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Exercise, oxidative stress and hormesis

  • Hungarian University of Sport Science

Abstract and Figures

Physical inactivity leads to increased incidence of a variety of diseases and it can be regarded as one of the end points of the exercise-associated hormesis curve. On the other hand, regular exercise, with moderate intensity and duration, has a wide range of beneficial effects on the body including the fact that it improves cardio-vascular function, partly by a nitric oxide-mediated adaptation, and may reduce the incidence of Alzheimer's disease by enhanced concentration of neurotrophins and by the modulation of redox homeostasis. Mechanical damage-mediated adaptation results in increased muscle mass and increased resistance to stressors. Physical inactivity or strenuous exercise bouts increase the risk of infection, while moderate exercise up-regulates the immune system. Single bouts of exercise increases, and regular exercise decreases the oxidative challenge to the body, whereas excessive exercise and overtraining lead to damaging oxidative stress and thus are an indication of the other end point of the hormetic response. Based upon the genetic setup, regular moderate physical exercise/activity provides systemic beneficial effects, including improved physiological function, decreased incidence of disease and a higher quality of life.
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Exercise, oxidative stress and hormesis
Zsolt Radak
*, Hae Y. Chung
, Erika Koltai
, Albert W. Taylor
, Sataro Goto
Institute of Sport Science, Faculty of Physical Education and Sport Science, Semmelweis University, Budapest, Hungary
Faculty of Health Sciences, University of Western Ontario, London, Canada
Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
Faculty of Pharmacy, Pusan National University, 30 Jangjeon-dong, Geumjeong-gu, Busan 609-735, Republic of Korea
Received 10 March 2007; received in revised form 27 April 2007; accepted 30 April 2007
Physical inactivity leads to increased incidence of a variety of diseases and it can be regarded as one of the end points of the
exercise-associated hormesis curve. On the other hand, regular exercise, with moderate intensity and duration, has a wide range of
beneficial effects on the body including the fact that it improves cardio-vascular function, partly by a nitric oxide-mediated
adaptation, and may reduce the incidence of Alzheimer’s disease by enhanced concentration of neurotrophins and by the
modulation of redox homeostasis. Mechanical damage-mediated adaptation results in increased muscle mass and increased
resistance to stressors. Physical inactivity or strenuous exercise bouts increase the risk of infection, while moderate exercise up-
regulates the immune system. Single bouts of exercise increases, and regular exercise decreases the oxidative challenge to the body,
whereas excessive exercise and overtraining lead to damaging oxidative stress and thus are an indication of the other end point of the
hormetic response. Based upon the genetic setup, regular moderate physical exercise/activity provides systemic beneficial effects,
including improved physiological function, decreased incidence of disease and a higher quality of life.
#2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Exercise; Oxidative stress; Hormesis
1. Introduction
The thesis of the hormesis theory is that biological systems respond to the exposure to chemicals, toxins, and
radiation with a bell-shaped curve. In toxicology, hormesis is a dose–response phenomenon characterized by a low
dose of stimulation, high dose of inhibition, resulting in either a J-shaped or an inverted U-shaped dose–response,
which is a non-monotonic response (Calabrese and Baldwin, 2001, 2002; Cook and Calabrese, 2006). Recently, we
have extended the hormesis theory to free radical species, which appear to plateau when modulated by aging or
physical exercise (Radak et al., 2005) Therefore, we have proposed that exercise modulates free radicals and the
effects can be described by the hormesis curve.
The most important effect of exercise on the body is the adaptation process. As any stressor, a single bout of
exercise has the capability to induce adaptation, although only in a restricted number of incidences, due to the limited
time frame and the characteristics of the loading (Radak et al., 2001c). According to the original stress theory,
Ageing Research Reviews xxx (2007) xxx–xxx
* Corresponding author at: Institute of Sport Science, Faculty of Physical Education and Sport Science, Semmelweis University, Alkotas u. 44,
H-1123 Budapest, Hungary. Tel.: +36 1 3565764; fax: +36 1 3566337.
E-mail address: (Z. Radak).
1568-1637/$ – see front matter #2007 Elsevier Ireland Ltd. All rights reserved.
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developed by Selye (1956), for a chronic stressor the body replies with a decreased (alarm reaction), and then with an
increased resistance (stage of resistance), which is followed by exhaustion of the body (stage of exhaustion).
Therefore, chronic stressors could be very dangerous since the resting period, which is obligatory for recovery and
efficient stress response, is missing. Using extremely long-duration exercise as an example, such as 18–24 consecutive
hours of running or swimming, even in superbly trained individuals, the body can suffer serious ‘‘exhaustion’’ which
could jeopardize the health of the individuals.
On the other hand, under normal conditions, exercise bouts are followed by rest periods and during rest the body has
the capability to cope with the exercise ‘‘stressor’’ and as a result, adaptation takes place (Radak et al., 2001c). Indeed,
the adaptive effects of regular exercise are systemic and, depending on the characteristics of exercise, the effects are
specific. In skeletal muscle, for example, a single bout of long-term aerobic exercise decreases the concentration of
glycogen, whereas the normal exercise-induced adaptation to a training regimen is an increase in glycogen
concentration which significantly exceeds the level which is found in untrained muscle. Similarly, intensive anaerobic
exercise increases the level of lactic acid, which can be as high as 20–25 mmol/l in the blood, but regular anaerobic
exercise-associated adaptation enhances the ability to cope with lactic acid by enhancing its elimination.
Regular exercise is carried out for the sole purpose of bringing about adaptation. One of the end points of the
exercise-related hormesis curve is physical inactivity, which unfortunately is associated with our modern ‘‘civilized’’
life-style. It is well documented that physical inactivity is associated with increased incidence of a variety of diseases
and pathological conditions, including cardiovascular diseases, Type II diabetes, muscular atrophy, Alzheimer’s and
Parkinson’s diseases and obesity (Booth and Lees, 2007).
