Results in Immunology 4 (2014) 23–29

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Systemic cytokine response to three bouts of eccentric exercise Stephen M. Cornisha , * , Steven T. Johnsonb a b

Faculty of Kinesiology & Recreation Management, University of Manitoba, Winnipeg, Manitoba, Canada Centre for Nursing and Health Studies, Athabasca University, Athabasca, Alberta, Canada

a r t i c l e

i n f o

Article history: Received 10 April 2014 Received in revised form 21 April 2014 Accepted 22 April 2014 Keywords: Eccentric exercise Inflammation Interleukin 6 Delayed onset muscle soreness

a b s t r a c t This research examined the changes in inflammatory cytokines interleukin 6 (IL-6), IL-1β, IL-10, as well as muscle force, muscle soreness, thigh circumference, and range of motion in response to 3 bouts of eccentric knee extension. Ten males were recruited to participate. The participants performed eccentric exercise on 3 consecutive days on the knee extensors on the right leg separated by 24 h. Participants performed 6 sets of 10 repetitions of isokinetic eccentric knee extension at 120◦ per second. Blood was sampled before and after each exercise bout and 24 h after the final exercise bout. Muscle isometric force, delayed onset muscle soreness (DOMS), thigh circumference, and range of motion were evaluated before and after each exercise bout and 24 h after the final exercise bout. There were no statistically significant differences noted for the changes in isometric strength, thigh circumference, and range of motion, or IL-6 over the 4 days (all p > 0.05). On the second day and third day there was a significant increase noted in DOMS as compared with baseline (p < 0.05). These results suggest that 3 consecutive days of eccentric exercise results in DOMS but does not produce a sustained systemic inflammatory reaction or changes in muscle function.  c 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-SA license (

1. Introduction High intensity eccentric exercise is known to cause skeletal muscle damage and micro-structural changes to muscle fibers with an associated inflammatory response [1,2]. This skeletal muscle damage has been shown to limit muscle strength and performance [3]; however, there is a phenomenon known as the repeated bout effect whereby a previous eccentric exercise bout seems to promote an adaptation that will limit muscle damage, inflammation, and loss of function if a similar bout of exercise is performed after a recovery period [4]. There are a number of theories surrounding the mechanism whereby the repeated bout effect functions including the mechanical theory, the neural theory, and the cellular theory [4]. Within the cellular theory there is a mechanism which proposes that there is less of an inflammatory reaction following the second bout of exercise and this may be the reason for the maintenance or return of muscle strength and function to a greater degree following the second bout as compared to the first bout of eccentric exercise [4]. Even though the mechanism whereby the repeated bout phenomenon occurs is not known, previous research has evaluated the cytokine response to eccentric exercise utilizing the repeated bout effect model. Prior research does indicate an increase in mRNA expression of interleukin-6 and interleukin-8 following a downhill treadmill

run [5]. Also, neutrophils, macrophages, and IL-1β do accumulate in skeletal muscle after an acute bout of eccentric exercise [1,6,7]. Further data suggests a systemic inflammatory response to high intensity eccentric resistance exercise where there is an increase in IL-6 and IL-10 [8]. After completing 2 bouts of downhill running, with 2 weeks of rest in between bouts, Smith et al. [9] demonstrated a decrease in IL-6 and an increase in IL-10 after the second bout of exercise when compared to the first in untrained males. Conversely, knee extensor eccentric exercise separated by 3 weeks did not reveal any change in the mRNA or blood IL-6 response to the exercise between the first and second bout [10]. Further, when compared to pre-exercise concentrations, two bouts of eccentric elbow flexion, separated by 4 weeks, demonstrated a decrease in TNF-α and IL-8 after the first bout of exercise and an increase in IL-10 and decrease in IL-8 following the second bout of exercise [11]. Thus, there does not seem to be any clear consensus as to the cytokine response to eccentric exercise during a repeated bout of exercise. The variation in the response of cytokines noted above is likely related to the type or amount of muscle activated during the eccentric exercise and may be related to the time interval between the exercise bouts. Eccentric exercise and the associated muscle damage will result in delayed onset muscle soreness (DOMS), reduced range of motion, decreased muscular strength, and increased fluid accumulation (edema) in the affected muscle [1]. All of these effects will likely result in reduced performance in a subsequent exercise bout. Nevertheless, the majority of research looking at the repeated bout effect has been done in studies with 1–3 weeks of recovery between the consecutive

* Correspondence to: Faculty of Kinesiology & Recreation Management, University of Manitoba, Winnipeg, Manitoba, Canada. E-mail address: [email protected] (S.M. Cornish). c 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-SA license ( 2211-2839/$ - see front matter  by-nc-sa/3.0/).


