Baygutalp et al. 
BMC Sports Science, Medicine and Rehabilitation          (2021) 13:145  
https://doi.org/10.1186/s13102-021-00375-0
RESEARCH
Impacts of different intensities of exercise 
on inflammation and hypoxia markers in low 
altitude
Fatih Baygutalp1*, Yusuf Buzdağlı2, Murat Ozan3, Mitat Koz4, Nurcan Kılıç Baygutalp5 and Gökhan Atasever6 
This study will be presented as an oral presentation in Eastern Black Sea Rheumatology Days on 18-19 
December 2021 in Turkey.
Abstract 
Background: This study aims to determine and compare the effects of exercise modalities with different intensities 
on the secretion of key inflammation and hypoxia markers in amateur athletes.
Methods: Twenty-three athletes with a mean age of 20.1 years, living at low altitude (1850 m) participated in this 
study. The participants’ maximal oxygen consumption values  (VO2 max) were determined with an incremental cycle 
exercise test as 54.15 ± 6.14 mL kg  min−1. Athletes performed four protocols: at rest, 50%  VO2 max, 75%  VO2 max 
and 100%  VO2 max (until exhaustion) with one-week intervals. 50%  VO2 max, 75%  VO2 max sessions were performed 
continuously for 30 min on a bicycle ergometer and 100%  VO2 max session was performed by cycling until exhaus-
tion. Blood samples were obtained at rest and immediately after each exercise session. Serum tumor necrosis factor 
alpha (TNF-α), C-reactive protein (CRP), interleukin-10 (IL-10), and hypoxia inducible factor-1 alpha (HIF-1α) levels were 
measured.
Results: There were significant differences in serum TNF-α levels in 75%  VO2 max and 100%  VO2 max sessions 
(489.03 ± 368.37 and 472.70 ± 365.21 ng/L, respectively) compared to rest conditions (331.65 ± 293.52 ng/L). Serum 
CRP levels of 50%  VO2 max and 75%  VO2 max sessions (1.19 ± 0.50; 1.07 ± 0.52 mg/L) were significantly higher 
than the rest condition (0.74 ± 0.35 mg/L). There were significant differences in serum IL-10 levels of rest condition 
and 50%  VO2 max; 50%  VO2 max, and 100%  VO2 max sessions (328.09 ± 128.87; 446.36 ± 142.84; 347.44 ± 135.69; 
324.88 ± 168.06 pg/mL). Serum HIF-1α levels were significantly higher in 75% VO2 max session compared to rest 
(1.26 ± 0.16; 1.08 ± 0.19 ng/mL) (P < 0.05 for all comparisons).
Conclusions: Both inflammatory and anti-inflammatory pathway is induced on different exercise intensities. Exer-
cise protocols performed until exhaustion may lead to activation of inflammatory pathways and hypoxia-induced 
damage.
Keywords: Anti-inflammatory cytokine, Exercise, Health, Hypoxia, Pro-inflammatory cytokine
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Background
The optimal exercise type and intensity should be care-
fully determined, particularly in acute exercise protocols. 
While moderate exercise generally improves immune 
function, excessive amounts of prolonged, high-intensity 
Open Access
*Correspondence:  drbaygutalp@gmail.com
1 Department of Physical Medicine and Rehabilitation, Ataturk University 
Faculty of Medicine, Erzurum, Turkey
Full list of author information is available at the end of the article
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Baygutalp et al. BMC Sports Science, Medicine and Rehabilitation          (2021) 13:145 
exercise may lead to impairments in immune function 
[1]. There are promising results from comparison stud-
ies demonstrating the equality or superiority of high-
intensity intermittent training (HIIT) programs over 
low-intensity regular exercise programs based on car-
diorespiratory and metabolic parameters [2–4]. For this 
reason, there is a growing interest in the studies with 
high-intensity intermittent training protocols since this 
training type is considered helpful for people who cannot 
exercise regularly, and HIIT protocols are time efficient 
[5, 6].
Exercise and intense training affect hormonal release, 
creating adaptive responses that will facilitate the organ-
ism to cope with exercise stress [7]. Further, exercise 
may be considered as a medicine against metabolic syn-
drome. The inflammatory response is the body’s reaction 
and defence against homeostasis disorders, particularly 
infection and injury [8]. It has long been recognized that 
exercise is related to anti-inflammatory pathways [9, 10]. 
