Unaccustomed physical exercise has been shown to cause a response of the immune system with significant changes in diverse immunological parameters such as interleukin-6 (IL-6) in addition to peripheral subsets of lymphocytes (20). The immunologic pattern of cytokines as well as other markers of muscular damage in plasma are influenced by the exercise protocol used (concentric vs eccentric muscle action; intensity; duration; accustomed vs unaccustomed), age, body composition, gender, and race (28). Unaccustomed eccentric muscle action leads to muscle-cell injury, which is known to cause an immediate loss of muscle strength, delayed-onset muscle soreness (DOMS), muscle inflammation (26), and increased cell-adhesion capacity (14). However, data on muscle inflammation after eccentric exercise are conflicting, as proved by Malm et al. (14), who have shown that eccentric physical exercise (downhill running) did not result in skeletal muscle inflammation 48 h postexercise, despite DOMS and increased creatine kinase (CK). Additionally, mononuclear cell infiltration in injured muscles after eccentric muscle action (9) and changes of monocyte function in the blood were observed (14). In contrast, high-intensity concentric muscle action leads to metabolic stress of the exercised muscles, which results in short, temporary muscle fatigue, but not in DOMS (14). Therefore, endurance training usually increases the muscles' resistance to fatigue by inducing increases in the number of mitochondria and in the activity and volume of oxidative enzymes (1), but not resistance to heavy muscle loading by eccentric muscle action. However, because of the high metabolic stress of the whole body, heavy concentric muscle action leads to a pronounced inflammatory response, which could result in a temporary reduction of the immunological defenses (15).
The aim of the present study was to investigate the influence of different forms of exercise on plasma markers of skeletal muscle injury and inflammation, peripheral lymphocyte subsets, and markers of mononuclear cell activation in endurance-trained runners. Previous studies have mainly used downhill running as an eccentric exercise condition, which is not an exclusively eccentric stress of the involved muscle groups. However, because runners are adapted to running regimes, it could not be ruled out that a given adaptation to downhill running might influence the eccentric test results. Therefore, highly endurance-trained men performed one bout of high-intensity concentric exercise (level running) and one bout of high-intensity single-leg eccentric exercise (leg press) after 2 wk of rest.
Fourteen highly endurance-trained male athletes between the ages of 20 and 44 yr were recruited for this study (Table 1). A local university ethics review committee approved the experimental protocol and procedures. Each participant gave written informed consent for voluntary participation before the experiment.
To qualify for the study, a subject had to have a minimum V˙O2 of 50 mL·kg−1. Each subject successfully performed an incremental load exercise test of his V˙O2peak on a treadmill ergometer (ErgoXELG3, Woodway, Waukesha, WI) before the study. After baseline measurements at rest were completed, individual V˙O2peak and maximal heart rate were recorded using a graded treadmill protocol starting at 8 km·h−1 on a 0% incline. Running speed was increased by 2 km·h−1 every 3 min until exhaustion. V˙O2 was measured every 30 s using an open-circuit sampling system (EOS-Sprint, Jaeger, Wuerzburg, Germany), and the highest level of V˙O2 was defined as V˙O2peak. The tests were done 1 wk before the first (concentric) exercise bout. Subjects were asked not to perform any intensive training sessions or to take any medicine for 1 wk before and during the whole study period.
Concentric exercise protocol.
The concentric exercise bout consisted of a 60-min heart rate-controlled outdoor level run at a targeted heart rate of 80% of the individual V˙O2peak. Heart rate was continuously measured using hand-wrist heart rate monitors (Polar, Kempele, FN). The individual running speed was determined via the previously assessed target heart rate (± 2 bpm).
Eccentric exercise protocol.
At least 14 d after the first test, the same subjects performed an eccentric exercise bout, which was conducted on a noncommercially available rack that had been specially designed to elicit eccentric action of the musculus quadriceps femoris of one leg. After a 10-min warm-up period on a treadmill, a special warm-up was performed on the exercise rack to instruct the subjects. Lying horizontally with a knee angle of 90°, each subject pressed the exercised leg against a tilted platform, which was moved by hydraulics. Each subject was instructed to straighten his knee against the pressure of the platform. However, given the arrangements, subjects could not help flexing their knees further, although they tried to resist. The hydraulic system allowed the operator to bring the platform to the starting position without any loading concentric exercise of the investigated leg. Each subject performed a single bout of eccentric exercise consisting of six sets of 10 maximal eccentric contractions using the nondominant leg. Each contraction lasted 1-2 s, with 15 s of rest between contractions. The six sets of contractions were each separated by 3 min of rest.
