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Thrita. 2020 June; 9(1):e105820.
Published online 2020 August 11.
doi: 10.5812/thrita.105820.
Research Article
Effects of Endurance Training, Hyaluronic Acid and Stem Cell
Treatments on the Quadriceps Muscle Fiber Count: Study on the Knee
Osteoarthritis Rats
Mahboubeh Tajik 1, Mohammad-Ali Azarbayjani 1, *, Maghsoud Peeri 1and Parvin Farzanegi 2
1Central Tehran Branch, Islamic Azad University, Tehran,Iran
2Sari Branch, Islamic Azad University,Sari, Iran
*Corresponding author: Central Tehran Branch, Islamic Azad University,Tehran, Iran. Email: m_azarbayjani@iauctb.ac.ir
Received 2020 May 27; Accepted 2020 June 11.
Abstract
Background: Osteoarthritis can impair muscle structure and function. Numerous methods may be helpful for its treatment, i.e.,
hyaluronic acid, cell therapy, and physical training.
Objectives: The present study investigated the independent and combined effect of these three interventions on the quadriceps
muscle fiber count in the rat model of knee osteoarthritis.
Methods: Fifty four rats were randomly divided into groups, including; healthy-control, osteoarthritis- control, osteoarthritis-
training, osteoarthritis-stem cell, osteoarthritis-hyaluronic acid, osteoarthritis-hyaluronic-stem cell, osteoarthritis-stem cell-
training, osteoarthritis-hyaluronic acid-training, and osteoarthritis-stem cell-hyaluronic acid-training. The exercise training pro-
gram consisted of 30 minutes of running on the treadmill with no slope at a speed of 16 m/min for the first week. Then, the duration
progressively reached 50 minutes in the eighth week. Stem cells were extracted from bone marrow and injected into the injured
joint. Hyaluronic acid was injected into the injured joint in three separate weeks and once a week. All animals were anesthetized 48
hours after the last training session and injections. The samples were removed and sent to the laboratory. All significant levels were
considered as P < 0.05.
Results: Osteoarthritis significantly decreased muscle fibers compared to healthy animals. Aerobic training, stem cell therapy,
hyaluronic acid, the interaction of training and stem cell, and the interaction of training, stem cell therapy, and hyaluronic acid
significantly increased muscle fiber count.
Conclusions: Concurrent use of aerobic training, stem cell, and hyaluronic acid treatments had more effect than each intervention
alone on enhancing the muscle fiber count in the rat model of knee osteoarthritis.
Keywords: Osteoarthritis, Aerobic Training, Stem Cell, Hyaluronic Acid
1. Background
Osteoporosis, osteoarthritis, and sarcopenia are the
most common musculoskeletal disorders (1). Osteoarthri-
tis is a chronic degenerative joint disease characterized by
pain, articular stiffness, and an incremental decrease in
the articular function, which significantly affects the qual-
ity of life (2). Synovial membrane inflammation, articular
capsule thickening, muscle weakness, and new bone for-
mation are complications of osteoarthritis. Therefore, os-
teoarthritis affects not only the tissues inside the capsule
but also the tissues surrounding the joint, including the
muscle (3). Due to its nature, it is reported that osteoarthri-
tis is closely associated with sarcopenia (4,5).
Muscle damage and weakness in people with os-
teoarthritis are usually associated with muscle fiber atro-
phy (6). It has been reported that in subjects with hip and
knee articular osteoarthritis, the cross-sectional area of the
muscle reduces by 12 to 19% (7).
Various methods are suggested to inhibit the negative
effects of osteoarthritis. One of the most common of these
methods is the use of physical training, which includes re-
sistance, stretching, or aerobic training in water and land.
Both high and low-intensity aerobic training are reported
to be suitable for people with osteoarthritis (8). Since the
main goal of osteoarthritis treatment is to alleviate joint
pain, minimize motor disability, and improve aerobic fit-
ness, therefore, aerobic or resistance training can be rec-
ommended as the main treatment for people with mild to
Copyright © 2020, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License
(http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly
cited.
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Tajik M et al.
moderate osteoarthritis (9).
There is evidence that the use of stem cells can have
therapeutic effects on osteoarthritis (10). In animal mod-
els, stem cell therapy can protect or improve induced os-
teoarthritis (11). Stem cells do not appear to become chon-
drocytes, but rather suppress synovial activation and indi-
rectly reduce cartilage damage (12).
Hyaluronic acid has also recently been used as a very ef-
fective treatment for osteoarthritis pain (13). Cell prolifer-
ation is one of the most important stages of muscle regen-
eration after injury (14). Hyaluronic acid is essential for the
removal of fibroblasts from the extracellular matrix and
mitosis (15).