However, the pro-inflammatory pathway may be acti-
vated, in eccentric exercise protocols [11, 12]. Therefore, 
optimal exercise protocol should be used for athletes and 
sedentary people to improve outcomes and prevent mus-
culoskeletal damages, cardiovascular, neurological, and 
endocrinological side effects [13, 14].
The release of pro-inflammatory cytokines and anti-
inflammatory cytokines into the circulation in response 
to exercise varies according to exercise type, duration, 
and intensity [1, 13].
Tumor necrosis factor alpha (TNF-α) is an essen-
tial mediator of the acute inflammatory response [15]. 
Interleukin-10 (IL-10) is one of the most important anti-
inflammatory cytokines [5]. Increased serum TNF- α 
and C-reactive protein (CRP) levels and decreased IL-10 
levels can be regarded as typical signs of a pro-inflamma-
tory state [9]. In addition, the IL-10/TNF-α ratio can be 
used as an indicator of the beneficial effects of exercise 
[16]. Many studies investigate the inflammatory response 
in exercise [11, 12] or training sessions [9, 17], and the 
results are inconsistent. These inconsistencies may arise 
from various exercise or training protocols (type, dura-
tion and intensity), blood sampling timing, lack of con-
trol group, small sample sizes, ethnicity and biological 
variations.
CRP is the main acute phase protein in tissue damage 
and other inflammatory conditions and is a sensitive and 
objective marker [18]. As a result of a systematic review 
on CRP, it was found that in trained athletes, when a 
single exercise protocol was applied, CRP temporarily 
increased as the acute phase response after exercise. In 
contrast, those who did higher levels of physical activity 
in longitudinal studies had lower CRP levels. In this con-
text, although physical activity has been found to raise 
the CRP level acutely, it has been found that chronically 
physical activity reduces CRP levels [19].
Hypoxia is one of the stress factors that can promote 
the inflammation process, including pro-inflammatory 
and anti-inflammatory pathways. Also inflammatory tis-
sues usually become hypoxic [20]. Hypoxia or decreased 
oxygen levels result in many changes at the cellular 
level, including mitochondrial biogenesis and angio-
genesis in rest [21, 22] and exercise conditions [23]. 
Peroxisome 
proliferator-activated 
receptor-gamma 
coactivator 1 alpha (PGC-1α), hypoxia-inducible fac-
tor-1 alpha (HIF-1α) and vascular endotheial growth 
factor (VEGF) play key roles in these adaptation mecha-
nisms. HIF-1α is a hypoxia-induced transcription factor 
that transcribes more than 100 enzymes and proteins 
involved in cellular responses caused by hypoxia [24].
There is a relationship between the body’s response 
to inflammation or exercise stress and its response to 
hypoxia, and in both cases, the hypoxia-inducible factor-
1a (HIF-1a) signaling pathway can be induced [25]. It is 
known that both exercise and hypoxia can alter mRNA 
expression and protein release of pro-and anti-inflam-
matory cytokines, activate lymphocytes, alter chemokine 
receptors, or induce other signaling pathways of the 
hypoxic inflammatory response [26, 27].
This study was conducted in a low altitude (1850  m) 
city [28], which is the highest city of Turkey. People living 
in altitudes higher than sea level have reduced hypoxic 
ventilatory response, decreased pulmonary hyperten-
sion under hypoxia, increased heart rate, and improved 
peripheral oxygen saturation [29]. The fact that the 
hypoxia and inflammatory responses were evaluated on 
different exercise intensities and that the study was con-
ducted in a low altitude region is prominent in our study. 
For these reasons, in this study, the acute effects of exer-
cise intensity on hypoxia and inflammatory responses in 
an amateur athlete group living in a low altitude region 
were investigated. The combined effects of hypoxia 
marker and exercise on inflammatory pathways were 
assessed.