Blood samples were obtained from a forearm vein immediately before and 1, 6, 24, 72, and 144 h after the two different exercise bouts. Blood was collected in 5-mL plastic syringes containing 1.6 mg of K-EDTA per milliliter of blood (Sarstedt, Nuembrecht, Germany). The samples were immediately processed and centrifuged at 4000 × g for 20 min (Laborfuge 400R, Heraeus, Stuttgart, Germany). Plasma CK activity was assayed on the same day, and aliquots of plasma samples for C-reactive protein (CRP) and IL-6 measurements were subsequently frozen and stored at −20°C until assayed.
CK was measured spectrophotometrically in duplicates with a commercially available assay using a kinetic method (Granutest 15, Merck, Darmstadt, Germany). The upper normal value for CK was set at 80 U·L−1 (25°C); exceeding values were considered exercise effects. The intra- and interassay coefficients of variation (CV) were 8.2 and 10.5%, respectively.
CRP was measured with a commercially available assay in duplicates using the N-Latex CRP mono Kit (Behring Diagnostics GmbH, Marburg, Germany) on the BNA nephelometer (Dade-Behring Diagnostics GmbH, Liederbach, Germany) by particle-enhanced immunonephelometry. The detection limit (standard dilution, 1:20) was 0.175 mg·L−1, with a measuring range of 0.175-1150 mg·L−1. The upper normal value for CRP was set at < 3 mg·L−1. The intra- and interassay CV were 3.5 and 3.4%, respectively.
IL-6 was measured in duplicate with a commercially available assay (Quantikine TM HS Kit, R&D Systems GmbH, Wiesbaden, Germany) using a microplate shaker (Micromix 5, DPC Biermann, Bad-Nauheim, Germany) and the Anthos 2010 elisa reader (Anthos, Wals, Austria). The detection limit was 0.039 pg·mL−1, with a measuring range of up to 10 pg·mL−1 without a dilution step. The normal value for IL-6 is 1.5 pg·mL−1. The intra- and interassay CV were 7.4 and 7.8%, respectively.
Lymphocyte subpopulations were measured using flow cytometry (Becton Dickinson, San Jose, CA, including software). Peripheral blood samples (20 µL) were incubated with antibody solution (10 µL) specific for CD3+, CD4+, CD8+, CD11a+, CD18+, CD19+, CD25+, CD45+, and HLA-DR (all from Cymbus Biotechnology, London, United Kingdom) in the dark on ice for 30 min. After that, cells were incubated with lysis buffer (NH4Cl in a concentration of 1:10) for 20 min in the dark and then centrifuged for 5 min (2000 × g) at 5°C. The sediment was washed twice with 250 µL of phosphate-buffered salt solution (PBS, Dulbecco, Berlin, Germany) containing 2% of fetal calf serum (FCS, Gibco, Grand Island, NY). Cells were then subjected to cytofluorometric analysis, which was performed on 104 cells from each sample using laser extinction at 585 nm (phycoerythrin) and 503 nm (fluorescein isothiocyanate).
Concerning CD3+, CD4+, CD8+, CD25+, and HLA-DR, an overlay was performed within a histogram of the respective fluorescence and a nonspecific IgG antibody. Gates were set at the crossing point of the two curves, and cells were defined with a common algorithm. Cells above the crossing points were considered positive. Nonspecific fluorescence was detected using a nonspecific antibody (IgG, Cymbus Biotechnology, London, Great Britain) and subtracted from the mean fluorescence measured with CD11a+ and CD18+ antibodies. This subtraction provides the specific fluorescence intensity. The values given for the lymphocyte subsets describe the percentage of each lymphocyte subset within the total lymphocyte population.
Statistical analysis was done with SigmaStat 2.0 for Windows. All variables were tested for normal distribution and equal variance. Means and standard errors were calculated to describe continuous variables. One-way and two-way ANOVA for repeated measurements with pairwise multiple comparison procedures (Student-Newman-Keuls method) were used to test statistical difference. A P value of < 0.05 was used to indicate statistical significance.