S.M. Cornish, Steven T. Johnson / Results in Immunology 4 (2014) 23–29

bouts [1,9–13]. This is not typical of an athlete’s training regime as many times athletes repeat training techniques (such as plyometrics) within 2–3 days. Also, tournament play may require athletes to perform eccentric muscle actions associated with the sport on the same or subsequent days. Thus, a further examination of the inflammatory response associated with repeated bouts of eccentric exercise performed on consecutive days will provide important new information regarding the effects of eccentric exercise in athletes. The amount of time given for rest and recovery following the initial bout of exercise may play a key role in the inflammatory response to exercise. Chen and Hsieh [14] reported an acute increase (after 1 day) in IL-1β and IL-6 after 30 maximal repetitions of the elbow flexors at 60◦ × s−1 with 24 h between bouts. This research was done in a relatively small group of muscles and therefore, it would be interesting to evaluate the effects that minimal rest between exercise bouts has on the systemic cytokine response to repeated bouts of eccentric exercise in a larger muscle group. Few studies have been conducted that evaluated short time intervals of rest between repeated bouts of eccentric exercise on consecutive days therefore, the main purpose of this study was to evaluate the systemic cytokine response to 3 repeated bouts of knee extensor eccentric exercise separated by a 24 h rest period in healthy young men. The main hypothesis was that there would be less of a pro-inflammatory reaction and more of an anti-inflammatory reaction to the eccentric exercise protocol on days 2 and 3 as compared to day 1.

2. Material and methods 2.1. Participants This study recruited healthy young males between the ages of 18 and 30 years. Participants were recruited by placing posters around the university campus and word of mouth. Participants were excluded from the study based on the following criteria: (1) consumption of anti-inflammatory medication (non-steroidal anti-inflammatory drugs, aspirin, or other immunosuppressive medication) within the past month, (2) diagnosed with an inflammatory disease (rheumatoid arthritis, inflammatory bowel disease etc.), (3) had sustained a recent injury, (4) had an illness (infection) within the past 2 weeks or, (5) were taking vitamin, mineral, or other nutritional supplements. The sample size estimated for this study was based on previous research [9] where IL-6 concentration was decreased by 50% immediately following the second bout of eccentric exercise when compared to the first bout of eccentric exercise. With a power of 80%, an alpha level of 0.05, and an expected attrition rate of 25%, 10 participants were recruited which accounted for the expected attrition rate (Statistica version 7, StatSoft Inc., Tulsa, Oklahoma, USA).

2.2. Procedures A single group design was used to evaluate the effects of three separate eccentric exercise bouts on inflammatory markers in males. Dependent variables included: serum concentration of IL-1β, IL-6, and IL-10 as well maximal knee extensor isometric torque, delayed onset muscle soreness, range of motion of the knee joint, and upper leg circumference. Participants were familiarized with all the measurement protocols and the exercise intervention protocol and performed the initial test of dependent variables on the first visit to the laboratory. In total, the participants visited the laboratory 4 times; 3 times for the exercise intervention/testing as well as one time 24 h after the final bout of eccentric exercise to measure the dependent variables again (see Fig. 1). This study was approved by the Human Participant Research Committee at the University of Lethbridge.