Methods
Twenty-three amateur male athletes (soccer) living at 
low altitude (1850  m), training 2  h/day, 5  days/week, 
were included in this study. Inclusion criteria were; to 
be an amateur athlete between the ages of 18–22, male 
gender, living in this location for at least 5  years, vol-
unteering to participate in research being healthy and 
not having a chronic or acute illness. Exclusion criteria 
were; having any chronic disease, using any medication 
or stimulants, smoking and alcohol use, having limitation 
of movement due to injury for any reason. Twenty-three 
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people who met the inclusion criteria were included to 
the study. Demographical characteristics of athletes are 
given in Table 1. Athletes were evaluated at rest and at 
three different exercise intensities: 30 min of exercise on 
a bicycle ergometer at 50% of the predetermined maxi-
mal oxygen consumption capacity  (VO2 max) values, 75% 
of the predetermined  VO2 max and exercise at 100%  VO2 
max-until the individual is exhausted. Venous blood sam-
ples were taken at rest state (1st session) and immediately 
after each exercise sessions (2nd, 3rd and 4th sessions).
Ethical ıssues
The informed consent form was obtained from all partic-
ipants, and they were enlightened with all matters related 
to the study. The study was approved by the Clinical 
Research Ethics Committee of Ataturk University Faculty 
of Medicine (27.05.2021).
Study design
The study design is summarized in Fig. 1. 2nd session can 
be defined as mild intensity exercise (50% for 30  min), 
3rd session as moderate-intensity exercise (75% for 
30 min) and 4th session as high-intensity exercise (100% 
to exhaustion).
Exercise sessions were carried out at one-week inter-
vals to prevent physiological adaptation.
Data collection
Demographical characteristics and height measurement
The athletes’ ages in the study were recorded based on 
their identity information, and the sports ages based on 
their declarations. The height of the athletes was meas-
ured with a mechanical measuring rod (Seca 216, Medis-
ave UK Co., UK).
Body composition measurement
Body composition parameters (weight and body fat per-
centage) were measured with the BOD POD body com-
position tracking system (Cosmed, USA). Body mass 
index (BMI) was calculated with the following formula: 
BMI = weight/height2 (kg/m2).
Maximal oxygen consumption capacity  (VO2 max) 
measurement (pre‑test − incremental cycle exercise test)
The participants were subjected to a maximal exercise 
test with an exercise protocol with increasing intensity 
following the test completion criteria used in the bicycle 
Table 1 Demographical characteristics of athletes
SD: standart deviation, CI: confident interval, BMI: body mass index, BFP: body 
fat percentage,  VO2 max: maximal oxygen consumption
Male athletes (n = 23)
Mean ± SD
95% CI
Age (year)
20.12 ± 0.15
13.51–26.49
BMI (kg/m2)
23.44 ± 1.29
22.44–23.56
BFP
15.19 ± 7.19
11.89–18.11
Sports age (year)
10.21 ± 2.31
9.00–11.00
VO2 max (mL kg  min−1)
54.15 ± 6.14
51.34–56.66
Fig. 1 Study design
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Baygutalp et al. BMC Sports Science, Medicine and Rehabilitation          (2021) 13:145 
ergometer protocols used for maximal oxygen consump-
tion capacity and power measurements.
Participants first cycled on the bicycle ergometer for 
5 min (50–60 RPM) to warm up. Then, the warming was 
completed by stretching for 2 min. As soon as the par-
ticipant is fully ready, the test is started with the start 
command and the continuously increasing load test is 
applied. The participant started the test at 60 revolutions 
per minute and by pedaling at 150 watts. Then, 30 watts 
were increased every 2 min, and the trial continued until 
the test pedal speed fell below 50 revolutions per minute 
or the subject could not continue anymore. The Rating 
of Perceived Exertion (RPE) was defined with the Borg 
scale to determine the  VO2 max of the participants [30]. 
Participant-reported Borg scale scores were used at each 
load-increasing phase of the exercise test in the first ses-
sion they visited the laboratory and immediately after 
each session.