CK increased by up to 152% during concentric exercise within 24 h (P < 0.001); with eccentric exercise, CK levels increased by up to 1072% at 72 h (P < 0.01) (Fig. 1). There was a significantly higher increase in CK after the eccentric exercise part compared with the concentric bout for the 72- and 144-h measurements (P < 0.001) (Fig. 1). IL-6 increased significantly (P < 0.001) 1 h after concentric exercise, from 0.99 to 5.09 pg·mL−1, whereas no increase could be found after eccentric strain. This led to differences between the groups at this time point (P < 0.001) (Fig. 1). For CRP, levels also increased significantly (P < 0.001) after concentric exercise by up to 192% just at 24 h postexercise (Fig. 1). This resulted in significantly higher values for the concentric part compared with the eccentric part at 6 and 24 h (P < 0.001) and also for the 72-h measurement (P < 0.05).
The total count of leukocytes showed a significant increase after both modes of exercise, increasing significantly more quickly and higher 1 h (P < 0.001) and 6 h (P < 0.05) after concentric exercise (concentric: 5935 to 10,750 μL−1; eccentric: 6036 to 7886 μL−1) (Fig. 1).
Monocytes performed an antidromic development. Although monocyte plasma levels decreased significantly (P < 0.01) under concentric exercise at 72 h, for eccentric exercise, levels rose significantly (P < 0.01) at the 6-h measurement (Fig. 2).
The total count of lymphocytes decreased markedly (P < 0.001) 1 h after both modes of exercise without any significant difference between the groups, returning to baseline after 6 h. In detail, CD3+ cells showed a significant difference between the exercise modes 24 h after exercise, with a higher increase for the eccentric part (Fig. 2). The CD3+/CD4+ cells showed significant increases for both exercise modes at 1 and 6 h (P < 0.001), with no significant training-mode differences for all time points between the groups. Additionally, there was an increase after 144 h of concentric exercise (P = 0.01) (Fig. 2). CD3+/CD8+ cells showed a marked decrease at 1 and 6 h (P < 0.01) after concentric exercise, returning to normal values within 24 h, resulting in a significant between-groups difference (P < 0.01) at 1 h (Fig. 2).
CD25+-marked CD8+ cells showed no significant changes after any mode of exercise, but CD25+/CD4+ cells rose by up to 17.5% for concentric and 19.3% for eccentric postexercise levels and leveled off at resting values within 24 h, leading to significant changes for both modes of exercise (P < 0.01) (Fig. 3).
HLA-DR+-marked CD8+ cells showed no significant changes after concentric exercise, even though numbers decreased to a level of 1.4% between the training modes at 6 and 12 h postexercise (Fig. 3). HLA-DR+/CD4+ cells showed no change after eccentric exercise, but they increased significantly within the first hour after the concentric bout (P < 0.001). There was a significant difference between each type of exercise at the 6-, 24-, and 72-h time points (P < 0.001) (Fig. 3).
B-lymphocytes were measured using CD19 and CD45 antibodies. A significant increase (P < 0.001) was found within the first hour after both forms of exercise (concentric: 17.9 ± 1.5%; eccentric: 14.3 ± 1.3%), showing a significantly higher increase after concentric exercise (P < 0.001).
The day after eccentric activity, CD11+ monocytes showed a marked increase (P < 0.01), which remained elevated for the subsequent 6 d. On the contrary, levels dropped significantly after concentric exercise at the 6-h measurement (P < 0.001), with further regression until day 6 (P < 0.001) (Fig. 4).
Monocytes with CD18+ surface markers showed a significant decrease at the 6-h margin for the concentric exercise mode (P < 0.001), but levels rose after eccentric exercise. This left a significant difference between the two groups after 72 h (P < 0.001) (Fig. 4).
In the present study, 14 highly endurance-trained male runners performed a level high-intensity concentric run and an eccentric leg-press exercise that was unfamiliar to them. Additionally, accustomed versus unaccustomed strain influenced the exercises performed. A highly significant increase in CK was only found after the eccentric bout, indicating exercise-induced muscle-fiber injury after unaccustomed exercise (5,27) and thus differentiating the two exercise bouts on the basis of muscle-cell damage (Fig. 1).
