EFFECT OF AEROBIC PHYSICAL EXERCISE ON EXPRESSIONS AND

DISTRIBUTION LEFT VENTRICULAR CONNEXIN43 OF JUVENILE AND YOUNG

ADULT RATS
Rustiana Tasya Ariningpraja1, Dewi Irawati S. Santoso2, Ahmad Aulia Jusuf3
1

Biomedical Science, Faculty of Medicine, Universitas Indonesia

Department of Physiology, Faculty of Medicine, Universitas Indonesia
3
Departement of Hystology, Faculty of Medicine, Universitas Indonesia
2

Running Tittle: Cardiac hypertrophy, extracelullar-matrix deposition, expressions and

distribution left ventricular connexin43 after aerobic physical exercise on juvenile and young
adults rats
Synopsis: Aerobic exercise was found to increased expression and predominance of
lateralization Cx43 in juvenile onset (8 and 12 weeks) and young adult onset (8 weeks). While,
decreased expression and predominance lateralization Cx43 in juvenile onset (4 weeks).
Abstrak
Latar belakang: Aktivitas fisik aerobik teratur dapat meningkatkan kesehatan sistem
kardiovaskular secara keseluruhan. Salah satunya menyebabkan peningkatan ukuran miosit yang
diikuti dengan peningkatan ekspresi connexin43 (Cx43) tanpa lateralisasi. Aktivitas fisik
sebaiknya dimulai sejak masa anak-anak, guna mencapai kesehatan kardiovaskular di masa
dewasa. Latihan Fisik merupakan bagian dari aktivitas fisik yang terprogram. Belum banyak
penelitian mengenai pegaruh onset latihan fisik terhadap jantung. Penelitian ini bertujuan untuk
mengetahui pengaruh onset latihan fisik terhadap eksspresi dan distribusi Cx43 dengan durasi
latihan yang sama dan berbeda.
Metode: Penelitian ini merupakan penelitian studi eksperimental in vivo menggunakan tikus
wistar jantan yang terbagi dalam dua kelompok usia, yaitu usia juvenile dan dewasa muda. Tikus
dari setiap kelompok usia dibagi secara acak dalam 2 kelompok, yakni kelompok perlakuan
latihan fisik dan kelompok kontrol. Jadi terdapat 7 kelompok pada penelitian ini, yaitu 1)
kelompok kontrol juvenile 4 minggu, 2) kelompok latihan fisik yang dimulai yang dimulai pada
usia juvenile selama 4 minggu, 3) kelompok kontrol juvenile 8 minggu, 4) kelompok latihan fisik
yang dimulai pada usia juvenile selama 8 minggu, 5) kelompok latihan fisik yang dimulai pada
usia juvenile selama 12 minggu, 6) kelompok kontrol dewasa muda 8 minggu, 7) kelompok

latihan fisik yang dimulai pada usia dewasa muda selama 8 minggu. Connexin43 ventrikel kiri
jantung diidentifikasi dengan pulasan imunohistokimia. Data di analisis menggunakan uji t-test
independent.
Kesimpulan: Latihan fisik aerobik baik pada kelompok latihan aerobik onset juvenile (durasi 8
dan 12 minggu) maupun kelompok onset dewasa muda (durasi 8 minggu) menunjukkan
peningkatan ekspresi dengan predominasi lateralisasi Cx43. Sedangkan, kelompok onset juvenile
(4 minggu) mengalami penurunan ekspresi dengan predominasi lateralisasi Cx43. Pengaruh
onset latihan lebih tinggi dibandingkan durasi latihan.
Abstract
Background: Aerobic exercise can improve the overall health of the cardiovascular system.
Aerobic exercise led to an increase in myocyte size that is followed by increased expression of
connexin43 (Cx43) without lateralization. Physical activity should begin in childhood, in order to
achieve cardiovascular health in adulthood. Physical exercise is part of a programmed physical
activity. Not been much research on effect of onset physical exercise on the heart. This study
aims to determine the effect of physical exercise onset with duration on expression and
distribution Cx43.
Methods: This was an in vivo experimental studies using male Wistar rats were divided into two
age groups, the age of juvenile and young adult. Each age group were randomly divided into 2
groups, the treatment group and control. So there are seven groups in this study: 1) Sedentary
control group juvenile 4 weeks, 2) Exercise group juvenile onset for 4 weeks, 3) Sedentary
control group juvenile 8 weeks, 4) exercise group juvenile onset for 8 weeks, 5) Exercise group
juvenile onset for 12 weeks, 6) Sedentary control group young adults 8 weeks, 7) Exercise group
young adult onset for 8 weeks. left ventricular cardiac Cx43 identified by immunohistochemical
staining. Data was analyzed using independent t-test.
Conclusion: In conclusion, aerobic exercise in juvenile onset (8 and 12 weeks duration) and
young adult-onset (duration of 8 weeks) showed increased Cx43 expression with predominance
lateralization. While, juvenile onset (4 weeks) showed decreased Cx43 expression with
predominance lateralization. Effect of exercise onset higher than duration.
Keywords: Aerobic exercise, left ventricle, connexin43, juvenile, young adult.