The observation of three of the criteria simultaneously 
was accepted to indicate that the maximal oxygen use 
capacity was reached, then the test was terminated. The 
criteria were; reporting a Borg scale score of 20 by the 
participant, the oxygen consumption does not increase 
despite the increase in workload, the ratio of carbon diox-
ide production to oxygen consumption RER (respiratory 
exchange ratio) reaches 1.15 and above, the heart rate is 
85% and above the maximum number of heart rates, the 
increase in the number of heart rates despite the increas-
ing workload [31]. In the gas analysis, minute ventila-
tion (VE), oxygen volume per minute  (VO2), produced 
carbon dioxide volume  (VCO2) per minute were directly 
measured and recorded. At the same time, the heart rate 
(HRmax) at which the athletes reached the maximal oxy-
gen use and the perceived difficulty values  at each step 
of increase were also recorded. Before the measurement 
sessions, the Cosmed K5 oxygen analyzer was calibrated 
with high-grade calibration gases provided by the man-
ufacturers. Gas was pumped from the flow meters with 
a 3-L calibration syringe following the manufacturer’s 
recommendations and heated for a minimum of 15 min. 
Mask size was determined individually before the first 
test, and measurements were taken with the same size in 
subsequent sessions.
Exercise protocols
All of the test protocols were carried out in our univer-
sity’s Sports performance laboratory and measurement 
center. Athletes were not allowed to perform vigorous 
exercise, using drugs, caffeine, alcohol and performance-
enhancing ergogenic supplements from 48  h before 
exercise protocols. Before starting exercise protocols 
(pre-test), the participants’ maximal oxygen consumption 
values  (VO2 max) were determined using the oxygen 
analyzer K5 (Cosmed, USA) as a pre-test with the gradu-
ally increasing load exercise test on the bicycle ergom-
eter. Participants were required to cycle continuously 
for 30 min on a bicycle ergometer at 50% and 75% of the 
predetermined maximal oxygen consumption capacity 
values.
Finally the participants were required to cycle at 
100%  VO2max until exhaustion.The term 100% VO2 
max defines the situation when the participant reaches 
exhaustion during exercise. [32]. The mean time to 
exhaustion of athletes was 16.35 ± 3.38  min. Venous 
blood samples were taken immediately after each session. 
All measurements were taken at the same time of day 
(morning time).
Biochemical analysis
5  mL of venous blood samples were taken from each 
athlete. After the serum was obtained, the samples were 
aliquoted and stored at -80 C° until analysis. Serum CRP, 
TNF-α, interleukin-10 and HIF-1α levels in all samples 
were analyzed by ELISA method with commercial kits 
(Bioassay Technology Laboratory-BT Lab, China pro-
duced all kits). Samples were collected once and meas-
ured duplicated.
Sample size calculation
The minimum number of patients required for the study 
was calculated in the G Power sample calculation pro-
gram (version 3.1.9.4) at the level of Type I error (α) 0.05) 
and Type II error (1-β) 0.95, with an effect size (Cohen’s 
f) of 0.4 (large) for a priori calculation of ANOVA test for 
4 repeated groups. Accordingly, the minimum number of 
samples was determined as 16. We included 23 partici-
pants to the study, in order to prevent a limitation caused 
by small sample size.
Statistical analyses
Statistical analysis was performed in SPSS 23.0 pack-
age program. Kolmogorov–Smirnov test was used to 
determine the normality of data. Descriptive statistical 
analysis, repeated measures ANOVA test, and Pearson 
correlation analysis were performed. Data were pre-
sented as mean ± SD (standard deviation). Kolmogo-
rov–Smirnov test revealed that data were distributed 
normally, and repeated measures ANOVA test was used 
to compare biochemical values of different sessions. Val-
ues of P < 0.05 at a 95% confidence interval were consid-
ered statistically significant. Eta-squared value (η2) was 
used to determine effect sizes within the ANOVA calcu-
lation. η2 values of 0.01, 0.06, and 0.14 were interpreted 
as “small”, “medium” and “large” effect sizes, respectively.
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Results
Serum IL-10, TNF-α, CRP and HIF-1α values obtained 
at rest conditions and different exercise sessions are 
given in Table  2. Additionally, IL-10/TNF-α ratio was 
used as a positive predictor of exercise and presented the 
results in Table 2. Results show that IL-10/TNF-α ratio 
was decreased in 100%  VO2 max session compared to 
both rest and 50%  VO2 sessions (P = 0.008 and P = 0.041, 
respectively).
