Annotated Bibliography

Motricidade © Edições Desafio Singular

2017, vol. 13, n. 3, pp. 69-78 http://dx.doi.org/10.6063/motricidade.10049

Manuscript received at September 26 th

2016; Accepted at April 11 th

2017

1 Laboratory of Protozoan Biochemistry and Immunophysiology of Exercise, LIFE, Department of Microbiology, Immunology

and Parasitology, Faculty of Medical Sciences, University of the State of Rio de Janeiro, UERJ, Brazil

2 Post-Graduation Program in Exercise and Sport Sciences – UERJ – Brazil

3 Laboratory of Exercise Physiology, LAFIEX, Estácio de Sá University, UNESA, Rio de Janeiro, Brazil

* Autor correspondente: Rua Sargento João Lopes, 608, Ilha do Governador, Rio de Janeiro, Brasil, CEP: 21931-420.

Faculdades. E-mail: [email protected]

Chronic effects of exhausting exercise and overtraining on the immune response: Th1 and Th2 profile

Thiago Teixeira Guimarães1,2,3*, Rodrigo Terra1, Patrícia Maria Lourenço Dutra1,2

REVIEW ARTICLE

ABSTRACT Although physical inactivity figures as one of the main causes attributed to mortality, the damage caused

by excessive exercise is also a reality. Professional athletes, amateur or uncompetitive modalities

beneficiaries are often affected by deleterious conditions resulting from excessive exercise, such as

neurological, endocrine and immune origin. The thin line between losses and benefits of successive

fatiguing sessions effort depends on the understanding of concepts and methodological training

principles. Exercise may have a paradoxical relationship and its consistent prescription in terms of public

health depends on a better understanding of their cellular mechanisms. In this sense, the purpose of this

review was to explore a promising topic in sports science, able to contribute to elucidate such

mechanisms: Th1 and Th2 profile of the immune response related with chronic exhausting exercise and

overtraining.

Keywords: overtraining, exhaustion, immune system, physical activity, cytokines.

INTRODUCTION

Although the expectation of global life has

increased, the number of people affected by

chronic diseases, such as cardiovascular,

diabetes, several types of cancer, mental

disorders, bone and joint diseases has also

increased (Handschin & Spiegelman, 2008; Lee

et al., 2012). Physical inactivity figures as one of

the main causes attributed to mortality (Hallal

et al., 2012). According to the World Health

Organization (2012), in addition to causing

suffering, functional dependence, intangible

costs on health systems and reduced quality of

life, these diseases account for 58.5% of all

deaths worldwide.

On the other hand, the damage caused by

excessive exercise is also a reality. The intense

physical exercise can optimize performance and

health (Gohil & Brooks, 2012), however,

strenuous loads of mental and physical stress

can cause numerous deleterious conditions such

as overtraining syndrome, pathological

remodeling and heart arrhythmia, and muscular

and skeletal injuries. The immune imbalance

seems to be the origin of the problem (Smith,

2000). In this sense, the purpose of this review

is to explore a promising topic in sports science,

able to contribute to the elucidation of such

mechanisms: Th1 and Th2 profile of the immune

response related with chronic exhausting

exercise and overtraining. Few chronic studies

involving protocols of exhaustion and

overtraining were carried out to investigate the

change in the relationship between Th1 and Th2

cells. For such, the following topics will be

addressed: 1) Thin line between risks and

benefits of heavy physical exercise; 2) General

characteristics of the immune response; 3) Basic

considerations on the immune response to

exercise; 4) Chronic effects of exhaustive

exercise and overtraining: Th1 and Th2 profile; 5)

Physical inactivity, excessive exercise and public

health.

70 | TT Guimarães, R Terra, PML Dutra

Thin line between risks and benefits of heavy

physical exercise

Exercise has been considered a "polypill"

(Fiuza-Luces, Garatachea, Berger, & Lucia,

2013), able to promote numerous biological and

functional benefits. There are intense exercise

protocols potentially beneficial, such as high

intensity interval training, for example

(Burgomaster et al., 2008; Burgomaster,

Hughes, Heigenhauser, Bradwell, & Gibala,

2005; Gibala & McGee, 2008). It can be found

in the literature results pointing out that

maximum exercise active areas of the brain

limbic system, regions could be related to the

promotion of pleasure, emotions and rewards

(Guimarães et al., 2014; Guimarães &

Deslandes, 2014). Other positive examples of

high intensity exercise include the greater

impact on energy expenditure (and possibly on

body composition), in addition to the

overreaching, temporary exhaustion induced by

excessive training, followed by physiological

overcompensation and improvement of physical

fitness.

