.
These circumstances could be decisive in determin-
ing whether supplementation is largely beneficial or
detrimental to training effectiveness. Meanwhile, few
practical recommendations can be made, other than
to realize that, at least for endurance athletes,
antioxidant supplementation is not a case of the
more, the better.
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