The increase of CRP and IL-6 after acute physical exercise is a commonly described phenomenon (3,29). These inflammatory markers generally increased after concentric exercise but were not elevated after eccentric exercise, indicating a pronounced systemic immune response after the level run (Fig. 1). In the literature, there is no consensus on which kind of exercise, eccentric (4,17,23,25) or concentric (3,16,29), induces the increase of these cytokines. It is not yet clear which cells produce and distribute IL-6. Besides the theory of activated T-cells and monocytes, there is also evidence for a muscular origin (endothelic cells, muscular cells) (4,19).
Smith et al. (25) compared their results with data from a concentric exercise test and concluded that the IL-6 increase was less significant and occurred later after the exercise. In agreement with the data of Brenner et al. (3) and in contrast to the results of Bruunsgaard et al. (4), our data show a significant increase of IL-6 after the level run (Fig. 1). The differences, especially after the concentric exercise bout, are most likely attributable to the different modes and diverse durations of the exercises. In the study of Bruunsgaard et al. (4), the subjects were loaded for 30 min at 65% V˙O2max, and Brenner et al. (3) loaded their subjects for 120 min at 60% V˙O2max. In our study, the subjects were loaded for 60 min at 80% V˙O2max. Therefore, the changes in immunological parameters probably depend on the intensity of exercise, as Gabriel and Kindermann have stated (6).
In contrast to the results of previous studies (4,23), we did not find a significant increase of IL-6 during the recovery of the leg-pressure test (Fig. 1). This could be attributable to the different timing of the blood sampling. The studies of Bruunsgaard et al. (4) and Rohde et al. (23) found a significant increase 90 min after exercise. Looking at our data and our measurement points (1 and 6 h), we cannot exclude this increase. The slightly higher 1-h value may indicate a further increase of IL-6. We did not measure any significant increases in IL-6 after an eccentric exercise bout; therefore, our data are contrary to the findings of Pedersen et al. (18), who discuss an IL-6-supported increase after eccentric exercise with a strong correlation to the muscle damage induced. Our findings are supported by Rohde et al. (23), who concluded that the measured increase of IL-6 is independent of the muscle proteolysis (23). Additionally, the missing increase of the CRP during the 6-d follow-up, which is in accordance with a previous study from our group (26), seems to be another indicator of the absence of a further inflammatory response after the eccentric exercise bout. The discrepancy in the rise of the inflammatory cytokines between the accustomed concentric and unaccustomed eccentric exercise may be attributable to the higher metabolic loading in the level run, exceeding the local inflammatory processes after leg press.
The 60-min level run resulted in a significant leukocytosis that was mainly ruled by neutrophilic granulocytes and in a short-term lymphopenia; this is consistent with other publications (7,15). In the eccentric bout, we found a similar leukocytosis and lymphopenia during the recovery phase, similar to the results of other groups (13). However, the leukocytosis was significantly less pronounced in contrast to the level run.
These results are in contrast to a study by Pizza et al. (22), who described a more pronounced leukocytosis after eccentric exercise. They also loaded runners with two different exercise bouts, one mainly concentric and one mainly eccentric bout. The eccentric exercise in this study was performed in a downhill run, putting a load on the organism that involved the whole body, or at least more than one muscle. However, runners are more or less accustomed to downhill running, which explains the only slight CK peak after 12 h, indicating the only moderate strain in the study of Pizza et al. (22). Contrary to this finding, Peake et al. (17) propose that neutrophil activation (and therefore also leukocytosis, as discussed above) remain unchanged after downhill running in trained subjects, despite increases in markers for muscle damage. This was also observed by Malm et al. (14), who took muscle biopsies after graded eccentric exercise and could not trace any signs of inflammation 48 h postexercise, despite increased DOMS and CK blood levels. Saxton et al. (24) conclude that systemic stress evoked during an acute bout of eccentric exercise, and not the degree of muscle damage induced, leads to increased activation of leukocytes. Our data therefore support the suggestion by Saxton (24) because our eccentric protocol clearly induced muscle-fiber injury without any metabolic load. This and the unaccustomed nature of the eccentric exercise may explain the different results of our study, although it does not explain the discrepancies between the studies discussed above.
Lymphocytes express a large number of different surface molecules marking different functions and particular stages of differentiation and activation. In this study we looked for CD4+ and CD8+ cells involved in this mechanism and their activation concerning expression of CD25 (the α-chain of the IL-2 receptor) and HLA-DR, B-cells (CD19+), and CD45 as a pan-lymphoid cell marker. The adhesion molecules CD11a and CD18 were also investigated as markers for transmigration.