Meeusen et al. (2006) defined functional

overreaching as a short-term performance

decrement without severe psychological or other

lasting negative symptoms that eventually leads

to improvement in performance after days of

recovery (Meeusen et al., 2006). This condition

is relatively easy to be recovered in the short

term, between two and four weeks (Fry &

Kraemer, 1997; Fry, Morton, & Keast, 1991).

Meeusen et al. (2006) characterized

nonfunctional overreaching as a performance

decrement that can be reversed after weeks or

months of recovery, while a performance

decrement in overtraining syndrome can last

months to years. It has been proposed that

overreaching is a stage prior to overtraining

(Rogero, Mendes, & Tirapegui, 2005). Short

periods of rest between exercise sessions, in

addition to increases in volume and intensity of

training, can make the practitioner routine

increasingly exhausting (Rogero et al., 2005).

Individual differences in recovery time, ability to

perform and tolerate physical effort, the impact

of adverse weather conditions, lack of nutritional

planning (control of carbohydrates, amino acids

and hydration, for example) and other stressors

not related to training (sleep, diet, family,

studies, work, leisure, finances) may explain

why each practitioner has a different answer for

the same routine or training planning (Freitas,

Miranda, & Bara Filho, 2009; Wanner, Wilke, &

Duffield, 2016).

Amateur or professional athletes are often

affected by deleterious conditions resulting from

excessive exercise, such as neurological,

endocrine and immune. These changes are the

overtraining syndrome characteristics, involving

mood and anxiety disorders, depression, general

apathy, emotional instability, loss of appetite,

sleep disorders, hormonal changes, increased

heart rate at rest and increased vulnerability to

infection and injury in addition to muscle and

joint pain (Kellmann, 2010; Matta Mello

Portugal et al., 2013; Reardon & Factor, 2010;

Schaal et al., 2011). Overtraining can be defined

as a condition of poor adaptation to a chronic

period of excessive stress caused by physical

exertion, resulting in the development of the

syndrome, compromising the health and sports

performance (Kreher & Schwartz, 2012).

The prevalence of the overtraining is rarely

studied, but it is estimated that 60% of

marathoners, 50% of football players and 33% of

basketball players have experienced its

symptoms (Armstrong & VanHeest, 2002).

However, frequently, fitness programs for people

who do not aim the competition involving

endurance exercise, strength and speed also

cause undesirable acute or chronic damage and

side effects (Rogero et al., 2005). One of the

most common symptom or consequence of the

muscle damage suffered by beginners is the

delayed onset muscle soreness, characterized as

a feeling of discomfort in the skeletal muscle,

which occurs a few hours after exercise,

triggered by inflammation from excessive

overloads (Foschini, Prestes, & Charro, 2007;

Tricoli, 2001). In addition to beginners, severe

stress caused by physical exertion in non-

competitive environment can also lead to

extreme complications, as in the study of case

presented in 2011, during the annual meeting of

the American College of Sports Medicine

(Hadeed, Kuehl, Elliot, & Sleigh, 2011). Three

Exhausting exercise and overtraining on the immune response | 71

days after a session of intense exercise, based on

the Crossfit method, a 33 year old male,

previously asymptomatic and physically active,

experienced a condition of rhabdomyolysis

(Hadeed, Kuehl, Elliot, & Sleigh, 2011). This

syndrome is characterized by damage to the

skeletal muscles, the result of extravasation of

intracellular content (Criddle, 2003; Lopes &

Costa, 2013). Microtraumas from exercise may

include disruption of extracellular matrix,

basement membrane, and the sarcolemma,

resulting in the release of intracellular proteins

such as myoglobin, lactate dehydrogenase,

aspartate aminotransferase and creatine kinase

(CK), for example, into the bloodstream

(Catanho da Silva & Macedo, 2011; Lazarim et

al., 2009). When the stress caused by physical

effort is controlled, the degenerative

microtrauma are followed by a regenerative

tissue repair phase resulting in remodeling of

damaged tissue (Catanho da Silva & Macedo,

2011; Smith, 2004). However, excessive stress

can result in muscle weakness, myalgia, nausea,

renal failure or even lead to death (Lopes &

Costa, 2013).