2.3. Maximal muscle force Maximum isometric knee extension force was measured on the right leg of each individual using an isokinetic dynamometer (CSMi Humac NORM, Stoughton, Maryland, USA). Participants assumed a seated position and were secured to the chair by stabilizing belts placed across the chest, over the lap, and on the distal one-third of the thigh on the tested leg. Participants sat against a back support with an 80◦ angle of the hip flexors. The rotational axis of the dynamometer was placed coaxial to the knee axis (lateral femoral epicondyle) and the lever arm of the dynamometer was secured to the distal shin by a strap. The knee angle was fixed at 60◦ of knee flexion for the isometric contraction with 0◦ being full knee extension. Participants were asked to exert maximal isometric force against the dynamometer for 10 s and they were verbally encouraged to do so during the entire test. The participants were given a 60 s rest and then the procedure was repeated two more times with the highest torque in Newton meters (N m) recorded. Maximal isometric knee extension force was measured immediately before and after the initial bout of eccentric exercise, before and after exercise bout 2 and 3, and 24 h after the final exercise bout. 2.4. Eccentric exercise intervention The intervention involved three sessions of maximal eccentric exercise of the knee extensors of the right leg separated by a 24 h recovery period. During the 24 h recovery period participants were asked to refrain from any form of physical activity or exercise. Participants performed 6 sets of 10 repetitions of maximal isokinetic eccentric knee extension (CSMi Humac NORM, Stoughton, Maryland, USA) at 120◦ × s−1 with 1 min of rest between each set on each day. This protocol has been used previously to induce muscle damage [13]. Participants were seated and secured to the dynamometer chair as described above but the range of motion of the dynamometer was set between 0◦ (full knee extension) and 90◦ (knee flexion) for the eccentric knee extension exercise. The participants were instructed to resist with maximal force against the dynamometer arm as it moved their knee from extension to flexion. The dynamometer motor was used to passively bring the leg back up to the starting position after each repetition was completed. All participants were verbally encouraged to exert maximal resistance to the dynamometer throughout each session. 2.5. Delayed onset muscle soreness A visual analog scale (VAS) was used to assess delayed onset muscle soreness (DOMS). The instrument consists of a 100 mm long line with the words “no pain” on the left hand side and “unbearable pain” on the right hand side of the line. Participants were asked to draw a vertical line on the scale to rate their current level of pain in their right leg. A pain-rating index was calculated by measuring the distance of the mark from the left hand side of the diagram in millimeters [15]. Pain was assessed before and after each exercise bout as well as 24 h after the final bout with the participants in a standing position. 2.6. Thigh circumference Thigh circumference was measured as an indicator of any edema that may have occurred due to the eccentric exercise intervention. To measure thigh circumference, the halfway distance between the greater trochanter of the femur and the lateral femoral epicondyle on the exercised leg was measured and marked with a horizontal line on each participant using a permanent marker. A measurement of the circumference of the thigh in centimeters was taken at this horizontal line and recorded in centimeters. The participant remained in a standing position with the thigh muscle relaxed and the feet

S.M. Cornish, Steven T. Johnson / Results in Immunology 4 (2014) 23–29


Fig. 1. Experimental design.

shoulder width apart while the thigh measurement was taken. Thigh circumference was measured before and after each exercise bout and 24 h after the final exercise bout. 2.7. Range of motion Range of motion of the knee joint (in degrees) used in the eccentric exercise bouts was assessed with a goniomoter using a protocol previously developed [16]. Briefly, the participant lay prone on the ground

with their right leg fully extended. The fulcrum of the goniomoter was placed on the lateral femoral epicondyle of the right leg. The stationary arm of the goniomoter was aligned with the greater trochanter of the femur while the moveable arm was aligned with the lateral fibula. The fully extended knee was considered the starting position of 0◦ . The participant was then asked to fully flex their knee actively until end range of motion, pain, or soreness was identified. Knee range of motion was measured before and after each exercise bout and 24 h after the final exercise bout.