Interestingly, the beneficial effects of exercise are highlighted according to the human genetic setup, and physical
activity has been an important and necessary part of our every day life (Goto and Radak, 2005). Hunting, gathering,
fighting and mobility were part of every day life some 100 years ago, and as a result the human genetic pool favors
physical activity. Modern life-style, on the other hand, at least in industrialized nations, has essentially eliminated
physical activity in the work place. Modern technology and fad diets have resulted in the extensive appearance of life-
style-related diseases, which easily can be treated and prevented with regular physical activity (Goto and Radak, 2005;
Radak et al., 2004b).
Excessive exercise or overtraining, the other end point of the hormesis curve, increases the risk of disease and
jeopardizes health. Indeed, it is also well established that during overtraining the adaptation process fails, and this is
primarily due to incomplete recovery from the exercise bouts and, as a result, some maladaptation occurs
(Ogonovszky et al., 2005).
Since the present review is limited in length and thus unable to cover the extremely complex systemic adaptation to
exercise or fully describe the effects of physical inactivity and overtraining, only some of the most important topics
have been selected.
2. Exercise and fatigue
Regular exercise is an interval stressor. During exercise, metabolic, mechanical and psychological loading result in
a wide range of alteration in different organs. During rest, the body recovers, compensates and/or over-compensates
the effects of the exercise-stressor. It is a well-known physiological fact that exercise must attain a certain level of
stress for adaptation to occur. Indeed, if the exercise-induced stress does not reach this threshold, adaptation will not
occur. Low-level exercise loading can be effective in case of low level physical fitness but for well trained individuals a
high level of exercise stress is obligatory. Adaptation will not occur without fatigue. The level of fatigue is important,
since extreme fatigue could cause very significant cellular alterations, even irreversible ones, and the recovery period
after extreme fatigue could be too long, which makes it difficult to establish an exercise regimen. On the other hand, if,
following fatigue, inadequate time for recovery is not accounted for, overtraining could occur. This would result in
decreased physiological performance, a disturbance of hormonal processes, a depressed immune function, an
increased susceptibility to infection, and an increased incidence of many diseases (Angeli et al., 2004; Armstrong and
VanHeest, 2002; Lakier Smith, 2003; Moeller, 2004; Nederhof et al., 2006; Smith, 2000). Inflammation, which is a
protective process, and necessary for the healing process to occur, can be deregulated and the generation of
inflammatory and anti-inflammatory cytokines could be the causative factors of the overtraining syndrome (Smith,
2000). Overtraining is a maladaptive process, which can seriously endanger health and decrease the ability to maintain
homeostasis. There is no question that overtraining is an end point of the exercise-associated hormesis curve.
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3. Muscle soreness and muscle hypertrophy
Exercise with unaccustomed loading often results in muscle soreness, which is associated with structural damage
to the sarcomeres, disruption of desmin and the myofilament network, splitting of the Z-band and increased
intramuscular pressure detected by slit-catheter (Friden et al., 1984, 1986, 1988). This damage activates
inflammatory processes, increases DNA binding of NF-kB, activates proteases of the proteasome complex, so that
degradation of damaged proteins will be enhanced (Malm et al., 2004; Peake et al., 2006; Goto and Radak, 2005). It
appears that this adaptive micro damage evokes the repair process. Hence, after the remodeling, the sarcomere will be
stronger and better able to withstand mechanical stress. Therefore, as a result of this muscular adaptation, the same
level of loading would not result in muscle soreness, decrease in maximal force production, or inflammation (Radak
et al., 1999b).
According to our current understanding of muscular hypertrophy, exercise loading has to reach a certain level,
which is above 60% of the maximal performance, in order to stimulate the process of hypertrophy (Macintyre,
1987). The enhanced secretion of anabolic hormones, growth hormone, testosterone and IGF-1, is an important
factor to increase protein synthesis and this does not happen if the loading is sub-threshold (Goto and Radak,
2005). All types of muscle fibers are capable of hypertrophy, although in the case of fast fibers, the increase of
protein synthesis is dominant, while slow fibers decrease the rate of protein degradation to gain greater size
(Goldspink, 1991).
It is claimed (Goldspink, 1991), that when the protein content of myofibrils increases and when they are under high
tension, longitudinal splitting takes place, which results in new filaments being formed. As a consequence of this
increased mechanical stress, the myofibrillar mass is subdivided, because the Z-bands, where the actin filaments are
anchored, are not able to withstand the increased tension. Therefore, it appears that muscular hypertrophy is mediated
by high mechanical tension that causes micro damage. Extreme mechanical stress, on the other hand, disintegrates
sarcomeres, and ruptures tendo-muscular junctions, which leads to apoptosis and necrosis, which, even if recovered
after a long period, would not cause increased muscle size, or enhanced physiological function (Armand et al., 2003;
Friden and Lieber, 1998; Koskinen et al., 2002).
Therefore, both muscle soreness and muscular hypertrophy can be described by the hormetic curve. Muscle
soreness is associated with decreased physiological function. As a result of this adaptive damage and after remodeling,
this would lead to improved performance. Similarly, for the splitting of myofibrils, tension is necessary which causes
damage to the Z-band and the formation of daughter filaments occurs. The damage-induced adaptation results in
increased muscle mass. If the damage is too large it can cause necrosis, or apoptosis and un-recoverable alterations can
occur. If the stimulus is missing or not strong enough, the adaptation process would not have been necessary, and thus
the physiological function would remain unchanged.
4. Adaptive gene expression in exercise
Two types of physical activity, i.e. resistance exercise and endurance training, cause adaptive responses of gene
expression in nuclear and mitochondrial genomes in the skeletal muscle. The changes of gene expression are
modulated by a variety of transcription factors constituting the basis of different or common mechanisms of adaptation
in the two paradigms. One of the most prominent changes induced by physical activities is upregulation of
mitochondrial energy metabolism. The increase involves transcriptional regulation of genes for mitochondrial proteins
encoded in the nuclear genome by the peroxisome-proliferator-activated receptor (PPAR) gamma co-activator-1 alpha
(PGC-1a) and control of mitochondrial gene expression by the mitochondrial transcription factor A (Tfam) (Hood,
2001). Endurance exercise activates PGC-1a, leading to phenotypes such as increased mitochondrial biogenesis and
efficient muscle contraction (Baar, 2004; Joseph et al., 2006). On the other hand, exercise causes an increase in AMP
concentration due to massive consumption of ATP sufficient to activate AMP kinase (AMPK) by phosphorylation via a
yet unknown mechanism (Atherton et al., 2005). Expression of PGC-1ais induced by AMPK by an uncharacterized
mechanism, thus the AMPK–PGC-1asignaling pathway is apparently being involved in adaptive responses to
endurance training that results in mitochondrial biogenesis (Atherton et al., 2005). PGC-1ais also involved in fiber-
type switching from glycolytic to oxidative fibers and the abundance of contractile proteins (Sandri et al., 2006). Thus,
PGC-1ais shown to lend resistance to muscle atrophy, providing a mechanism for protecting age-related sarcopenia
by exercise.