2. Objectives
The current study aimed to investigate the indepen-
dent and combined effect of aerobic training, stem cells,
and hyaluronic acid treatments on the quadriceps muscle
fiber count in the rat model of knee osteoarthritis.
3. Methods
3.1. Ethical Considerations
The present study was in accordance with the National
Institute of Health Publication, and all the ethical princi-
ples were observed regarding working with laboratory an-
imals. It was also approved by the Animal Care and Main-
tenance Committee of the Islamic Azad University of Sari
Branch (no.: IR.MIAU.RECE.1396.132).
3.2. Animals
Fifty four Wistar male rats, aging 2 to 3 months with
a mean initial weight of 250 to 300 g, were divided into
9 groups (each with six subjects), including healthy-
control, osteoarthritis- control, osteoarthritis-training,
osteoarthritis-stem cell, osteoarthritis-hyaluronic acid,
osteoarthritis-hyaluronic-stem cell, osteoarthritis-stem
cell-training, osteoarthritis-hyaluronic acid-training, and
osteoarthritis-stem cell-hyaluronic acid-training. Rats
were housed in cages (each shelf held three rats) with
dimensions of 42 ×26.5 ×15 and in a room with con-
trolled conditions (i.e. 22 ±2°C, 55 ±5 % humidity, and
a 12:12 light-dark cycle with appropriate ventilation). The
animals were fed a daily pellet of 10 g per 100 g of body
weight made by Karaj Behparvar Co. (according to weekly
weighing) and had access to free water through special
bottles.
3.3. Induction of Knee Osteoarthritis
Osteoarthritis was induced using a surgical procedure
developed by Bendele et al. (16). Rats were anesthetized
by ketamine (30 - 50 mg/kg) and xylazine (3 - 5 mg/kg). Af-
ter correcting the right knee, a 1 cm incision was made to
make the knee joint appear. Then, the knee joint was im-
mediately opened by a lateral dislocation of the patellar
bone and the patellar ligament. A longitudinal incision
was made through the parapatellar medial incision. The
lateral dislocation of the patella and patellar ligament was
performed by forceps and then an incomplete incision was
made in the anterior cruciate ligament without damage to
the articular cartilage and other ligaments. Finally, an ar-
ticular capsule with 6 absorbable sutures and skin with 6
silk sutures were closed. The rats were fed standard food
and water for three weeks (16).
3.4. Hyaluronic Acid Treatment
In the hyaluronic acid receiving groups, hyaluronic
acid was injected into the injured joint in three separate
weeks and once a week. The intra-articular injections of
25 µL of HA (Hyalgan®sodium hyaluronate; FidiaFarma-
ceutici S.p.A., AbanoTerme, Italy) was administered using a
27 gauge, 0.5-inch needle. The dose calculated for rats was
determined with reference to the human, as suggested by
Paget and Barnes (17).
3.5. MSCs Intra-Articular Preparation and Injection
MSCs were extracted from the bone marrow of healthy
Wistar rats (250 - 300 g) after inducing anesthesia with ke-
tamine (30 - 50 mg/kg) and xylazine (3 - 5 mg/kg). Isolated
MSCs were cultured in the DMEM medium with 20% FBS in-
cubated overnight to select adherent cells. Cultures were
changed from flask medium every three days to remove
unadhered cells, and MSCs reached < 90% purity after 3
to 4 times passage and were selected for injection. Rats in
the MSCs group received 1 ×106cells/kg by intra-articular
injection of MSCs. MSCs were injected into the right knee
joint of the rats (18).
3.6. Preparation of Tissue Samples and the Way to Measure the
Number of Muscle Fibers
After performing the study, all animals were anes-
thetized and sacrificed by an intraperitoneal injection of
ketamine (60 mg/kg of body weight) and xylazine (5 mg/kg
of body weight), followed by 12 to 14 hours of fasting and 48
hours after the last training session and injections (to elim-
inate the acute effects of training and supplementation),
a completely similar process was used for all cases. The
cartilage and quadriceps muscle were carefully separated
2 Thrita. 2020; 9(1):e105820.
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Tajik M et al.
and washed with distilled water in 10% formalin (Merck,
Germany). After 48 hours of tissue fixation, tissue sam-
ples underwent paraffin molding for histological prepara-
tion. The specimens were then placed in ascending series
of alcohols from 70% to 100% (Merck, Germany), and then
they were exposed to xylol (Merck, Germany) and paraffin
(Merck, Germany) and molded; then using a microtome
(Leica, USA), a 5-micron incision was provided. Each speci-
men was then stained with hematoxylin and eosin (Merck,
Germany) and imaged by light microscopy (Lambda, USA).