The pairwise comparisons of biochemical values 
between rest state and different sessions were per-
formed with the repeated measures ANOVA test, and 
the results are summarized in Table 2. Results showed 
significant differences in serum TNF-α levels between 
rest condition and 75%  VO2 max; rest and 100%  VO2 
max session. There were significant differences in 
serum CRP levels between rest and 50%  VO2 max; rest 
and 75%  VO2 max sessions. There were significant dif-
ferences in serum IL-10 levels between rest and 50% 
 VO2 max, 50%  VO2 max, and 100%  VO2 max sessions. 
There were significant differences in serum HIF-1α lev-
els between rest and 75%  VO2 max session (P < 0.05 for 
all comparisons). All other comparisons were not sta-
tistically significant (P > 0.05 for all other pairs). The 
alterations in pro-inflammatory and anti-inflammatory 
pathways are shown in Fig. 2 with the results of IL-10 
and TNF-α.
Pearson correlation analyses were performed to evalu-
ate the relationships between biochemical parameters in 
rest conditions and each exercise session. Results showed 
a high negative correlation between serum HIF-1α 
and TNF-α levels on 50%  VO2 max session (r: − 0.634, 
P = 0.003). There was a moderate positive correlation 
between serum HIF-1α and IL-10 levels at 75%  VO2 max 
session (r: 0.593, P = 0.006) (Fig. 3).
Correlation analysis showed that serum HIF-1α levels 
were negatively related to serum TNF-α levels and posi-
tively related to serum IL-10 levels. Changes in HIF-1α 
concentrations during exercise may have negatively 
affected the pro-inflammatory pathway and positively 
affected the anti-inflammatory pathway as a protection 
mechanism.
Discussion
In this study, the acute effects of different exercise inten-
sities on serum IL-10, TNF-α, CRP and HIF-1α levels 
were reported for the first time. Additionally, the study 
was conducted in a low altitude (1850 m) city. Exercise 
practice until exhaustion caused significant pro-inflam-
matory effects (demonstrated with TNF-α) and the 
optimal IL-10 response on 50%  VO2 max decreased to 
nearly baseline level as the exercise intensity reached to 
100%  VO2 max. Thus, we can suggest that exercise inten-
sity should not reach to exhaustion due to there was no 
improvement in the anti-inflammatory marker IL-10 and 
there was an increment in the pro-inflammatory marker 
TNF-α with the potential increase in inflammation. 
There is a high altitude camping center for athletes in our 
Table 2 Biochemical values of athletes
η2: Eta-squared value
a,b,c,d Show repeated measures ANOVA Bonferroni post-hoc test P values
a Significant difference (P < 0.05) between rest state and 50%  VO2 max session
b Significant difference (P < 0.05) between rest state and 75%  VO2 max session
c Significant difference (P < 0.05) between rest state and 100%  VO2 max session
d Significant difference (P < 0.05) between 50%  VO2 and 100%  VO2 max sessions
Rest state
50%  VO2 max
75%  VO2 max
100%  VO2 max
η2
IL-10 (pg/mL)
328.09 ± 128.87a
446.36 ± 142.84d
347.44 ± 135.69
324.88 ± 168.06
0.546
TNF-α (ng/L)
331.65 ± 293.52b,c
395.59 ± 319.82
472.70 ± 365.21
489.03 ± 368.37
0.309
IL-10/ TNF-α
1.63 ± 1.20 c
1.49 ± 0.93d
1.34 ± 0.97
0.99 ± 0.67
0.566
CRP (mg/L)
0.74 ± 0.35a,b
1.19 ± 0.50
1.07 ± 0.52
0.97 ± 0.55
0.773
HIF-1α (ng/mL)
1.08 ± 0.19b
1.12 ± 0.32
1.26 ± 0.16
1.18 ± 0.21
0.453
Fig. 2 Alterations of cytokine levels in rest state and different 
seessions
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Baygutalp et al. BMC Sports Science, Medicine and Rehabilitation          (2021) 13:145 
city, and athletes from all over the country use this center. 
For this reason, the study has regional and national added 
value.
Several studies have investigated the responses of pro-
inflammatory cytokines, inflammatory cytokines and 
inflammatory markers to different exercise intensities 
and modalities, and these studies report distinct results 
[11, 13, 16, 17, 33, 34]. The conflicting results from pre-
vious literature may arise from differences in exercise 
intensities, exercise modalities, VO2 max capacities, the 
timing of blood sampling and biological variations.