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In addition to the impact on energy homeostasis, exercise inevitably increases ROS and NOS generation that can
be harmful to unprepared tissues but may also activate adaptive responses to oxidative stress inducing antioxidant
defense systems by upregulation of responsible gene expression (Powers et al., 1999; Ji et al., 2006). An acute bout of
exercise activates the transcription factor NF-kB (nuclear factor kappa B) to enhance transcription of genes for
antioxidative enzymes such as mitochondrial Mn superoxide dismutase (MnSOD) and inducible nitric oxide
synthase (iNOS) via increased generation of ROS (Hollander et al., 2001; Hemmrich et al., 2003). Regular exercise
also increases antioxidant defenses in the skeletal muscle upregulating SOD and glutathione peroxidase gene
expression, thereby adapting stronger oxidative stresses (Powers and Lennon, 1999; Leeuwenburgh and Heinecke,
2001). It thus appears that ROS serves as messengers in exercise-induced adaptive gene expression. Franco et al.
reported that myotubes exposed to H
exhibit upregulation of mRNA for antioxidant enzymes (catalase,
glutathione peroxidase, Cu, ZnSOD and MnSOD), suggesting that ROS is involved in the adaptive upregulation of
antioxidant gene expression by exercise (Franco et al., 1999). In support of this suggestion, Khassaf et al. (2003)
found that supplementation of vitamin C, a nutritional antioxidant, attenuates antioxidant defense including increase
in shock protein (HSP) 70 in human lymphocytes and skeletal muscle. Similarly, the active isoform of another dietary
antioxidant vitamin E and vitamin C inhibits induction of the mRNA of HSP 72, an important component of cellular
protection, by exercise in human skeletal muscle (Fischer et al., 2006). Gomez-Cabrera et al. (2005) reported that the
induction of antioxidative enzyme MnSOD and iNOS induced by exhaustive exercise is abolished by allopurinol, an
inhibitor of xanthine oxidase, in the skeletal muscle of rats. Since the expression of these enzymes appears to be
dependent on NF-kB that is activated by ROS, the adaptive process is suggested to be induced by ROS (Gomez-
Cabrera et al., 2005). These findings illustrate essential roles of ROS in protective adaptation induced by exercise.
Too much generation of ROS in unaccustomed muscles is obviously harmful while the modest generation by regular
exercise is apparently beneficial to upregulating defense mechanisms against oxidative stress, thus forming a basis of
hormetic effects of exercise.
5. Exercise and the immune system
There is an accumulating body of evidence which suggests that exercise induces considerable alterations to the
immune system (Chung et al., 2005). The interaction between exercise-associated stress and the immune system
provides an excellent opportunity to study hormesis in this unique condition (Pedersen and Hoffman-Goetz, 2000;
Chung et al., 2005). In general, exercise of a high intensity or long duration can cause immunosuppression and
increased susceptibility to infection. Indeed, upper respiratory tract infections are often reported after strenuous
exercise (Heath et al., 1992). This level of exercise load is associated with glutamate debt, which could alter the
efficiency of the immune system (Lehmann et al., 1995). As well, long-term exercise results in increased secretion
of cortisol, which also could lead to immunosuppresion (Okutsu et al., 2005; Smith and Myburgh, 2006)since
cortisol likely plays a role in maintaining the neutrophilia and lymphopenia after prolonged exercise. As a result, the
activity of natural killer cells is suppressed to below the pre-exercise values, especially after exercise of a high
intensity or long duration, when the lowest natural killer cell activity is measured 2–4 h after the strenuous exercise
bouts (Pedersen et al., 1990). Therefore, exercise of high intensity or long duration creates an ‘‘open window’’
which indicates a higher risk of infection. On the other hand, exercise of moderate intensity and duration generally
can be regarded as an up-regulator of the immune system, leading to increased resistance against infection and a
lower risk of appearance of disease, including certain types of cancer (Chung et al., 2005; Radak et al., 2005; Woods
et al., 2006).
6. Exercise and free radicals
Exercise can increase the generation of ROS and this is especially true for single bouts of exercise (Alessio and
Goldfarb, 1988; Alessio et al., 1988; Davies et al., 1982; Radak et al., 1999b). As a consequence of increased
concentration of ROS, oxidative damage of lipids, proteins and DNA have been reported following single bouts of
exercise (Alessio et al., 1988; Davies et al., 1982; Gomez-Cabrera et al., 2006; Ikeda et al., 2006; Ji et al., 2006;
Mahoney et al., 2005; Paroo et al., 2002; Poulsen et al., 1998; Radak et al., 1995, 1996, 1998, 1999b, 2004a; Russell
et al., 2005). Redox sensitive transcription factors and signaling pathways are induced by exercise, and these pathways
are obligatory for adaptive responses to occur.
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An interesting finding has been reported by Gomez-Cabrera et al. (2005), which demonstrates that administration
of allopurinol, a potent inhibitor of xanthine oxidase, prevents exercise-induced adaptation. This observation
underlines the importance of ROS, at least in the concentration generated during exercise, to induce adaptation, and
questions the uncontrolled administration of antioxidants.