From each sample, 5 different fields were randomly eval-
uated at 400 magnification using Image J software (NIH
USA), and the percentage of osteoarthritis injury and the
number of peripheral muscle nuclei were counted by soft-
ware.
3.7. Training Protocol
One month after surgery, one week was spent for famil-
iarizing and adjusting to the research environment and
the treadmill. For this purpose, animals were planned to
run on the treadmill 3 days a week for 10 minutes at a speed
of 16 m/min with 60% - 70% of Vo2max and 0% slope. No
stimuli were applied to move the animals at this stage. The
training protocol consisted of 30 minutes of running on
the treadmill with no slope at a speed of 16 m/min for the
first week. Then, to observe the principle of overload, the
training duration progressively reached 50 minutes in the
eighth week. Before each training session began and af-
ter it was completed, the animals performed warm-up and
cooling for five minutes at a speed of 8 m/min. The control
group was only on the off treadmill during the training ses-
sion with the same time period.
3.8. Statistical Analyses
Descriptive statistics were used to classify and deter-
mine the distribution parameters. The Shapiro-Wilk test
was used to detect data distribution. To investigate the
changes between the groups, a three-way analysis of vari-
ance (ANOVA) and t-test were used. The results were fol-
lowed with a Bonferroni post hoc test. All significant levels
were considered as P < 0.05 (using the SPSS (version 22))
for determining the difference between variables.
4. Results
4.1. Articular Cartilage Area Repair in Different Experimental
Groups
According to the results of the histology section of the
articular cartilage, the extent of tissue damage in the artic-
ular cartilage in the groups receiving hyaluronic acid alone
or in the bone marrow stem cells was not significantly dif-
ferent from the observed model in articular cartilage. Al-
though new cells were found at this site, they were not able
to lead to complete repair of the damaged area. On the
other hand, the results of the combination therapy section
that was associated with exercise training indicated signif-
icant improvement. Based on the results shown in the tis-
sue images, exercise training along with stem cell therapy
or hyaluronic acid also produced a 50% improvement in
tissue, but the combination of all factors led to a better
chondrocyte orientation (Figure 1).
4.2. Evaluation of the Quadriceps Muscle Fiber Count in Differ-
ent Experimental Groups
Based on the results in this section, the number of mus-
cle fibers with a magnification of 400 and at a cross-section
of 300 µm was significantly reduced in the model group;
besides, according to the results, the quadriceps muscle
fiber count in the combination groups was significantly
higher than the model group or the treatment group alone
(Figures 2-4).
4.3. The Effect of Study Interventions on Quadriceps Muscle
Fiber Count
The results showed that the fiber count significantly
decreased responses to knee osteoarthritis (P = 0.001) (Fig-
ure 3).
Aerobic exercise training significantly increased the
fiber count (F = 3006.846, P = 0.001, µ= 0.987). Stem cell
therapy also increased the fiber count significantly (F =
2492.665, P = 0.001, µ= 0.984). Hyaluronic acid intake sig-
nificantly increased the fiber count (F = 794.089, P = 0.001,
µ= 0.952).
Interaction of aerobic exercise training and stem cell
therapy (F = 39.148, P = 0.001, µ= 0.495) increased the
fiber count. A combination of aerobic exercise training
and stem cell therapy increased the fiber count more com-
pared to each one alone.
Although the number of fibers in the aerobic exer-
cise training and hyaluronic acid combination group was
higher than that of the hyaluronic acid alone group, their
combination (F = 0.734, P = 0.397, µ= 0.018) had no signif-
icant interactive effect on the fiber count. Interaction of
stem cell therapy and hyaluronic acid (F = 0.164, P = 0.397, µ
= 0.004) also had no additive effect on the fiber count. On
the other hand, when the three interventions of the exer-
cise training, stem cell therapy, and hyaluronic acid were
applied concurrently, they had an additive effect on the
number of fibers (F = 174.21, P = 0.001, µ= 0.813) (Figure 4).
Thrita. 2020; 9(1):e105820. 3
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Tajik M et al.
Figure 1. Knee articular cartilage in the injured area after treatment with stem cells, hyaluronic acid, aerobic exercise training, or a combination; magnification of images is
400×, with hematoxylin-eosin staining. EXE, Aerobic exercise training; Hyalon, hyaluronic acid; MSCs, stem cell therapy.