In a study conducted with 20 soccer players with a 
mean age of 25.75 ± 3.99  years, participants were sub-
jected to a single bout high high-intensity interval train-
ing and plasma IL-6, IL-1 and TNF- α levels determined 
before and immediately after training. There was a sig-
nificant increase in plasma interleukin-6 levels after exer-
cise; however, no significant increase in IL-1 and TNF- α 
levels showing an anti-inflammatory condition might 
occur through high-intensity interval training sessions 
[34]. The training protocol of this study and the exer-
cise protocol of the current research is different, and it’s 
known that metabolic changes may occur differently in 
training and exercise. However, the type of sports and 
age of the participants in the two studies are similar. 
We observed increments in both anti-inflammatory and 
pro-inflammatory cytokines; anti-inflammatory marker 
(IL-10) was increased at 50%  VO2 session, and pro-
inflammatory marker (TNF-α) was increased 75%  VO2 
and 100%  VO2 sessions, and inflammatory (CRP) marker 
was increased at 50%  VO2 and 75%  VO2 sessions. We 
used high-intensity exercises, and researchers have used 
high-intensity interval training (HIIT). We could not 
show the anti-inflammatory effects of high intensity exer-
cise in our study, although other researchers have shown 
the anti-inflammatory effects in their study using high-
intensity interval training (HIIT).
The TNF-α level is decreased by moderate exercise 
(exercise intensity HRmax 60–70%) [33], and mRNA 
expression of TNF-α is known to be slightly elevated in 
skeletal muscle by endurance exercise [35]. In the previ-
ous study, a gradient increment was observed in serum 
TNF-α levels as exercise intensity increases. The high-
est TNF-α response to exercise was found at 100%  VO2 
max session when the athlete presents his maximum 
endurance.
A systematic review including 18 articles investigat-
ing the effects of moderate and intense exercise on 
inflammatory response concluded that intense long 
exercise protocols might activate pro-inflammatory 
pathways. Instead of this, moderate or high-intensity 
intermittent exercise protocols with suitable rest condi-
tions may be preferred [1]. We are in line with this con-
clusion since we observed an inflammatory profile by 
determining high TNF- α and CRP levels in 75%  VO2 
max and 100%  VO2 max sessions and optimal IL-10 
concentration at 50% VO2 max session. Although there 
is evidence of minimal pro-inflammatory cytokine 
response and high anti-inflammatory cytokine release 
from a study conducted on athletes competing in an 
ironman triathlon race [36], it should be considered 
that triathlon race is a type of ultra-endurance exer-
cise. We suggest IL-10 levels were not increased as 
expected at 75% VO2 max and 100% VO2 max exercise 
Fig. 3 Scatter-dot graphs of Pearson correlation analysis. A Significant negative correlation between HIF-1α and TNF-α at 50%  VO2 max session; (r: 
− 0.634, P = 0.003). B Significant positive correlation between HIF-1α and IL-10 at 75%  VO2 max session (r: 0.593, P = 0.006).
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Baygutalp et al. BMC Sports Science, Medicine and Rehabilitation          (2021) 13:145 
 
intensities because of pro-inflammatory effects. CRP 
level partially supported this suggestion, being signifi-
cantly higher in the 75% VO2 max session than the rest 
state. Among studies investigating the impact of exer-
cise on CRP release, most of them reveal increased 
CRP levels immediately after moderate [37]and intense 
exercise [38]. Yet, a study reports no effect of exercise 
modality on acute CRP response [39]. As determined 
the highest CRP value in 75% VO2 max session and 
elevated values in 75% VO2 max session compared to 
rest state in the present study, we can conclude that 
CRP partly acts together with the pro-inflammatory 
pathways. However, we could not determine any signifi-
cant correlation between CRP and TNF- α. Although 
we determined optimal IL-10 levels and relatively low 
TNF- α levels (compared to 75% VO2 max and 100% 
VO2) at 50% VO2 max session, we can not recommend 
using this intensity to athletes since this intensity is 
not related to training for fitness improvements/adap-
tations, and as well as for soccer as the participants in 
the current investigation were indeed soccer players. 