There is ample evidence to suggest that regular exercise increases the activity of antioxidant enzymes and
increased levels of ROS appear to be necessary during the exercise session. In addition to the first line of antioxidant
enzymes, the second line, the oxidative damage repair systems, are important to minimize the dangerous effects of
ROS (Crawford and Davies, 1994; Davies, 1986). It has been demonstrated that regular exercise increases the
activity of proteasome complex in the myocardium, and decreases the level of carbonylated proteins. Administration
of hydrogen peroxide for 2 weeks, every second day, to sedentary rats, resulted in increased activity of the
proteasome, and the carbonyl concentration increased. On the other hand, hydrogen peroxide treatment did not
increase the oxidative protein damage in the heart, but the induction of proteasome activity was most prominent,
indicating that exercise increases the resistance against oxidative stress and also increases the efficiency of the repair
process (Radak et al., 2000). This observation can be extended to DNA as well, since our data suggest that marathon
running increased the activity of OGG1, the enzyme which preferentially repairs 8-hydroxydeoxyguanosine (8-
OHdG) in skeletal muscle of runners (Radak et al., 2003). The up-regulation of the activity of DNA repair enzymes
could be an important means by which exercise decreases the DNA damage in nuclei (Radak et al., 1999a, 2002,
2005, 2007).
Exercise also has a large impact on the availability and bioactivity of endothelial-derived nitric oxide (NO). The
stimulus for endothelial NO production is the increased flow through the vessels, which results in shear stress and
increased activation of endothelial nitric oxide synthase (Kojda and Hambrecht, 2005; McAllister and Laughlin,
2006). NO then acts as a vasodilator. Exercise results in increased blood flow and shear stress, and increased
bioactivity of NO (Clarkson et al., 1999; McAllister and Laughlin, 2006). Data suggest that at least 10 weeks of
exercise training are necessary to significantly improve endothelium-dependent vasodilation in healthy young man
(Clarkson et al., 1999), while for patients with depressed NO bioactivity, even 4 weeks of training is beneficial
(Hambrecht et al., 2000a,b; Hamilton et al., 2001; Hambrecht et al., 2000). There is an intriguing relationship between
NO and ROS, especially with regards to superoxide. NO at low concentrations serves as an antioxidant, while at high
concentrations, the end product of superoxide and NO interaction results in peroxynitrite (ONOO
) which is very
reactive and highly cytotoxic (Pacher et al., 2007).
Although the available information on exercise load-dependent bioactivity of NO is still sparse, data indicate that
low intensity exercise may fall below the threshold level which is necessary to improve NO-related vascular function
(Goto et al., 2003; Bergholm et al., 1999). Interestingly, exercise of a very high intensity could also have little effect on
vascular function, since the bioavailability of NO can be abolished through scavenging by ROS generated at high
intensity exercise (Goto et al., 2003).
Therefore, the effects of exercise on ROS production, NO and dependent vascular function fit the hormesis curve.
It is our view that the ROS-generation effects of exercise are very important, because this process can initiate
adaptive processes, which result in lower base levels of ROS, increased activity of antioxidant and damage repair
enzymes, and lower levels of oxidative damage (Radak et al., 2005). This ROS mediated adaptation could play a
significant role by which exercise decreases the incidence of ROS-associated diseases, including specific
cardiovascular diseases, stroke, Alzheimer disease, and certain types of cancer (Perry et al., 2005; Radak et al., 2005;
Mattson and Magnus, 2006; Mattson and Wan, 2005; Yu and Chung, 2006).
7. Exercise and aging
In the present review, we have been discussing the relationship of exercise to the context of hormesis. The link
between exercise and aging can also fit the hormesis curve. Generally, during aging, the ability of the body to maintain
homeostasis decreases, and regular exercise increases the ability to cope with a variety of stressors. Aging is associated
with significant decreases in physical activity, which in turn facilitate the aging process. Aging is a very complex
process, which affects each organ, and even each cell differently. The mass and function of skeletal muscle decrease.
However, it has been shown that regular exercise significantly prevents this age-associated loss (Roos et al., 1997).
Recently, it has become clear, that exercise also has a very similar beneficial effect on brain function (Mattson, 2005;
Radak et al., 2001a). There is evidence that physical inactivity raises the incidence of Alzheimer disease, one of the
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most well-described age-related disorders (Booth and Lees, 2007; Booth et al., 2002; Feher and Lengyel, 2006; Taylor
and Poston, 2006; Thompson, 2006; Wendel-Vos et al., 2004). Muscular activity results in increased capillarization
and better oxygen supply to different regions of the brain, and, naturally, the increased metabolic activity of neurons
results in increased oxygen uptake, which probably is associated with increased activity of antioxidant and oxidative
damage repairing enzymes (Cotman and Berchtold, 2002; Fabel et al., 2003; Radak et al., 2001a, 2006). Moreover,
physical activity results in up-regulation of neutrophins, which not only enhance brain function but play a critical role
in cell survival, and increase resistance against a variety of stressors (Mattson and Wan, 2005; Mattson et al., 2004;
Mattson, 2005).
A causative relationship has been shown between the accumulation of carbonyl groups in amino acid residues, due
to the interaction with ROS, and specific brain functions (Carney et al., 1991; Radak et al., 2001b). We have shown that
regular exercise can increase the activity of proteasome complex, which is responsible for the degradation of
carbonylated and other damaged proteins. A recent study by Lazarov et al. (2005) has shown that physical activity
reduced the b-amyloid content in the brain of transgenic mice and this is due to the increased activity of neprilysin.
The systemic effects of exercise can also be observed in the liver, in which single bouts of exercise significantly
increase the level of ROS and cause oxidative damage to lipids (Davies et al., 1982; Radak et al., 1995, 1996).
Furthermore, we have demonstrated that regular exercise decreases the ROS concentration in liver, and attenuates the
age-associated increase in ROS and the associated oxidative damage (Radak et al., 2004a). In addition, the DNA
binding of NF-kB, which is one of the most potent inflammatory transcription factors, is modified by aging, and
regular exercise and has a rejuvenating effect in the context of NF-kB.
Therefore, the available information suggests regular exercise at moderate intensity can retard the aging process
and ameliorate the insidious onset of age-associated diseases.