INTRODUCTION
Aerobic exercise can improve overall health of cardiovascular system 1. Physical exercise should
be started since childhood, in order to achieve cardiovascular health in adulthood. WHO 2 and the
American Heart Association (AHA) recommends3 physical activity during childhood as a
program to reduce the risk of cardiovascular disease in adulthood. Physical exercise in children
should be carried out with the intensity gradually and maintained at moderate intensity4.
Various physiological adaptations occur in the body of individuals who perform physical
exercise5. Heart can adapt to physical exercise through increase size 6. Cardiac hypertrophy can
be broadly defined as the increase cardiac mass 7. Heart muscle adapt its size due to increased
pressure and / or volume with hypertrophy6,7. Cardiac hypertrophy in response to exercise can be
classified as physiological hypertrophy, reversible and characterized by normal morphology and
cardiac function8. In contrast to pathological hypertrophy that occurs in the setting of disease, is
detrimental to cardiac structure and function and can cause cardiac failure8.
Physiological hypertrophy at the cellular level is marked also by an increase in protein synthesis
and the fibrosis absence8,9. To keep it running good cardiac function, communication between
increased cardiomyocytes size should maintained10,11. Many service allows communication
between cardiomyocytes, including through gap junction (GJ) 11. GJ remodeling also occurs
with increased formation of GJ in the response and adaptation to cardiac hypertrophy 12. GJ in the
heart mainly serve to allow the heart's electrical excitation rapid and coordinated, as a
prerequisite to the rhythm of normal heart function11.12.
GJ normally found in many different structures and specialized in end myocytes called
intercalated disk13. This structure also contains many desmosomes and adherent junctions which
provides mechanical stability to the cardiac network13. GJ is a component part of a protein called
connexin(Cx). Cx43 is the major connexin isoform in GJ of left ventricular myocyte 12,14,15.
Impaired Cx43 expression and distribution in ventricles heart can cause cardiac disease 13,16.
Disorders are often characterized by a decrease in intercalated disk Cx43 and a shift to the lateral
edge of myocytes, a process known as lateralization 13,17. Cx43 changes can lead to changes in
conduction velocity so as to contribute to cardiac arrhythmias 10,16,18. Reviewing research on the

benefits of physical exercise from childhood on cardiac function in adulthood has not been done,
including the expression and distribution of Cx43 ventricles heart.
Therefore, it is necessary to study the differences review the benefits of physical exercise that
began in childhood and young adulthood on the expression and distribution of left ventricle
Cx43.
METHODS
This experimental study was done on cardiac left ventricular tissue from male albino Rattus
novergicus, Wistar strain rats, aged 4 weeks (juvenile) and 8 weeks (young adult), weighing 60250 grams. Rat randomly divided into 2 groups, the treatment group physical exercise and
control groups were sedentary. So there are 7 groups in this study: 1) Sedentary control group
juvenile 4 weeks, 2) Exercise group juvenile onset for 4 weeks, 3) Sedentary control group
juvenile 8 weeks, 4) exercise group juvenile onset for 8 weeks, 5) Exercise group juvenile onset
for 12 weeks, 6) Sedentary control group young adults 8 weeks, 7) Exercise group young adult
onset for 8 weeks (Table 1). This research was conducted in Biomedical science laboratory
Kemenkes Republik Indonesia. Rat were given a standard diet including vitamin and drink ad
libitum with age-appropriate portions and the number of rat in a cage. Cage is kept clean and
organized 12 hours of light and 12 hours of dark. The ambient temperature is maintained at a
temperature 23 1C. Before starting the exercise, rats adapted to the environment in advance
cage for 1 week, then adapted to the treadmill (acclimation exercises) for 1 week. Rat exercise
program started at age 5 and 9 weeks old.
Training Acclimation
All animal treatment group was given exercises running using animal treadmill at a speed of 9
meters/minute for 10 minutes each day. All control group is placed in animal treadmill that does
not function for 10 minutes each day.
Exercise
Treadmill speed is adjust with rats age-appropriate19, running speed in juvenile and children (in
humans) should be done gradually and then maintained at a moderate intensity with a frequency