Excessive endurance exercise in people with

different levels of physical fitness, as well as

muscular and skeletal injuries, can induce

pathological remodeling of the heart structures

and adjacent arteries (O'Keefe et al., 2012).

Marathons, ultramarathons, triathlons, too long

bike races, can cause acute volume overload in

the atria and ventricles, with transient decreases

in ventricular ejection fraction and cardiac

biomarker elevations, which return to normal

within a week. Over months and years of

repetitive stress, this process may result in

fibrosis of the myocardium, particularly in atria,

ventricles and interventricular septum, which

may develop fibrillations and arrhythmias

(O'Keefe et al., 2012; Patil et al., 2012).

The desirable effects of exercise seem to

depend on an adequate dose, or a dose that

cannot cause side effects. Excessive exercise can

damage health of practitioners from many

different levels of physical fitness and sports

purposes, inducing a reduction in physical

performance and ends the competitive athlete's

career early. Table 1 summarizes possible risks

and benefits of exercise in prolonged durations,

extreme loads and/or high frequency.

Table 1

Summary of risks and benefits of exercise in prolonged durations, extreme loads and/or high frequency.

Potential Benefits Potential Risks

Overreaching; Overtraining syndrome, cellular and functional lesions;

Increased caloric expenditure, reduced body fat; Pathological remodeling of the heart and arrhythmias;

Activation of the limbic system of brain rewards,

pleasure.

Loss of performance and health;

Reduction of adherence to exercise, physical inactivity

and development of chronic diseases.

General characteristics of the immune

response

The immunological response may be

understood in two steps: innate and adaptive

response. The innate response includes physical

barriers (i.e., skin), chemical (i.e., tear

complement system) and the participation of

cells such as macrophages, neutrophils,

dendritic cells, natural killer cells (NK) and

microbicides molecules such as nitric oxide

(NO) and superoxide anion (O2-). The adaptive

immune response involves mainly T (TCD4 +

and TCD8 + ) and B lymphocytes and their

products, cytokines and antibodies, respectively.

It can be divided into humoral (mediated for

antibodies) and cellular immune response (cell-

mediated, such as T lymphocytes and

macrophages). The TCD4 + lymphocytes

(helper/helper-Th0) can differentiate into

various cell subpopulations as Th1 (T helper type

1) and Th2 (T helper type 2), that produce

different standards of cytokines (Del Prete,

2008; Romagnani, 1991; Terra, Silva, Salerno, &

Dutra, 2012). The differentiation of TCD4 + in

Th1 lymphocytes can be stimulated by

interleukin 12 (IL-12) produced by antigen-

presenting cells (macrophages and dendritic

cells), whereas differentiation into Th2 is

induced by autocrine action of IL-4 produced by

72 | TT Guimarães, R Terra, PML Dutra

TCD4 + . The Th1 cells predominantly produce

interferon-gamma (IFN-γ) and are related to

cellular immune response control caused by

intracellular microorganism’s infections. The Th2

cells produce mainly IL-4 and are related to the

humoral immune response and control of

extracellular infections. Various factors such as

predominant cytokines in the activation

microenvironment, costimulatory molecules, the

type of antigen and early events occurring during

the innate immune response involving dendritic

cells and NK cells can drive predominant

response, determining control or not of an

infection (Ostrowski, Rohde, Asp, Schjerling, &

Pedersen, 1999; Pedersen & Febbraio, 2008;

Pedersen & Hoffman-Goetz, 2000; Terra et al.,

2012).

Basic considerations on the immune response

to exercise

According to the American College of Sports

Medicine, aerobic activities ranging from 40 to

59% of VO2max, 55 and 69% of maximum heart

rate and 12-13 on the Borg scale are considered

moderate, while aerobic activities ranging from

60 to 84% of VO2max, 70 and 89% of maximum

heart rate and 14-16 on the Borg scale are

considered high intensity (ACSM, 1998;

Febbraio & Pedersen, 2002; Pedersen &

Febbraio, 2008). The International Society of

Exercise and Immunology (ISEI), in its official

position, points out that immune dysfunction

observed after exercise is more pronounced

when the effort is continuous, prolonged (> 1.5

hours) and held in intensity ranging from

moderate to high (55 and 75% of VO2max)

(Pedersen et al., 2003; Walsh et al., 2011).