Further, 50% intensity will not be adequate to stress the 
body to induce an adaptation. Acute exercise sessions 
lead to a complex cascade of inflammatory and pro-
inflammatory pathways [40–42]. We are in line with 
this conclusion with altered TNF-α, IL-10, and CRP 
levels among sessions.
Considering the current study results and related stud-
ies, we can speculate that moderate intensity exercise 
with durations longer than 30  min (providing higher 
endurance than the present study) may be beneficial to 
prevent/reduce pro-inflammatory response.
It is known that disease-induced hypoxia is closely 
related to the activation of inflammatory pathways, but 
less information is available about the effects of exercise-
induced hypoxia on inflammation. There is a relationship 
between hypoxia and the release of pro-inflammatory 
cytokines. Moreover, HIF-1α is important in control-
ling excessive inflammation [23]. Also, hypoxia, inflam-
mation, and exercise can induce the HIF-1α pathway. It 
was shown that skeletal muscle HIF-1 protein content 
increased by 120% with hypoxia, and HIF-1α released in 
response to hypoxia was triggered by the effect of exer-
cise [43]. In the present study, serum HIF-1α levels were 
significantly increased in 75% VO2 max session com-
pared to rest state in a high-lander athlete population liv-
ing in this location for at least 5 years.
At hypoxia conditions in the exercising person, the 
inflammatory pathways are regulated differently. The 
hypoxic and exercise stimuli are stronger in vivo than the 
hypoxic or inflammatory stimuli isolated in vitro [24].
Of note, when considering HIF-1α results, it should 
be kept in mind that high interindividual variability may 
be seen in the expression of HIF and its target genes in 
response to inflammatory or hypoxic stimuli, and sin-
gle nucleotide polymorphisms (SNPs) are thought to be 
involved in these changes [25].
There is a relation between hypoxia and inflammation. 
Hypoxia can induce inflammation, and inflamed tissues 
may become hypoxic [20]. Limited studies investigat-
ing the effects of exercise on inflammatory pathways in 
hypoxic conditions revealed no changes in pro-inflam-
matory cytokines, and increases in anti-inflammatory 
cytokines, indicating the positive effects of exercising in 
hypoxic conditions.
The triple relation of exercise, inflammatory pathways, 
and oxygen consumption in a low altitude location were 
investigated in a previous study. HIF-1 α response is 
maximum on 75%  VO2 max session and decreases from 
this maximum value on exhaustion. This result follows 
the finding that high-intensity exercise in hypoxia can 
further induce HIF-1α expression [43]. It is well known 
that high-lander athletes show better exercise perfor-
mance and greater  VO2 max capacity than sea-landers 
since athletes have adapted to hypoxia, and maybe some 
have a genetic basis, thanks to the effect of altitude [44, 
45].
Although there is no agreement to define the term 
“high-intensity”, it widely refers to exercise intensity 
higher than 75%  VO2 max [23]. A speculative model 
suggests that HIF-1α and PGC-1α act as mediators in 
the adaptation of skeletal muscle. The mediators lead to 
upregulation of mitochondrial biogenesis, angiogenesis 
via activation of VEGF and a shift in the skeletal mus-
cle fibre type. Both high-intensity exercise/training and 
hypoxia lead to this mechanism to upregulate skeletal 
muscle adaptation [23].
We observed the optimum HIF-1 α response in a 75% 
VO2 max session in the present study.
HIF-1 α response did not increase when the exercise 
intensity was reached from 75%  VO2 max to 100%  VO2 
max in the present study. We attribute this because the 
athletes have developed a physiological adaptation to 
hypoxia thanks to living at low altitudes. Correlation 
analyses revealed a high negative correlation between 
serum HIF-1α and TNF-α levels on 50%  VO2 max ses-
sion (r: − 0.634, P = 0.003) and a moderate positive cor-
relation between serum HIF-1α and IL-10 levels at 75% 
 VO2 max session (r: 0.593, P = 0.006). Results suggest 
that increased HIF-1α levels reflect the pro-inflammatory 
condition in 50%  VO2 max session and the anti-inflam-
matory condition in 75%  VO2 max session. We deter-
mined maximum TNF-α response and similar IL-10 
response compared to baseline in 100%  VO2 max ses-
sion. We can conclude that the pro-inflammatory effects 
of hypoxia and anti-inflammatory effects of the exercise 
Page 8 of 9
Baygutalp et al. BMC Sports Science, Medicine and Rehabilitation          (2021) 13:145 
was probably due to activating the release of anti-inflam-
matory cytokines and downregulating toll-like receptor 
(TLR) signalling [23].