of 5x in a week. Duration of exercise 20 minutes with a 1.5 minute breaks every 5 minutes run to
avoid fatigue19,20. Training for juvenile group begins with a speed of 12 m/minute for the first 2
weeks, 15 m/minute for 2 weeks of the second, and 20 m/minute for next 4 weeks 20,21. Exercises
for the group of young adults conducted at a speed of 20 m/minute from the first week until the
last week21.
Sacrifice and immunochemistry
After 60 minutes of final practice, to get the chronic effect of exercise and avoid acute effects
exercise21. Heart taken and isolated parts of the left ventricle. Pieces are placed in a container of
10% formalin buffer and allowed to stand at room temperature for 24 hours. Once the fixed
network, further processing of the network starting with dehydration, clearing, and impregnation
be making paraffin blocks (embedding). Paraffin block cooled at the cooling plate or ice cubes
and blocks of paraffin cut with a microtome with a thickness of 4-5 micrometers. Ventricle tissue
pieces left glued to a glass slide. Performed on the slide stained with immunohistochemical
staining technique.
Parameters assessment
The positive cells expressing Cx43 were cells showing brown on intercalated disk and lateral
myocyte. These slides were observed under a light microscope binocular (Olympus CH-20
binokuler) with a 400x magnification and photographed by microscope build-in camera
(Optilab), and the we took 5 visual fields randomly for each preparation. Photo preparations that
have been obtained are then processed with ImageJ22 program to determine the amount of protein
expression and distribution of Cx43. Evaluation is based on the percentage of imunoreactivity
expression and distribution Cx43 by dividing the the large area expression with total large image.
Ethical approve was obtained from the Research Ethics Committee of Faculty of Medicine
Universitas Indonesia.

RESULTS
Cx43 expression
Figure 1 showed a representative immunohistochemistry image from each condition. Percentage
of expression Cx43 in intercalated disk left ventricle after exercise juvenile and young adult
onset is presented in Figure 2. The decline in the total area of Cx43 expression occurred in all
treatment groups of juvenile onset (69.87%, 74.98% 82.03%, p = 0.068, p = 0.186, p = 0.071) as
well as young adult onset (82.59%, p = 0.000) compared to control. Percentage of the highest
area Cx43 expression at intercalated disc in the exercise group juvenile onset of 8 weeks with
88.39%.
Intercalated disc Cx43 percentage of the same and different exercise duration on different onset
can be seen in Figure 3. Comparison of exercise on juvenile and young adult onset with the same
duration showed significant differences in the percentage of expression of Cx43 intercalated disc
(p = 0.001) with higher values in young adult (82.59% ) compared juvenile 8 weeks (74.98%).
Comparison onset juvenile and young adults with end-of sacrifice also show a significant
difference in the percentage area Cx43 expression in the intercalated disc (p = 0.768) with higher
values in young adults (82.35 %) compared to 12 weeks of juvenile onset (82.03%).
Cx43 distribution
Figure 4 shown an increase in the average area lateralization Cx43 expression occurred in all
treatment groups both at juvenile onset (30.13%, 25.02%, 17.97%, p = 0.000, p = 0.000) as well
as adult onset young (17.41%, p = 0.068, p = 0.187) compared to control. Cx43 highest
percentage lateralization in the aerobic exercise group of juvenile onset 4 weeks (30.13%).
Comparison of the effect of exercise onset juvenile and young adult with the same and different
exercise duration on percentage Cx43 lateralization can be seen in Figure 5. Comparison of
exercise onset juvenile and young adults with long same exercise showed significant differences
in the percentage of the total area Cx43 lateralization (p = 0.000, p <0.05) with higher values in
juvenile onset 8 weeks (25.02%) compared to young adult onset (17.41 %). Comparison onset
juvenile and young adults with end-of sacrifice also show significant differences in the
percentage of expression of Cx43 lateralization (p = 0.000) with higher values in juvenile onset
of 12 weeks (17, 97%) compared to young adult onset (17.41%).