S.M. Cornish, Steven T. Johnson / Results in Immunology 4 (2014) 23–29

2.8. Blood assays All blood samples were drawn by venipuncture from the ante® cubital vein into serum separator tubes (BD Vacutainer , Franklin Lakes, NJ, USA) under sterile conditions. After inversion, tubes were allowed to clot for 30 min and then centrifuged at 1065g for 10 min at 4 ◦ C. Approximately 3 mL of serum was aliquoted into Eppendorf tubes (3 × 1 mL per tube) and frozen at −80 ◦ C until analysis. All serum samples were evaluated for IL-1β, IL-6, and IL-10 using a high sensitivity enzyme linked immunosorbent assay (ELISA) kits according to the manufacturer’s instructions (R&D Systems, Minneapolis, Minnesota, USA). All assays were analyzed in duplicate within the same microplate to reduce variation. All cytokine assays were read for absorbance on a microplate reader at 490 nm (BioTek ELx808, Winooski, Vermont, USA). When the assay was completed, controls of low, moderate and high concentrations of the cytokines were performed to ensure the kit was functional. All controls were positive in the assay. Blood samples were drawn before and after each exercise bout and 24 h after the final exercise bout. 2.9. Statistical analysis A single factor (time) repeated measures ANOVA was utilized to analyze changes in all dependent variables over time. If there were differences noted in the repeated measures ANOVA, a Tukeys HSD post-hoc test was performed to evaluate mean differences. The statistical analyses were performed using STATISTICA version 7 (StatSoft, Tulsa, Oklahoma, USA) software. The p-value was set at ≤0.05. 3. Results The participants had the following baseline characteristics: mean ± SEM, age: 21.9 ± 0.6 years; height: 179.5 ± 1.6 cm; and weight: 82.9 ± 2.7 kg. There were no differences noted for the changes in isometric strength over the 4 days (see Table 1, p = 0.066). On the second and third day both before and after the eccentric exercise intervention there was a significant increase in DOMS compared to baseline (see Fig. 2). There were no other differences noted for DOMS at any of the other time points. The average of the peak torque produced in each of the 6 sets performed each day was taken and compared over the 3 days. There was no statistical difference noted for the change in average power generated over the 3 days (Day 1: 266.7 ± 26.1 vs. Day 2: 242.7 ± 16.9 vs. Day 3: 263.7 ± 13.7 N m, p = 0.328). There were no differences noted in thigh circumference over the 4 days (see Table 1, p = 0.319). Further, there were no differences between time points for the range of motion produced about the knee joint over the 4 days (see Table 1, p = 0.328). Over the 4 day measurement period IL-6 did not show any significant changes as a result of the eccentric exercise intervention (see Table 1, p = 0.983). Interleukin-1β and interleukin-10 were undetectable in the ELISA. 4. Discussion The main results of this study demonstrate that while there was an increase in delayed onset muscle soreness on the second and third day of the intervention there was no change in the markers of inflammation measured due to 3 days of repeated bouts of eccentric exercise with the knee extensor muscles. This is comparable to previous results where the investigators used a similar eccentric exercise intervention and demonstrated an increase in soluble IL-6 receptor but did not observe any changes in IL-6 or C-reactive protein [13]. However, the current results are different from the increase in IL-6 and IL-1β 1 day after eccentric exercise of the elbow flexors [14]. The results of the current study suggest that there was no acute inflammatory reaction to eccentric knee extension and is in contrast to Chen and Hseigh who demonstrated an acute increase in IL-6 and