We observed a difference in activation of CD4+ and CD8+ lymphocytes between concentric and eccentric exercise. For the unaccustomed eccentric exercise, the activation was comparably higher in the HLA-DR+/CD4+ and HLA-DR+/CD8+-cell groups and also for CD25+/CD4+ cells 6 h after the eccentric bout (Fig. 3). This increase might be attributable to a real activity change of the suppressor cells, because no significant changes in the CD3+/CD8+ cells are observed (Fig. 2). Pizza et al. (22) evaluated for CD25+/CD8+ cells a significant increase after a downhill run; therefore, a more pronounced increase of CD25+/CD8+ cells for our eccentric bout might be possible, given that data for the time span between the 6- and 24-h measurement are missing. However, we consider this unlikely, because our eccentric test regime only induces stress on a single muscle group, in contrast to the previous studies. This difference in activation might be attributable to two contributing factors: the unaccustomed nature of a single-muscle exercise and the reduced metabolic loading in bench press. One limitation of our study is the lack of hormone measurements. However, hormonal reaction to exercise mainly happens within the first minutes after exercise (11). Because our follow-up was focused on the long-term effects of exercise-induced immunological reactions, and because other factors such as nutrition and circadian patterns of hormone secretion are critical to examining the hormonal responses, we omitted tracing hormones.
Three days after the concentric exercise bout the monocytes showed a significant decrease (Fig. 2). Also, the LFA-1 (CD11a+/CD18+) activity measured on the monocytes decreased 3 d after the concentric exercise after a short initial increase (Fig. 4). This observation is consistent with Gabriel et al. who also measured a decline below preexercise values for monocytes after concentric exercise, along with a suggested increase in avidity of LFA-1 (8). This increase in avidity and/or the activation of this molecule improves the cellular adhesion and supports the migration, which plays a vital part in the recovery of the muscle. This is also described for eccentric exercise (2,12). It seems that there has been an activation of LFA-1 through exercise with a following deactivation or migration (e.g., into the muscle) of the activated monocytes. Six hours after eccentric exercise, an initial increase in the monocyte-count was followed by a significant decrease at 24 h. This trend has previously been described (8,13). LFA-1-activation demonstrated a significant increase during the same time and ceased on a high activity level up until 6 d after exercise (Fig. 4). Because of a significant decrease of the monocyte-count at this period, this displays a real activation of the LFA-1. MacIntyre et al. (12) promote a bimodal stress response after an unaccustomed eccentric exercise bout; the initial phase (0-4 h) marks the mechanical injury, and the second phase (20-24 h) with an acute inflammatory response marks the phagocytic acitivity at the injury site. Our findings can be retraced along this model.
We did not observe LFA-1 activation after the concentric bout in the same extent as in the eccentric bout, so it may be possible that the degeneration of muscle cells after eccentric exercise induced the expression of LFA-1 on monocytes. Other authors have reported similar results for MAC-1 (CD11b+/CD18+) on monocytes, which is considered to be a similar marker for activation like LFA-1 (10,13,21). Along with our study, these studies prove the importance of adhesion molecules following exercise, as the adhesion of circulating monocytes to the site of mechanical injury represents one of the key events in monocyte recruitment.
In summary, the results of this study in endurance-trained male runners showed for accustomed concentric exercise mainly an acute-phase response with increased CRP and IL-6 responses, which were probably attributable to the high metabolic loading. In the absence of significant signs of muscle-cell injury, we observed only an activation of the subsets of the CD4+ lymphocytes.
In contrast, unaccustomed eccentric exercise provided a marked delayed increase in CK accompanied by an activation of monocytes and CD4+ and CD8+ lymphocyte subsets. This and the lacking increase of CRP and IL-6 may reflect the lower metabolic loading of bench press exercise, leading to a local inflammatory process with invasion of monocytes into the injured muscle.
We conclude that the immunological reaction after exercise is not only dependent on the type of contraction (concentric/eccentric) but also depends to the adaptation to the nature of the exercise (accustomed/unaccustomed).
We thank Dominik Grathwohl for the organization of the athletes and the continued support throughout all aspects of this research, as well as Sabine Jotterand, Karsten Maurer and Ansgar Seibel for technical advice.
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