During and immediately after the exertion

the leukocytes appear to suffer an increase

(transient leukocytosis), followed by a fall

(leucopenia) (Catanho da Silva & Macedo,

2011). The period in which agents of the

immune system are suppressed after the

exhaustion caused by a training session or

competitive event is known as the "window of

opportunity" (Febbraio & Pedersen, 2005). The

increased risk of respiratory tract infections or

other deleterious condition from the opportunity

for pathogens may vary within one to nine hours

(Pedersen & Fischer, 2007), 72 hours

(Steensberg et al., 2000) or even two weeks

(Fischer et al., 2004). In addition, it has been

hypothesized that overtraining begins at the

time when new strenuous exercise sessions are

performed without the necessary time to recover

from immunosuppression (Nielsen & Pedersen,

2008).

Mechanical, hormonal and metabolic factors

can modulate the immune response to exercise

(Costa Rosa & Vaisber, 2002). As examples of

mechanical factors, hypoxia, hyperthermia and

muscle injury are capable of generating a

localized inflammatory process (Costa Rosa &

Vaisber, 2002). Overtraining induced by

downhill running training sessions is associated

with DNA damage in peripheral blood and

skeletal muscle cells, with oxidative stress in

skeletal muscle cells and total blood (Pereira et

al., 2013). DNA damage observed in

lymphocytes, provoked by strenuous exercise,

may compromise immune function (Dong et al.,

2011; Wierzba, Olek, Fedeli, & Falcioni, 2006).

The hypothalamus is the structure

responsible for coordinating responses resulting

from the interaction between the nervous

system and secretory glands of hormones

(cortisol and growth hormone, for example). Its

action changes when there is a neuroendocrine

imbalance (Mackinnon, 2000; Meeusen et al.,

2004; Smith, 2004). Cytokines are able to

modulate the activity of the hypothalamic-

pituitary-adrenal axis and other areas of the

brain responsible for mood control and anxiety.

Activation of the autonomic nervous system and

the hypothalamic-pituitary-adrenal axis together

with suppression of the hypothalamic-pituitary-

gonadal axis can be governed by cytokines such

as IL-1β, IL-6 and TNF-α representing

consequences related to the overtraining

syndrome (Smith, 2000). Athletes with chronic

pain have enhanced production of IL-1, IL-2,

TNF-α and IFN-γ and reduced performance in

the ergospirometric test (Vaisberg, de Mello,

Seelaender, dos Santos, & Costa Rosa, 2007).

In relation to metabolism, during catabolic

states like infections, surgeries, traumas,

acidosis and strenuous physical exercises,

plasma glutamine undergoes a reduction

Exhausting exercise and overtraining on the immune response | 73

(Mackinnon, 2000), correlating with an increase

in symptoms of upper respiratory tract

infections (dos Santos, Caperuto, de Mello, &

Costa Rosa, 2009). Several studies have shown a

decrease in plasma glutamine concentration

after exhaustive exercise in humans and animals

(Bassit, Sawada, Bacurau, Navarro, & Costa

Rosa, 2000; Castell, 2002; dos Santos et al.,

2009; Koyama, Kaya, Tsujita, & Hori, 1998;

Walsh, Blannin, Robson, & Gleeson, 1998), as

well as in the presence of overtraining syndrome

(dos Santos et al., 2009; Parry-Billings et al.,

1992; Rowbottom, Keast, Goodman, & Morton,

1995). Macrophages use high rates of glutamine

to generate energy and biosynthesis (dos Santos

et al., 2009). Mice submitted to moderate and

strenuous eight weeks training protocols,

relative to sedentary control, suffered an

increase in macrophage post-exercise function,

which was supported by enhanced glutamine

consumption and metabolism (dos Santos et al.,

2009).