IL-1β after one day of eccentric elbow flexion [14]. They did find that continued eccentric exercise over the next 6 days did not further exacerbate the inflammatory event, in fact, the inflammatory markers measured returned to baseline levels and did not rise with the repeated bouts of eccentric elbow flexion exercise. The results of current study combined with Chen and Hseigh [14] suggest that the inflammatory markers measured in these studies may not be substantially exaggerated following repeated bouts of eccentrically based exercise. The reason for the lack of an acute inflammatory response with the first bout of eccentric exercise in this study could be due to several factors. Firstly, the participants may not have been exerting maximal effort and therefore did not produce muscle damage and an initiation of the infiltration of inflammatory markers to degenerate and repair the damaged tissue. Our results indicated that the participants developed approximately 12% less force during the eccentric contractions as compared to the isometric contractions (data not shown) which suggest that a maximal effort was not given. This is in contrast to data from Amiridis et al. [17] who demonstrated that eccentric torque produced at 120◦ × s−1 was between 8% and 14% higher than maximal isometric torque suggesting our participants were giving a sub-maximal effort. This sub-maximal effort likely would not have resulted in much muscle damage as has been previously demonstrated [18] and this could explain the lack of a systemic inflammatory event. Also, our high velocity of movement (120◦ × s−1 ) may have been too fast for the participants to react to and activate their musculature thus, negating the ability of the participants to fully contract the musculature eccentrically which in turn would have produced less fatigue and muscle damage. This certainly remains a possibility as previous research on eccentric contractions at higher velocities (180◦ × s−1 ) has demonstrated that maximal eccentric torque did not change over 3 bouts of 32 maximal voluntary contractions [19] suggesting that higher velocity movements do not develop as much muscle fatigue. Although the scores on the DOMS assessment showed an increase on the second and third day compared to baseline, the scores were not very high suggesting lack of maximal effort on the eccentric knee extension tests. Also, the timing of the blood draws may have influenced the results of this study in that there may have been a cytokine response within the 24 h time period where no measurement was taken. Blood was drawn immediately before and immediately after each exercise bout and there were no blood draws taken in between the 24 h rest period between the 3 days of eccentric exercise. A recent review on exercise-induced muscle damage and inflammation indicates that IL-6 has been shown to increase immediately after and from 1–4 h after eccentric exercise bouts of the quadriceps [20]. Previous research has suggested that, IL-1β is elevated maximally at 2–3 h post exercise [21]. Although this may support the lack of response in IL-1β, other work has demonstrated an elevation of IL-6 beyond 24 h after an eccentric exercise intervention [8]. However, Peake et al. [1] found that IL-6 increased 460% immediately after a 40 min downhill run and stayed elevated at 410% 1 h post exercise but had returned to baseline concentrations at 24 h post exercise. Furthermore, Bruunsgaard et al. [22] found that IL-6 was not elevated 20 and 30 min after eccentrically based cycling exercise but was elevated 2 h after exercise and returned to baseline levels 48 h after the exercise. Another study indicated that after 15 min of one-legged eccentric knee extensor exercise there was not an increase in IL-6 but, at 45 and 90 min there was an approximate 2 fold increase that persisted for 2–4 days after the exercise bout [23]. Additionally, Croisier et al. [12] showed that IL-6 was increased immediately post exercise and at 30 min but returned to baseline levels at 48–96 h after the participants completed the two-legged knee flexor and extensor eccentric exercise. Thus, there does not seem to be any clear consensus as to the timing of the cytokine response to eccentric based exercise but some research does suggest that IL-6 peaks a second time between 8 and 12 h after an eccentric exercise bout [24] which would have been

S.M. Cornish, Steven T. Johnson / Results in Immunology 4 (2014) 23–29


Table 1 Effect of repeated eccentric knee extension on inflammatory response and muscle function in healthy young males (mean ± SEM; n = 10). Variable

Day 1

Day 2

Day 3

Day 4


IL-6 (pg/mL) Pre Post

0.81 ± 0.16 0.95 ± 0.22

0.93 ± 0.15 0.90 ± 0.19

0.85 ± 0.14 0.95 ± 0.16

0.81 ± 0.19


Thigh circumference (cm) Pre Post

57.9 ± 0.76 58.2 ± 0.76

58.0 ± 0.82 58.3 ± 0.85

58.0 ± 0.85 58.2 ± 0.88

58.2 ± 0.79


Range of motion (deg) Pre Post

110.5 ± 2.5 109.0 ± 3.0

108.3 ± 2.3 106.2 ± 1.9

107.5 ± 2.6 106.6 ± 2.1

108.6 ± 5.1


Isometric strength (N m) Pre Post

304.3 ± 17.6 305.4 ± 14.6

291.1 ± 22.6 291.2 ± 17.3

304.3 ± 21.6 309.5 ± 19.6

337.6 ± 14.7


Note: Pre to post refers to measurements made immediately before and immediately after the eccentric exercise intervention on each of the 3 days.

Fig. 2. Delayed onset muscle soreness visual analogue scale. *p < 0.05 from baseline pre measure.

missed in the present study. Although a sustained and prolonged inflammatory response did not occur in the present study, there may have been a more acute inflammatory response that was missed due to the timing of the blood draws. Further, it may be that the eccentric exercise performed in this study was not severe enough to induce an inflammatory reaction. Interestingly, IL-6 is released from contracting skeletal muscle especially under times of glycogen depletion [25]. Although speculative, as glycogen was not measured directly, it may be that with the exercise stress provided in this study that there was not any appreciable extent of glycogen depletion and this may explain the lack of response with IL-6. However, this does not explain the lack of a response of IL-6 from other sources such as neutrophils and macrophages which may infiltrate damaged muscle tissue and release IL-6 and IL-1β to aid in the degradation and repair of the damaged skeletal muscle. It is known that muscle damage produced by eccentric exercise will shift the sarcomere length and will cause less force production at longer muscle angle [26] however, we only tested isometric force