8. Conclusion
The response of biological systems to stressors can be described by a U-shaped curve. Physical exercise also evokes
this hormesis curve-response by the organism. The two end-points of the hormesis curve are inactivity and
overtraining, and both of these result in decreased physiological function (Fig. 1). Normal and positively adapted
function of the organism can be achieved with regular moderate exercise bouts. The effects of exercise on the immune
system, free radicals, muscle function, vascular function and aging appear to fit the hormesis curve.
The present work was supported by Hungarian grants: ETT 38388 awarded to Z. Rada
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Fig. 1. Typical hormesis curve and the effects of exercise. Moderate exercise increases the physiological function of different organs, increases the
rate of prevention against diseases and improves quality of life. Physical inactivity and strenuous exercise and overtraining increases the risk of
diseases and decreases physiological function.
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... Redox mechanisms are proposed as main drivers of adaptive mechanisms and responses to physical exercise [24]. Low level of reactive oxygen species (ROS) generated by chronic aerobic or endurance training would elicit a down-stream signaling cascade leading to upregulation of antioxidant defense genes and a range of beneficial physiological effects [25][26][27]. However, excessive training or a pathological condition disrupting redox homeostasis [28,29] would generate high ROS levels leading to harmful oxidative reactions in proteins, lipids and nucleic acids. ...
... However, excessive training or a pathological condition disrupting redox homeostasis [28,29] would generate high ROS levels leading to harmful oxidative reactions in proteins, lipids and nucleic acids. Similar exercise-induced redox mechanisms and adaptive responses have been reported in skeletal muscle, heart, liver, and brain [25,26,29,30]. Therefore, there is a hormesis response to physical exercise at least partially modulated by oxidative stress levels in several organs including brain [26]. ...
... Similar exercise-induced redox mechanisms and adaptive responses have been reported in skeletal muscle, heart, liver, and brain [25,26,29,30]. Therefore, there is a hormesis response to physical exercise at least partially modulated by oxidative stress levels in several organs including brain [26]. ...
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Physically active lifestyle has huge implications for the health and well-being of people of all ages. However, excessive training can lead to severe cardiovascular events such as heart fibrosis and arrhythmia. In addition, strenuous exercise may impair brain plasticity. Here we investigate the presence of any deleterious effects induced by chronic high-intensity exercise, although not reaching exhaustion. We analyzed cardiovascular, cognitive, and cerebral molecular changes in young adult male mice submitted to treadmill running for eight weeks at moderate or high-intensity regimens compared to sedentary mice. Exercised mice showed decreased weight gain, which was significant for the high-intensity group. Exercised mice showed cardiac hypertrophy but with no signs of hemodynamic overload. No morphological changes in the descending aorta were observed, either. High-intensity training induced a decrease in heart rate and an increase in motor skills. However, it did not impair recognition or spatial memory, and, accordingly, the expression of hippocampal and cerebral cortical neuroplasticity markers was maintained. Interestingly, proteasome enzymatic activity increased in the cerebral cortex of all trained mice, and catalase expression was significantly increased in the high-intensity group; both first-line mechanisms contribute to maintaining redox homeostasis. Therefore, physical exercise at an intensity that induces adaptive cardiovascular changes parallels increases in antioxidant defenses to prevent brain damage.
... В зависимост от първоначалната оценка на клиничния и сърдечно-съдовия рисков профил, е необходимо изготвяне на индивидуална програма за физическа активност. Тя е биологичното лекарство, което трябва да бъде предписано в необходимата доза при всеки пациент [35]. Физическата активност може да бъде модулирана по интензитет, честота и скорост на изпълнение, за да се адаптира под формата на оптимална програма при тази нова група пациенти с COVID-19. ...
... Depending on the initial assessment of patients' clinical and cardiovascular risk profile, an individual program for physical activity should be prepared. Physical exercise is a biological drug, that should be prescribed in the right dose for every patient [35]. It can be modulated by intensity, frequency, speed of execution, so that it can easily be adapted as an optimal program for performance in COVID-19 patients. ...
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Recent data has revealed the cardiovascular complications of COVID-19 infection. The mechanism of cardiovascular impairments involves binding of severe acute respiratory syndrome (SARS) coronavirus-2 (CoV-2) to the protein angiotensin-converting enzyme 2 (ACE2), thus penetrating into the cells. There are other mechanisms, most of which are under research and will be explained. Cardiovascular complications of COVID-19 infection are heart failure, cardiomyopathy, acute coronary syndrome, arrhythmias, and venous thromboembolism. This article aims to collect scientific evidence by exploring PubMed, Scopus, and Pedro databases to show the cardiovascular complications of COVID-19 infection and the benefit of physiotherapy treatment for these patients. Exercise training is a powerful element in physiotherapy and an important part of cardiac rehabilitation. It contributes to significant changes of the cardiovascular system - recovery of endothelial dysfunction and prevention of thromboembolic complications. In conclusion, due to the wide variety of programs of exercise training, as well as patient monitoring, physical activity is appropriate strategy for the treatment of cardiovascular complications of various degrees in post-COVID patients.
... Ageing is characterized by the normal and progressive decline of various physiologic functions leading to a decrease in the ability of the whole organism's capacity response [1]. From all biological theories of ageing, the mitochondrial theory [2], based on Harman's free radical theory of ageing [3] is one of the most accepted since it offers one of the best mechanisms to elucidate the degenerative processes as well as other age-related alterations, as age-related diseases [4]. This theory considers the implication of mitochondria as producers and targets of reactive oxygen species (ROS). ...