Insulin metabolism also appears to be

compromised by overtraining status, affecting

factors related to immune function (Pereira et

al., 2014). Besides the liver suffer an up

regulation of gluconeogenesis, promoting a

high-caloric state and redirecting even more

amino acids (like glutamine) to this function,

insulin presents its metabolism altered. An

eight-week protocol involving three groups of

rats under different training combinations

(sedentary, moderate, and strenuous), evidenced

an impaired insulin signaling pathway with

concomitant increases in enzymatic complex

linked to the cellular response to inflammation,

the stress-activated protein kinases/Jun

aminoterminal kinases and the suppressor of

cytokine signaling 3 (SOCS3) (Pereira et al.,

2014).

Chronic effects of exhaustive exercise and

overtraining: Th1 and Th2 profile

Even if several studies associate extreme

exercise damages with immunosuppression, the

increase in incidence of disease is not exclusive

of immunosuppression, but, above all, a change

in the immunological profile, from an increase in

humoral immunity coupled with the suppression

of cellular immunity (Lakier Smith, 2003).

While the moderate intensity exercise promotes

a protection against infections caused by

intracellular microorganisms, because it directs

the immune response to the predominance of a

response profile of Th1 type, vigorous activities

generate increasing concentrations of anti-

inflammatory cytokines. This condition

promoting the predominance of a Th2 response

profile, in order to decrease the muscle tissue

damage resulting from inflammation, although

this may result in increased susceptibility to

infections (Terra et al., 2012).

Data collected by Terra et al. (2013) showed

that lymph nodes cells from mice submitted to

swimming activity of moderate intensity for 12

weeks presented an elevation in IFN-γ and TNF-

α concentrations and IL-4 and IL-10 significantly

decreased compared to sedentary group. These

data suggest that moderate exercise promote the

predominance of a protective immune response

type Th1 in mice (Terra et al., 2013). On the

other hand, a review written by Smith (2000)

suggests that trauma generated in muscle and

skeletal system, from the extreme stress

provoked by exercise, produce large amounts of

proinflammatory cytokines such as IL-1β, IL-6

and TNF-α (Smith, 2000). The positive feedback

of the anti-inflammatory components becomes

imminent and the imbalance in Th1 and Th2

profile can reflect a disturbing condition of

homeostasis. Successive chronic stimuli,

without proper recovery of stable physiological

state, may develop symptoms related to

overtraining.

Few studies, however, have tested the

hypothesis that Th1 and Th2 profile are

chronically altered by overtraining. There are

ethical limitations in studies with humans and

animals, therefore, are more frequently used.

Despite the different protocols of chronic

exhaustion and populations used, the results

indicate a predominance of the Th2 response on

Th1.

Protocols of four to six days of exhaustion.

Mice experienced a suppression in antigen

presentation by macrophages three and 24 hours

after four days of exhaustive training when

74 | TT Guimarães, R Terra, PML Dutra

compared to moderate group (Ceddia & Woods,

1999). Macrophages are antigen presenting cells

capable of causing differentiation of TCD4 +

lymphocytes into Th1. The authors suggested

that cellular immunosuppression is a

consequence in reducing differentiation of Th1

new cells, causing an imbalance in Th1 and Th2

profile. In another study, seven cyclists under six

days of intensified training also experienced an

imbalance in the ratio Th1/Th2 immediately after

an exhaustive effort session and the end of two

weeks of rest (Lancaster et al., 2004). It was

observed a reduction in IFN-γ while IL-4

remained unchanged. Therefore, the ratio IFN-

γ/IL-4 reduced with severe stress and was

associated with the window of opportunity

(Lancaster et al., 2004).

Studies with longer intervention time

(overtraining).

The study of Ru and Peije (2009) found that

eight rats submitted to nine weeks of

progressive training, six days a week, provoked a

cellular immunosuppression by predominance of

Th2 response, reduced systemic hemoglobin

concentration and decreased in testosterone and

corticosterone 36 hours after the last training

session. Seven days after the last session, the

authors found in the spleen a reduction of

natural killer T cells and IFN-γ in addition to IL-

4 increased, unbalancing the ratio Th1/Th2

through IFN-γ/IL-4 compared to the control

group (Ru & Peijie, 2009).