production at one muscle length (60◦ of knee flexion) which may not have exhibited as much of a force decrement compared to testing at a longer muscle length. If we had tested muscle force production at longer muscle lengths it is feasible that we would have observed a significant difference in muscle strength which would be a noninvasive method of assessing muscle damage as previously reported by Warren et al. [27]. Previous studies have indicated that peak torque decrements of 15–43% occur as a result of eccentrically induced muscle damage [28,29]. In our study from day 1 to day 2 there was only approximately a 5% decrease in isometric muscle torque with a return to baseline on day 3 which suggests that there was minimal, if any, muscle damage on day 1 to produce a significant force decrement. Thus, our results indicate that the participants were not giving a maximal effort but it was in fact a submaximal effort. Also, even though our results indicate that DOMS was increased, Nosaka et al. [30] have shown that DOMS is not a good reflection of muscle damage as induced by eccentric exercise. Furthermore, we did analyze myoglobin levels in the blood samples as well (data not shown) which


S.M. Cornish, Steven T. Johnson / Results in Immunology 4 (2014) 23–29

indicated that in the majority of the samples that no protein was present which again suggests that muscle damage did not occur and thus the participants were giving a sub-maximal effort. Thus, the submaximal effort given by the participants in this study was the likely reason for a lack of an inflammatory response. Although there was no measured inflammatory response in this study, our results are in agreement with previous studies performed that suggest there is no inflammatory reaction to eccentric cycling or downhill running exercise [31,32]. Further research out of the same laboratory indicated there is no difference in the expression of inflammatory markers in muscle and epimysium at 48 h after downhill running compared to a control group but, upregulation of leukocytes in the blood after eccentric exercise [33] was observed. The lack of response of the cytokines that were measured in this study does suggest that there was no inflammatory reaction that occurred due to the exercise intervention; however, as mentioned previously there may have been a transient increase in the cytokines measured which was undetected due to the timing of the blood draws. Indeed, Croisier et al. [12] did find that there was an increase in IL-6 of 6-fold immediately post exercise and 8-fold 30 min after exercise which returned to baseline levels 2–4 days post exercise and that this response was similar after the participants underwent a 3 week eccentrically based training program. In the Croisier et al. [12] study, they utilized more musculature than in our study as they performed two-legged eccentrically based exercise of the knee flexors and extensors which again demonstrates that our exercise intervention was not as severe as in previous research. Another limitation of our study is that we only assessed three cytokines whereas if we had assessed more cytokines (such as TNF-α) or other inflammatory markers (such as C-reactive protein) we may have observed an increase in inflammation due to the eccentric exercise intervention. 5. Conclusion The current research suggests that muscle function will not be compromised after sub-maximal eccentric exercise and that there was no prolonged inflammatory cytokine response to consecutive days of eccentric exercise. This may have implications for individuals who participate in eccentrically based exercise or sport as it proposes that performance may not be impaired despite an increase in DOMS produced due to an initial bout of eccentric exercise. However, previous research has indicated that skeletal muscle performance was significantly decreased following an initial bout of high intensity eccentric exercise [18]; thus our results should be interpreted cautiously as the intensity of the eccentric activity in the present study was likely sub-maximal. In summary, while 3 days of eccentric isokinetic dynamometer exercise did result in an increase in DOMS it did not result in any change in the circulating cytokines IL-6, IL-1β, or IL-10 or muscle function at the measured time points. Future research should include more measurement points and evaluate if different modes of eccentric exercise (such as downhill running) or speeds of eccentric isokinetic dynamometer exercise over consecutive days would result in an inflammatory reaction and if this inflammatory reaction would result in loss of muscle function. Acknowledgments This study was kindly supported by the Sports Science Association of Alberta. References [1] Peake JM, Suzuki K, Wilson G, Hordern M, Nosaka K, Mackinnon L, et al. Exercise-induced muscle damage, plasma cytokines, and markers of neutrophil activation. Medicine and Science in Sports and Exercise 2005;37:737–45., 15870626.

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Systemic cytokine response to three bouts of eccentric exercise.

This research examined the changes in inflammatory cytokines interleukin 6 (IL-6), IL-1ß, IL-10, as well as muscle force, muscle soreness, thigh circu...
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