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Most studies on the effects of physical exercise have focused on its influence on muscle tissue, forgetting its interference in liver function. Ageing leads to the progressive impairment of hepatic functions. Several biochemical and bioenergetics parameters were determined to test the impact of a lifelong aerobic training program in the hepatic age-related and the development of an adaptative response. Liver samples were collected from 28 male Wistar rats (4-week-old, 159.4 ± 11.9 g at the beginning of the protocol), randomly distributed into two groups: non-exercised or exercised and submitted to a treadmill exercise program (60 min/day, 5 days/week, at 70% of maximal running speed), for 24 (n = 9) or 54 weeks (n = 10). A maximal running speed test was performed to determine the training speed. Antioxidant enzyme activity, cellular redox status, oxidative stress, mitochondrial respiratory chain enzymes and respiratory activity were performed in liver samples. Lifelong exercise decreased the age-associated decline in mitochondrial dysfunction, increasing the respiratory rate in state 2 (mitochondrial respiration stimulated by the substrate in the absence of added ADP) (p = 0.03) and citrate synthase enzymatic activity (p = 0.007). Complex II (p < 0.0001) and IV (p < 0.001) showed a decrease in enzymatic activity. Ageing-related oxidative stress was also attenuated by physical exercise, as showed by the increase in first-line defense antioxidant enzymes (superoxide dismutase (p = 0.07) and catalase (p = 0.03)), decreased lipid peroxidation levels (p = 0.864 for total fraction, p = 0,27 for mitochondrial fraction) and higher glutathione reduced/oxidized ratio (p = 0.02). According to our results, the regular practice of exercise can prevent the liver’s mitochondrial dysfunction and loss of antioxidant system efficacy that may arise from ageing, highlighting the benefit of lifelong aerobic exercise in preventing age-related hepatic impairment and associated diseases.
... It is important to note that excessive, prolonged, and strenuous overtraining can lead to damaging oxidative stress, with an attendant decrease in NO bioavailability. The concept of redox and exercise-induced hormesis has been advanced and previously reviewed; therefore, it appears that too much of a good thing may not necessarily be effective when it comes to EXER [80,[108][109][110][111][112]. ...
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The monolayer of cells that line both the heart and the entire vasculature is the endothelial cell (EC). These cells respond to external and internal signals, producing a wide array of primary or secondary messengers involved in coagulation, vascular tone, inflammation, and cell-to-cell signaling. Endothelial cell activation is the process by which EC changes from a quiescent cell phenotype, which maintains cellular integrity, antithrombotic, and anti-inflammatory properties, to a phenotype that is prothrombotic, pro-inflammatory, and permeable, in addition to repair and leukocyte trafficking at the site of injury or infection. Pathological activation of EC leads to increased vascular permeability, thrombosis, and an uncontrolled inflammatory response that leads to endothelial dysfunction. This pathological activation can be observed during ischemia reperfusion injury (IRI) and sepsis. Shear stress (SS) and pulsatile shear stress (PSS) are produced by mechanical frictional forces of blood flow and contraction of the heart, respectively, and are well-known mechanical signals that affect EC function, morphology, and gene expression. PSS promotes EC homeostasis and cardiovascular health. The archetype of inducing PSS is exercise (i.e., jogging, which introduces pulsations to the body as a function of the foot striking the pavement), or mechanical devices which induce external pulsations to the body (Enhanced External Pulsation (EECP), Whole-body vibration (WBV), and Whole-body periodic acceleration (WBPA aka pGz)). The purpose of this narrative review is to focus on the aforementioned noninvasive methods to increase PSS, review how each of these modify specific diseases that have been shown to induce endothelial activation and microcirculatory dysfunction (Ischemia reperfusion injury-myocardial infarction and cardiac arrest and resuscitation), sepsis, and lipopolysaccharide-induced sepsis syndrome (LPS)), and review current evidence and insight into how each may modify endothelial activation and how these may be beneficial in the acute and chronic setting of endothelial activation and microvascular dysfunction.
... After an injury, leucocyte subpopulations relocate to the impaired tissue for healing by discharging Reactive and Nitrogen-Oxygen Species (RONS). Besides, when an athlete's immune status is suppressed, an enhanced presence of pro-inflammatory cytokines occurs [9,10]. Cytokines, such as IL-6, play a central role in controlling inflammation, clearing antigens, and repairing tissue [11]. ...
Introduction: The present study aimed to review the acute and long-term variations in variables related to redox, inflammation and hormonal status in male footballers.
... To optimize the "beneficial outcomes", for example, a periodized approach to nutrition should be fully considered to adequately support exercise/training in order to achieve a balance between the potential for recovery and adaptation [6,12]. This might be partially supported by the concept of exercise-induced hormesis theory, which purports that biological systems respond with a bell-shaped curve [97,98]. Furthermore, the first half of the "stratification" of burst references (2014-2019) in Figure 6A reflects and corroborates this. ...
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Numerous studies have covered exercise-induced muscle damage (EIMD) topics, ranging from nutritional strategies to recovery methods, but few attempts have adequately explored and analyzed large volumes of scientific output. The purpose of this study was to assess the scientific output and research activity regarding EIMD and protein intake by conducting a bibliometric and visual analysis. Relevant publications from 1975–2022 were retrieved from the Web of Science Core Collection database. Quantitative and qualitative variables were collected, including the number of publications and citations, H-indexes, journals of citation reports, co-authorship, co-citation, and the co-occurrence of keywords. There were 351 total publications, with the number of annual publications steadily increasing. The United States has the highest total number of publications (26.21% of total publications, centrality 0.44). Institutional cooperation is mostly geographically limited, with few transnational cooperation links. EIMD and protein intake research is concentrated in high-quality journals in the disciplines of Sport Science, Physiology, Nutrition, and Biochemistry & Molecular Biology. The top ten journals in the number of publications are mostly high-quality printed journals, and the top ten journals in centrality have an average impact factor of 13.845. The findings of the co-citation clusters and major keyword co-occurrence reveal that the most discussed research topics are “exercise mode”, “nutritional strategies”, “beneficial outcomes”, and “proposed mechanisms”. Finally, we identified the following research frontiers and research directions: developing a comprehensive understanding of new exercise or training models, nutritional strategies, and recovery techniques to alleviate EIMD symptoms and accelerate recovery; applying the concept of hormesis in EIMD to induce muscle hypertrophy; and investigating the underlying mechanisms of muscle fiber and membrane damage.
... [28][29][30] In humans, it has been proposed that PA may intervene excitability and inhibition in the CNS, [31][32][33] and anti-inflammatory and antioxidant effects of regular PA might diminish the processes contributing to central sensitisation. [34][35][36] Other proposed mechanisms in humans include the activation of opioid and serotonin pathways 37 or involvement of endocannabinoid system 38 induced from regular PA which could exert analgesic effects. While further research is needed to elucidate how much and what type of PA can induce such changes to modulate pain, our results suggest that PA between 300 and 600 min per week may be sufficient for spinal conditions and upper extremity pain, with PA exceeding 750 min associated with higher likelihood of shoulder pain. ...