Farhangimaleki et al. (2009) found in cyclists

that combined a maintenance of intensity with a

decrease in the duration (tapering) within one to

three weeks, immediately after eight weeks of

training with increasing volume, an

improvement in performance compared to a

control group. The control group, who trained

for eleven weeks progressively from the first to

the eleventh, did not improve performance as

well as IL-1 β , IL-6 and TNF-α increased in

relation to tapering group. Although the authors

did not evaluate the Th2 profile, the findings

suggested the importance of tapering period to

prevent disturbances in physiological

homeostasis, risk of infections and fatigue

(Farhangimaleki, Zehsaz, & Tiidus, 2009).

Figure 1. Excessive chronic stress caused by

physical training generates an imbalance in Th1 and

Th2 profile with predominance in Th2, cellular

immunosuppression, increased susceptibility to

infections, signs and symptoms of overtraining. The

sedentary condition, studied through control groups

without exercise, also represents risks to cellular

immunity and health. Moderate training seems to

promote the balance between Th1 and Th2 with

predominance in Th1, generating a cellular

immunoprotected response.

Gholamnezhad et al. (2014) investigated the

effect of eight weeks of moderate training and

eleven weeks of severe training (overtraining),

immediately, 24 hours and two weeks after in

the plasma concentration of cytokines. Although

TNF-α has increased in overtraining and

overtraining post two weeks recovery, IL-10 and

IL-4 increased in both conditions, and IFN-γ

increased just at moderate group. Even though

the authors have not shared the results of

physical capacity, moderate training promoted

cellular immunity while in other groups,

including the control, was observed cellular

immunosuppression (Gholamnezhad,

Boskabady, Hosseini, Sankian, & Khajavi Rad,

2014). These groups had a response directed to

the Th2 profile while the response of moderated

group was directed to the Th1 profile. In this

study, two weeks of recovery (tapering) were

not enough to reverse the cellular

immunosuppression, as the findings of

Exhausting exercise and overtraining on the immune response | 75

Farhangimaleki et al. (2009). Figure 1

summarizes the changes of different types of

chronic stress caused by physical training in Th1

and Th2 profile.

Overtraining can be seen as the third stage of

the General Adaptation Syndrome, originally

described by Hans Selye in 1936. The depletion

stage (third stage) refers to recover for survival,

unlike the latter, in which the body resists the

alarm (first stage) and adapts. The third stage is

to protect the body against excessive

physiological stress. The signs and symptoms of

overtraining syndrome are the positive

precaution point of view against even more

severe damage (Smith, 2000). Numerous models

to explain the mechanisms of acute and chronic

fatigue have been developed, but few discuss the

relationship of cytokines between the need to

repair and regulate afferent feedbacks that

process signals that might lead to sensations and

feelings of exhaustion (Vargas & Marino, 2014).

The organism requires absolute repose and

negative changes in Th1 and Th2 profile appear to

help the immune system to repair even greater

injuries.

Physical inactivity, excessive exercise and

public health

According to the concept of Hormesis

favorable biological responses generally occur

due to the properly controlled exposure to

stressful stimuli (Radak, Chung, & Goto, 2008).

In the context of public health, not only physical

inactivity should figure as the main concern. The

exercise has been considered a miracle drug

because there is epidemiological evidence to

corroborate this statement. However,

experimental studies question the effectiveness

of any configuration of a physical training

program in relation to the intensity and

duration. Regular exercise has benefits before

the development of overtraining, however,

according to Farhangimaleki et al. (2009),

overtraining is a poorly understood process.

The state of physical and mental exhaustion

not only impairs performance. Its signs and

symptoms are consistent with the development

of damage to health similar to chronic

noncommunicable diseases. The difference

between medicine and poison is the dose. With

physical exercise does not seem to be different.

In this context, we suggest more attention of

researchers and policy makers not only to

physical inactivity, but at the excessive exercise.

The immune imbalance and cellular

immunosuppression represent a promising topic

in sports science that can help broaden the

understanding and discussion of the paradox of

exercise.

CONCLUSION

Chronic exhaustive training may cause the

imbalance in Th1 and Th2 profile with

predominance in Th2, resulting in cellular

immunosuppression, increased susceptibility to

infections, inflammation, signs and symptoms of

overtraining. On the other hand, the moderate

training seems to promote the balance between

Th1 and Th2 with predominance in Th1,

generating a cellular immunoprotection.

Acknowledgments:

Nothing to declare

Conflict of interest:

Nothing to declare

Funding:

Nothing to declare

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