DISCUSSION
This study shows that remodeling GJ (responsible for electrical conduction of the heart) caused
by long-term aerobic exercise is a dynamic and complex process. Data analysis showed
increased total Cx43 expression (pixel). However, increased expression of Cx43 is
disproportionate, there was a shift from the expression of which should increase the intercalated
disc turn into an increase in the lateral side (lateralization).
Analysis of the results of this study showed increased expression of Cx43 post-aerobic exercise
either on juvenile onset (8 and 12 weeks) or young adult onset with values statistically
significant (p = 0.001, p = 0.002, p = 0.000), consistent with findings in experimental studies
with mechanical stretch stimulation in cultured cardiomyocytes. Several in vitro studies in
cultured cardiomyocytes, to see the effects of mechanical stimulation on the expression GJ strain,
showed an increased expression of Cx43 and cardiomyocyte formation of a new interstate GJ.
Zhuang, et al23 reported that increased expression of Cx43 is accompanied by an increase in
conduction velocity in tissue culture cardiomyocytes. Meanwhile, Salameh, et al 24 who did
research on the culture of cardiomyocytes with mechanical stretch stimulation with maturities of
up to 48 hours, reported the prolongation of cardiomyocytes, increased expression of Cx43 and
Cx43 polarization at the tip of cardiomyocytes; where these changes do not occur in the control.
Animal studies of treated rat with aerobic exercises running also showed increased expression of
Cx43. Bellafiore, et al25 using aerobic physical exercise protocol, the running speed of 4.8
meters/ minute for 300 minutes. Analysis of the data in the study also shows the longer exercise
done caused higher Cx43 expression. However, this study did not analyze the distribution pattern
of Cx43expression in cardiomyocytes of the left ventricle cardiac rat tissue as measured using
Western blot technique.
Increased expression of Cx43 post-exercise in the aerobic exercise group juvenile onset (8 and
12 weeks) and young adult onset in this study correspond to those reported by previous studies.
In addition, there are also groups that experienced a decrease in total expression of Cx43,
although not statistically significant in exercise juvenile onset 4 weeks (p = 0.153). Differences
in the findings in this study are difficult to explain. It can be caused by several factors; the

subject of different studies (rats and mice), the sex of the subject of research, the difference the
study protocol (running and swimming; intensity physical training), technical analysis of the
number of Cx43 (Western Blot, PCR, or IHC) is expected to may lead to differences in results
analysis.
The downward trend Cx43 can lead to pathological hypertrophy within defined borders.
Research on pathological cardiac hypertrophy by Jin et al 26 in mice post-binding of the ascending
aorta (aortic stenosis resembles condition in humans) also found increased expression of Cx43 in
early hypertrophy (4 weeks), accompanied by a moderate decrease in conduction velocity.
Increased expression of Cx43 is accompanied by a decrease in conduction velocity is due to
increased Cx43 phosphorylation. Whereas at a more advanced stage (8 weeks) decreased
expression of Cx43 and Cx43 increased non-functional, which led to a decrease in conduction
velocity is more severe.
Another factor is the strongest candidate is the possibility that the burden of training and
implementation methods of exercise that does not comply with juvenile rats. The international
health agency recommendations state that physical activity is good for health since childhood.
Exemplary forms of activity is related activity played with a minimum of stress. In the study
Wagener, et al88 forms of physical activity play with saving tool rottarot in cages the rats and rat
will play in these required time, thus providing significant results against measured parameters.
In this protocol, the treatment is more similar to the conditioning training (training) that forces
juvenile rats ran at a certain speed and duration. In execution, it is often a rat wedged in the tail
for lazy running and the condition declines with age and an increase in longer workouts.
Other new findings influence the onset of exercise on the total Cx43 expression. Statistical test
the average difference comparison group having the same old exercises with the group to
sacrifice the same age showed a non-significant in the total Cx43 expression (p = 0.961). The
differences of the average total Cx43 expression was higher in the group compared with the
group with the same old exercises. It concluded that prolonged exercise more influence
expression of Cx43 in comparison with the onset of exercise. But still, there are fears that if true