5. Discussion
The findings of this study primarily showed that
quadriceps muscle fiber count was significantly reduced
by the induction of osteoarthritis. There are several possi-
ble mechanisms that may explain this reduction: (1) It is re-
ported that expression of MuRF-1 (as one of the major pro-
teins involved in the activation of the muscular atrophy
pathway) increases under conditions of knee osteoarthri-
tis induction in quadriceps (19); (2) osteoarthritis intensi-
fies the pain, and due to the decreased motion, the me-
chanical pressure required to stimulate protein synthesis
pathways in the muscle decreases (20,21). In this regard, De
Ceuninck et al. (22) noted that in the conditions of hip and
knee articular osteoarthritis, lower limb muscle strength
reduces. These changes in muscle protein content, bring
about atrophy and subsequently cause muscle strength
to similarize to non-training and inactive conditions (23);
(3) another possible mechanism for osteoarthritis-affected
muscle mass decrease is inflammation (24,25). In os-
teoarthritis, serum concentrations of inflammatory mark-
ers increase, which is correlated with decreased muscle
mass, physical function, and muscle strength (26,27).
Aerobic exercise training, stem cell therapy, and
hyaluronic acid treatment may have a positive effect on
the muscle affected by osteoarthritis. Aerobic training may
reduce the process of muscle destruction in osteoarthritis
patients through reducing inflammation, an issue that
needs further researches. There are several possible mech-
anisms regarding the effect of stem cell therapy. There is
evidence that cell therapy can heal damaged muscles (28).
It has been reported that in rats with muscle destruction,
stem cell infusion induced new myofibrils and stimulate
satellite cell activity (29). On the other hand, stem cells
can modulate macrophage activity and thus inhibit in-
flammatory processes that lead to muscle atrophy (30).
Regarding hyaluronic acid, it has been reported that the
use of hyaluronic acid can reduce pain in osteoarthritic
conditions and increase joint function (31). Accordingly,
reducing pain increases the motor ability and subse-
quently increases one’s ability to perform physical activity,
which can reduce muscle atrophy processes and maintain
muscle mass and subsequently, muscle strength.
5.1. Conclusions
The present study showed that the concurrent use of
aerobic exercise training, stem cell, and hyaluronic acid
4 Thrita. 2020; 9(1):e105820.
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Tajik M et al.
Figure 2. Histological cross-sections of quadriceps muscle fiber count in different groups examined. Eachcell nucleus is considered to represent muscle fiber. Cross-sections
were prepared at a magnification of 400×and stained with hematoxylin and eosin. EXE: Aerobic exercise training; Hyalon, Hyaluronic acid; MSCs, stem cell therapy.
*
0
0.02
0.04
0.06
0.08
0.1
0.12
Control- Osteoarthritis Control-Healthy
Count Fiber/300µm
Figure 3. The comparison of quadriceps muscle fiber count in the healthy-control
and rat model of knee osteoarthritis. Data are presented as mean ±SD. The rats
are six in each group. *represents a significant decrease in quadriceps muscle fiber
count compared to the osteoarthritis-control group.
treatments had more effect than each intervention alone
on enhancing the muscle fiber count in the rat model of
knee osteoarthritis. Therefore, it is recommended that in
the induced osteoarthritis model, concurrent use of these
three interventions could be effective in reducing muscle
damage as one of the major complications of osteoarthri-
tis. However, further studies are needed, particularly in the
human model, to better understand the effects of these in-
terventions.
Acknowledgments
The authors thank all the teachers of the Central
Branch, Islamic Azad University, who helped them with the
research.
Footnotes
Authors’ Contribution: Study design and coordina-
tion: MAA. Performing the experiment: MT. Drafting the
manuscript: MAA, PF, MP, and MT. All authors read and ap-
proved the final manuscript.
Conflict of Interests: The authors report no conflicts of
interest.
Thrita. 2020; 9(1):e105820. 5
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Tajik M et al.
0
0.05
0.1
0.15
0.2
0.25
0.3
Training-
Hyaluronic acid-MSCs
Training- MSCs Training-
Hyaluronic acid
MSCs-
Hyaluronic acid
Training MSCs Hyaluronic Acid Control
Count Fiber / 300 µm
Figure 4. The comparison of quadriceps muscle fiber count in the different groups of thepresent study. Data are presented as mean ±SD. The rats are six in each group.
Ethical Approval: The present study was in accordance
with the National Institute of Health. Regarding working
with Laboratory Animals. Also, it was approved by the Ani-
mal Care and Maintenance Committee of the Islamic Azad
University of Sari Branch (no.: IR.MIAU.RECE.1396.132).
Funding/Support: None.
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