Studies with different exercise protocols have shown 
that high-intensity exercise (above 75% of the peak 
power output) provides similar or even higher benefits 
than a low-intensity continuous exercise in improving 
heart health, respiratory health, and metabolic health. 
Increases in peak power outputs during exercise result 
in increased metabolic responses, compromising skel-
etal muscle integrity, which can cause early onset of 
fatigue and exhaustion. Therefore, the selection of exer-
cise intensity should be made carefully to avoid undesir-
able consequences. Taken together, TNF-α, IL-10, CRP, 
and HIF-1α results, we again suggest that exercise inten-
sity should not reach to exhaustion. Despite its original-
ity, the current study has a limitation. It would be better 
ELISA results should be supported with western blotting 
analysis and mRNA expression levels of proteins.
Conclusions
There is a tight connection between hypoxia and inflam-
mation, and studies investigating the effects of exercise 
intensity in hypoxic and inflammatory pathways are 
limited. There is no available study in any athletic popu-
lation reporting the acute changes on serum IL-10, TNF-
α, CRP and HIF-1α levels induced by different exercise 
intensities. We noted that both inflammatory and anti-
inflammatory pathway is induced on different exercise 
intensities. As the need for oxygen increases, the inflam-
matory pathway (by TNF- α and CRP) is induced, and 
anti-inflammatory cytokine IL-10 reaches optimal value 
on exercise intensity of 50%  VO2 max. Exercise regimens 
(not reached to exhaustion) are recommended to prevent 
inflammation, hypoxia-induced damage, and existing 
muscle damage progression if any. Further studies on dif-
ferent athlete groups should be conducted to determine 
the optimum exercise intensity and maximum benefit.
Abbreviations
VO2 max: Maximal oxygen consumption values; TNF-α: Tumor necrosis factor 
alpha; IL-10: Interleukin-10; CRP: C-reactive protein; HIF-1 α: Hypoxia inducible 
factor-1 alpha.
Acknowledgements
The authors would like to thank the athletes that took part in this study. The 
authors would like to thank to Prof. Mostafa Abdelaty HASSIBELNABY for his 
scientific contribution to the study.
Authors’ contributions
FB: concept, design, inspection of all participants, writing article, critical review 
of the article; YB: performing exercise protocol, writing article, critical review 
of the article; MO: performing exercise protocol, writing article, critical review 
of the article; MK: critical review of the article; NKB: biochemical analysis, 
statistical analysis, critical review of the article; GA: determining exercise 
protocol, critical review of the article. All authors read and approved the final 
manuscript.
Funding
None.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from 
the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The informed consent form was obtained from all participants, and they were 
enlightened with all matters related to the study. The study was approved 
by the Clinical Research Ethics Committee of Ataturk University Faculty of 
Medicine (27.05.2021).
Consent for publication
Not applicable.
Competing interests
Not applicable.
Author details
1 Department of Physical Medicine and Rehabilitation, Ataturk University 
Faculty of Medicine, Erzurum, Turkey. 2 Department of Physical Education 
and Sports, Erzurum Technical University Faculty of Sport Sciences, Erzurum, 
Turkey. 3 Department of Physical Education and Sports, Ataturk University 
Kazım Karabekir Education Faculty, Erzurum, Turkey. 4 Department of Sports 
Health Sciences, Ankara University Faculty of Sport Sciences, Ankara, Turkey. 
5 Department of Biochemistry, Ataturk University Faculty of Pharmacy, Erzu-
rum, Turkey. 6 Department of Recreation, Ataturk University Faculty of Sport 
Sciences, Erzurum, Turkey. 
Received: 25 June 2021   Accepted: 15 November 2021
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Impacts of different intensities of exercise on inflammation and hypoxia markers in low altitude.
Baygutalp, Fatih,Buzdağlı, Yusuf,Ozan, Murat,Koz, Mitat,Kılıç Baygutalp, Nurcan,Atasever, Gökhan