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: thiagotguimaraes@yahoo.com.br
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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