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Objective To explore the association of physical activity (PA) with musculoskeletal pain (MSK pain). Design Cross-sectional study Setting 14 countries (Argentina, Australia, Austria, Brazil, Chile, France, Germany, Italy, the Netherlands, Singapore, South Africa, Spain, Switzerland and the USA). Participants Individuals aged 18 or older. Primary and secondary outcome measures PA volumes were assessed with an adapted version of the Nordic Physical Activity Questionnaire-short. Prevalence of MSK pain was captured by means of a 20-item checklist of body locations. Based on the WHO recommendation on PA, participants were classified as non-compliers (0–150 min/week), compliers (150–300 min/week), double compliers (300–450 min/week), triple compliers (450–600 min/week), quadruple compliers (600–750 min/week), quintuple compliers (750–900 min/week) and top compliers (more than 900 min/week). Multivariate logistic regression was used to obtain adjusted ORs of the association between PA and MSK pain for each body location, correcting for age, sex, employment status and depression risk. Results A total of 13 741 participants completed the survey. Compared with non-compliers, compliers had smaller odds of MSK pain in one location (thoracic pain, OR 0.77, 95% CI 0.64 to 0.93). Double compliance was associated with reduced pain occurrence in six locations (elbow, OR 0.70, 95% CI 0.50 to 0.98; forearm, OR 0.63, 95% CI 0.40 to 0.99; wrist, OR 0.74, 95% CI 0.57 to 0.98; hand, OR 0.57, 95% CI 0.40 to 0.79; fingers, OR 0.72, 95% CI 0.52 to 0.99; abdomen, OR 0.61, 95% CI 0.41 to 0.91). Triple to top compliance was also linked with lower odds of MSK pain (five locations in triple compliance, three in quadruple compliance, two in quintuple compliance, three in top compliance), but, at the same time, presented increased odds of MSK pain in some of the other locations. Conclusion A dose of 300–450 min WHO-equivalent PA/week was associated with lower odds of MSK pain in six body locations. On the other hand, excessive doses of PA were associated with higher odds of pain in certain body locations.
... In particular, physical exercise can extend the peak of the hormesis curve, that is, it can extend or stretch the levels of reactive species associated with better physical functions. In this vein, moderate exercise, despite inactivity or overtraining, has been suggested to optimize the hormetic response (113). Indeed, recalling the bellshaped curve that defines the response of biological systems to stressors, Radak and colleagues (114) suggested that this hormesis curve (with physical function on Y-axis and levels of ROS on X-axis) can be interestingly evoked by PA. ...
The present work aims to link the redox and cell-centric theories of chronic processes in human biology, focusing on ageing. A synthetic overview of cellular redox pathways will be integrated by the concept of hormesis, which disruption leads to several physiopathological processes. The onset of age-related diseases due to the restriction of homeodynamic capacity will be herein considered in a redox fashion. Up-to-date arguments on hormetic agents, such as geroprotectors, dietary interventions, and physical exercise are refining the presented theoretical framework, integrated by insights from extracellular vesicles, microbiota, pollutants, and timing mechanisms. The broad concepts of exposome encompass the redox-based alteration of cellular hormesis for providing meaningful perspectives on redox biogerontology.
... Intensity, mode, and duration of exercise are key modulators of metabolic, cardiovascular, and central nervous systems [78][79][80]. Regular moderate-intensity exercise enhances endogenous antioxidant levels [81] and reduces lipid peroxidation in animals [82], whereas in schizophrenia patients, the duration of moderate physical activity per week was positively correlated with sleep quality [83]. In particular, acute moderate-intensity exercise improves sleep more than high-intensity aerobic exercise or high-intensity resistance exercise [84]. ...
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Background: (1) Sleep disorders are prevalent in coronary artery disease (CAD) patients and predict cardiac events and prognosis. While increased oxidative stress (OS) has been associated with sleep disorders, less is known about its relationship with sleep quality. Similarly, little is known of how this relationship might change with exercise, which can improve sleep quality. Factors of sleep quality, such as sleep duration and disturbances, are also important as they predict cardiovascular diseases better than a global score alone. This study investigated whether OS was associated with self-rated sleep quality and its factors before and after completing a 24-week exercise intervention. (2) Methods: CAD patients undergoing an exercise program were recruited. OS was measured at baseline by the concentrations of early- (lipid hydroperoxides, LPH) and late-stage (8-isoprostane, 8-ISO) lipid peroxidation products and their ratio. Sleep quality was measured by the self-reported Pittsburgh Sleep Quality Index (PSQI) instrument at baseline and termination. Three sleep factors-perceived sleep quality, sleep efficiency, and daily disturbances-were derived from the PSQI. (3) Results: Among CAD patients (n = 113, 85.0% male, age = 63.7 ± 6.4 years, global PSQI = 5.8 ± 4.0), those with poor sleep (PSQI ≥ 5) had higher baseline 8-ISO levels (F(1, 111) = 6.212, p = 0.014, ηp2 = 0.053) compared to those with normal sleep. Concentrations of LPH (F(1, 105) = 0.569, p = 0.453, ηp2 = 0.005) and 8-ISO/LPH ratios (F(1, 105) = 2.173, p = 0.143, ηp2 = 0.020) did not differ between those with poor sleep and normal sleep. Among factors, perceived sleep quality was associated with 8-ISO and 8-ISO/LPH, and daily disturbances were associated with 8-ISO. (4) Conclusions: A marker of late-stage lipid peroxidation is elevated in CAD patients with poor sleep and associated with daily disturbances, but not with other factors or with sleep quality and its factors after exercise intervention.