will always be a linear increase between the increase in longer workouts with increased Cx43
expression.
Tiscornia, et al29| doing research in mice trained (trained) and untrained (Untrained) by treatment
with physical exercise swim (training load: up to 2 hours of swimming /day). Cx43 expression of
mice were trained at the initial state looks higher than the group of untrained mice. The
interesting thing is the finding of a reduced expression of Cx43 mice were trained during
physical exercise (not in mice untrained). Decreased expression of Cx43 which occurs during
physical exercise is also reported not to cause changes in the electrical activity of the heart. This
is expected because the amount of expression of Cx43 after a decline is still pretty and there
were not much different from the number of Cx43 in rats were not trained.
Physiologically, Cx43 GJ as a constituent of the left ventricle is located in the intercalated disc.
Increased total Cx43 expression followed by an increase in the percentage of GJ intercalated disc
with little or without lateralization. This study showed an increase Cx43 in the exercise group
both juvenile or young adult onset with an increased percentage of Cx43 lateral. Cx43 expression
predominance on the lateral side of cardiomyocytes (lateralization) with significant statistical test
(juvenile onset 8 weeks and the young adult onset) were also frequently reported in pathological
cardiac hypertrophy. Kostin et al91 using cardiac left ventricular biopsies of patients with
pathological cardiac hypertrophy caused by aortic stenosis. Kostin et al 28 reported that in patients
with cardiac hypertrophy pathological compensated (meaning the myocardium still works well,
the ejection fraction> 50%) showed increased expression of Cx43 and occurs predominance of
expression of Cx43 lateralization (with the proportion of 40% expression in lateralization, when
compared with control only 10%).
However, increased Cx43 expression is accompanied by a predominance of this lateralization
can not be associated with an increased risk of arrhythmias in humans. While the experienced
decompensated cardiac hypertrophy (ejection fraction <30%) showed significant decreased
expression of Cx43 and Cx43 distribution interference occurs, these two things are not expected
to cause a decrease in the conduction velocity, which in turn can increase the risk of the
incidence of cardiac arrhythmias.

Another study by Uzzaman, et al29 right ventricular cardiac hypertrophy rats with pathological
(caused by hypertension induced by monocrotaline pulmoral) did not show an increased
Cx43expression, Cx43 distribution but an interruption occurs, the increased proportion of
lateralization and expression in the cytoplasm. In the conduction velocity analysis showed a
decrease in the conduction velocity of longitudinal (along cardiomyocytes) which is significant
compared with the controls; while the conduction velocity transverse (sideways into the adjacent
cardiomyocytes) unchanged. Decrease in longitudinal conduction velocity is estimated as
decreased Cx43 expression in intercalated disc, whereas the transversal conduction velocity does
not change due to lateralization Cx43.
Seidel, et al30 conduct simulation studies the relationship between the size of the cardiomyocytes
and lateralization Cx43 in relation to the speed of conduction cardiomyocytes. The study shows
that the effect decreased expression in cardiomyocytes widened GJ more prone to disturbances in
conduction velocity compared with cardiomyocytes stretching. Lateralization GJ accompanied
by an increase in the diameter of cardiomyocytes increased susceptibility to conduction disorders
that can ultimately lead to arrhythmias.
Statistical test the average difference comparison group having the same old exercises showed
significant results in the area of lateralization percentage Cx43 expression (p = 0.009). The
differences of the average percentage of area lateralization Cx43 expression was higher in the
group with the same old workout compared to the age group with the same sacrifice. So far,
lateralization often linked to the duration of the exercise, the longer the physical exercise
performed the greater the proportion of Cx43 expression lateralization. This adaptation process is
temporary (reversible), as seen in the group of post-stop-trainer who experienced regression of
the number of Cx43 expression. Even so, the proportion of post-lateralization of physical
exercise can not be fully air-regression, it indicates that the train stopping treatment causes only
partially reversible.
Therefore not many research that examined the impact of age commencement exercises to
increase lateralization. Thus, further research should be done. Are there factors other than
exercise, including the basic factors affecting growth and distribution of Cx43 expression

changes. Adan see an increasing trend of lateralization Cx43 in the control group.
Ultimately, the increased likelihood of lateralization expression of Cx43 are accompanied by
disturbances miofibriler arrangement and increased fibrosis thought to cause the heart's electrical
conduction disturbances. We recommend that you exercise at the age of juvenile need to consider
a few important things to avoid stress that it will be negative. Children should do physical
exercise in the form of the game so as not to cause stress that may arise. The exercise program on
children must also consider the ability of the individual child, so as not to cause fatigue or stress.
In conclusion, physical exercise can improve both Cx43 expression, which began juvenile or
young adult with an increased tendency to predominance of the lateral side of the myocyte.
These trends lead to the possibility of arrhythmias anatomically, but not yet proven to be
functional.
Limitation
Further research is needed to assess the effect of aerobic exercise to assess physiological
parameters such as ECG.
Advantage
Study on Cx43 expression and distribution in juvenile rat or children are still not many,
especially cause by prolonged aerobic exercise. This study can be a future reference for another
aerobic exercise in children, especially on the onset and another duration exercise to be used.
Acknowledgment
The author are greatfull to Department of Physiology and Department of Hystology, Faculty of
Medicine, Universitas Indonesia which have supported this research both material and nonmaterial.

Table 1. Subdivision of control and treatment group

Group
L.J.4
K.J.4
L.J.8
K.J.8
L.J.12
L.DM.8
K.DM.8

Treatment
Aerobic exercise juvenile onset for 4 weeks
Control juvenile onset for 4 weeks
Aerobic exercise juvenile onset for 8 weeks
Control juvenile onset for 8 week
Aerobic exercise juvenile onset for 12 weeks
Aerobic exercise young adult onset for 8 weeks
Control young adult onset for 8 weeks

Duration of Treatment
4 weeks
4 weeks
8 weeks
8 weeks
12 weeks
8 weeks
8 weeks

Figure 1. Immunohistochemistry Cx43 left ventricular heart Wistar rats with physical
exercise since juveniles (for 4, 8, and 12 weeks) and young adults. A1: Control A2, A2:
Exercise juvenile onset for 4 weeks, B1: Control B2, B2: Exercise juvenile onset for 8
weeks, C1: Control C2 and D1, C2: Exercise juveniles for 12 weeks, D1: Exercise young
adult onset.
A1

A2

B1

B2

C1

C2

Figure 2. A comparison of the total area Cx43 expression Wistar rats were started Physical
Since Juvenile and Young Adults With Control.
(*)

100.00
90.00
80.00
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00

69.87

79.72

74.98

88.39

Exercise

82.03 84.92

82.59 84.92

Column1

Mean, * significant difference compared to the control group (p <0.05, unpaired t

test)

Figure 3. Comprehensive comparison of the percentage of Cx43 expression in intercalated

disc Wistar rats were started Physical Since Juvenile and Young Adults With long
comparison exercise to test the average difference both groups.
84.00

82.59

82.03

82.00

82.59

80.00
78.00
76.00

74.98

74.00
72.00
70.00

7,60

(*)

Same of duration

2,69
Different of duration

Juvenile Onset for 8 and 12 weeks

Young Adult Onset

Mean, * significant difference compared to the control group (p <0.05, unpaired t

test)

Figure 4. A comparison of the percentage of area Lateralization Cx43 expression on Wistar

rats that start Physical Fitness From Juvenile and Young Adults With Control.
35
30
25
20
15
10
5
0

30.13
20.28

25.02
17.97

(*)

11.61

Exercise

15.08

17.41 15.08

Column1

Mean, * significant difference compared to the control group (p <0.05, unpaired t

test)

Figure 5. Comprehensive comparison of the percentage of Cx43 expression lateralization

Wistar rats were started Physical Fitness From Juvenile and Young Adult By comparison
prolonged exercise, coupled with a test average difference both groups.
30.00
25.00
20.00

25.02

(*)
(*) 17.41
17.97

17.41

15.00
10.00
5.00
0.00

(*)

7,60

2,69

Same of duration

Different of duration

Juvenile Onset for 8 and 12 weeks

Young Adult Onset

Mean, * significant difference compared to the control group (p <0.05, unpaired t

test)

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