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Neuroinflammation occurs throughout the pathogenesis of Alzheimer’s disease (AD). Here, we investigated the effects of treadmill exercise on neuroinflammation in APP/PS1 transgenic AD mice and the potential involvement of microbe–gut–brain axis (MGB) mechanisms based on growing evidence that AD’s pathogenesis is correlated with a deterioration in the function of gut microbiota. APP/PS1 transgenic AD mice were subjected to 12 weeks of treadmill exercise, followed by spatial memory tests. After the behavioral study, the amyloid (Aβ) pathology, gut microbes and metabolites, bacterial lipopolysaccharide (LPS) displacement, and degree of neuroinflammation were analyzed. We found that this strategy of exercise enriched gut microbial diversity and alleviated neuroinflammation in the brain. Notably, exercise led to reductions in pathogenic bacteria such as intestinal Allobaculum, increases in probiotic bacteria such as Akkermansia, increased levels of intestine–brain barrier proteins, and attenuated LPS displacement. These results suggest that prolonged exercise can effectively modulate gut microbes and the intestinal barrier and thereby reduce LPS displacement and ultimately alleviate AD-related neuroinflammation.
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Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
Fatigue is a common presenting complaint in primary care offices. Nearly everyone experiences fatigue at one time or another, typically caused by overexertion or lack of sleep. Fatigue in the athlete is problematic as it may affect training and competitive performance. The possible causes of fatigue are widely varied, and the workup of fatigue can be very frustrating for the patient and physician alike. Making an accurate diagnosis is important to help the athlete return to effective training and maximal performance. Overtraining syndrome is a possible cause, but at this time remains a diagnosis of exclusion. (C) 2004 American College of Sports Medicine
Conference Paper
The ability of a cell, tissue, or organism to better resist stress damage by prior exposure to a lesser amount of stress is known as adaptive response. It is observed in all organisms in response to a number of different cytotoxic agents. One of these agents, oxidative stress, is known to induce an adaptive response in bacteria that is accompanied by the induction of many proteins. De novo protein synthesis is required for adaptive response to oxidative and other types of stress, indicating that newly synthesized protective proteins are necessary for adaptation. Adaptive response to oxidative stress also has been observed in mammalian cells. Several studies suggest it is necessary to first preexpose mammalian cells to a somewhat toxic oxidative stress in order to observe significant resistance to a subsequent highly lethal dose of oxidant. Cross-resistance of oxidatively stressed cells to other toxic agents including gamma- and X-irradiation, heat shock, aldehydes, heavy metals, MNNG, N-ethylmaleimide, and heme also has been reported. Understanding oxidant adaptive response in more detail and identifying the protective proteins involved may prove to be of clinical benefit.
Overtraining syndrome (OTS) is a major threat for performance and health in athletes. OTS is caused by high levels of (sport-specific) stress in combination with too little regeneration, which causes performance decrements, fatigue an possibly other symptoms. Although there is general consensus about the causes and consequences, many different terminologies have been used interchangeably. The consequences of overreaching and overtraining are divided into three categories: (i) functional overreaching (FO); (ii) non-functional overreaching (NFO); and (iii) OTS. In FO, performance decrements and fatigue are reversed within a pre-planned recovery period. FO has no negative consequences for the athlete in the long term; it might even have positive consequences. When performance does not improve and feelings of fatigue do not disappear after the recovery period, overreaching has not been functional and is thus called NFO. OTS only applies to the most severe cases. NFO and OTS could be prevented using early markers, which should be objective, not manipulable, applicable in training practice, not too demanding, affordable and should be based on a sound theoretical framework. No such markers exist up to today. It is proposed that psychomotor speed might be such a marker. OTS shows similarities with chronic fatigue syndrome and with major depression (MD). Through two meta-analyses, it is shown that psychomotor slowness is consistently present in both syndromes. This leads to the hypothesis that psychomotor speed is also reduced in athletes with OTS. Parallels between commonly used models for NFO and OTS and a threshold theory support the idea that psychomotor speed is impaired in athletes with NFO or OTS and could also be used as an early marker to prevent NFO and/or OTS.
Overtraining syndrome (OTS) occurs where an athlete is training vigorously, yet performance deteriorates. One sign of OTS is suppressed immune function, with an increased incidence of upper respiratory tract infection (URTI). An increased incidence of URTIs is also associated with high volume/intensity training, as well as with excessive exercise (EE), such as a marathon, manifesting between 3–72 hours post-race. Presently, there is no encompassing theory to explain EE and altered immune competence. Recently, it has been conclusively established that T helper lymphocytes (TH), a crucial aspect of immune function, represent two distinct functional subsets: TH1 and TH2 lymphocytes. TH1 lymphocytes are associated with cell-mediated immunity (CMI) and the killing of intracellular pathogens, while TH2 lymphocytes are associated with humoral immunity and antibody production. When TH-precursor cells are activated, the balance is tipped in favour of one or the other. Furthermore, the most appropriate means of determining the TH-subset, is by the prevailing cytokine ‘pattern’. This paper hypothesises that exercise-related immunosuppression is due to tissue trauma sustained during intense exercise, producing cytokines, which drive the development of a TH2 lymphocyte profile. A TH2 cell response results in simultaneous suppression of CMI, rendering the athlete susceptible to infection. Additionally, increased levels of circulating stress hormones (cortisol and catecholamines), as well as prostaglandin E2, support up-regulation of TH2 lymphocytes. Marathon-related data are presented to support this hypothesis. It is concluded that an increased incidence of illness associated with OTS and in response to EE is not due to immunosuppression per se, but rather to an altered focus of immune function, with an up-regulation of humoral immunity and suppression of CMI.
When prolonged, excessive training stresses are applied concurrent with inadequate recovery, performance decrements and chronic maladaptations occur. Known as the overtraining syndrome (OTS), this complex condition afflicts a large percentage of athletes at least once during their careers. There is no objective biomarker for OTS and the underlying mechanism is unknown. However, it is not widely recognised that OTS and clinical depression [e.g. major depression (MD)] involve remarkably similar signs and symptoms, brain structures, neurotransmitters, endocrine pathways and immune responses. We propose that OTS and MD have similar aetiologies. Our examination of numerous shared characteristics offers insights into the mechanism of OTS and encourages testable experimental hypotheses. Novel recommendations are proposed for the treatment of overtrained athletes with antidepressant medications, and guidelines are provided for psychological counselling.