Abstract
Objectives
There are conflicting data on the influence of physical activity on paraoxonase1 (PON1) activity. The purpose of this study is to investigate the effect of maximal exercise (ME) on plasma paraoxonase (PON) and arylesterase (ARE) activity in elite rugby players. In addition, the influence of training experience and PON1 Q192R polymorphism on PON1 activity changes at ME was evaluated.
Methods
Twenty-five elite rugby players ages 22.0 ± 3.71 years, consisting of 11 juniors – J (2–7 years of training) and 14 seniors – S (8–15 years of training), completed ME on a cycle ergometer. PON and ARE activity, ferric reducing activity of plasma (FRAP), uric acid (UA), and total bilirubin concentration, as well as thiobarbituric acid reactive substances and lipid profile were investigated in the plasma before, at the bout, and 30 minutes after ME.
Results
At the bout of ME we found an increase in PON1 activities, ARE/high-density lipoprotein C ratio, TBil, and TChol. However, ARE activity changes were not observed in the group of rugby players training for ≤7 years. FRAP and UA increased later – 30 minutes after ME.
Conclusion
We conclude that in rugby players PON1 changes during ME depend on age, body composition, and training experience. The influence of PON1 Q192R polymorphism on PON1 changes at ME remains debatable.
Introduction
Regular physical activity is considered a factor in preventing the development of cardiovascular disease (CVD). It is associated with beneficial changes in plasma lipoprotein content, i.e. an increase in high-density lipoprotein cholesterol concentration (HDL-C) and antioxidant defense.Citation1,Citation2 A single bout of strenuous exercise, on the contrary, results in an increase of oxygen consumption and excessive free radicals formation. It is, therefore, of interest to study antioxidant mechanisms, which are repeatedly evoked during exercise sessions leading to favorable changes in the plasma of trained individuals. The adaptation mechanisms involve the stimulation of enzymatic and non-enzymatic antioxidants. Aerobic exercise was found to induce the expression and synthesis of antioxidant enzymes.Citation3,Citation4
Paraoxonase1 (PON1) is an exceptional enzymatic antioxidant as it is the only enzyme associated with lipoproteins, particularly high-density lipoprotein (HDL), which protects low-density lipoprotein (LDL) from oxidation.Citation5 Moreover, PON1 exhibits homocysteine thiolactonase activity. Therefore, it plays a protective role toward proteins, as highly reactive homocysteine thiolactone damages the structure of the protein molecule and impairs its physiological properties.Citation6 These properties of PON1 determine its anti-atherogenic role.
PON1 activity in humans is modified by genetic and lifestyle factors such as genetic polymorphism and the level of physical activity.Citation7 The Q192R variant of polymorphism is most known and significant for the modification of PON1 activity. Alloenzyme Q, as compared to alloenzyme R, has greater antioxidant activity toward lipoproteins and is associated with a lower risk of CVD. Both isoforms hydrolyze phenyl acetate (arylesterase activity – (ARE)) at the same rate and paroxon (paraoxonase activity – PON) at different rate.Citation7 Due to different substrate specificity, PON1 192 genotypes may be distinguished by the ratio of PON/ARE activity.Citation8
The level of physical activity may also influence PON1 as trained subjects were found to have higher PON1 levels (activity and/or concentration) in comparison to sedentary individuals.Citation9 However, research on the influence of regular and single physical exercise on PON1 activity has given incoherent and often contradictory results (see in RefCitation7). In our previous study on very young novice amateur sportsmen engaged in an aerobic training program, we observed an increase in both, PON and ARE activities at the bout of ME at the treadmill. We concluded that PON1 may be a co-factor of the first line of antioxidant defense during ME.Citation10 However, it was still questionable, if the observed PON1 changes at the bout of ME would only apply to sportsmen with the aforementioned characteristics or if the phenomenon was more generalized, applying to other groups of sportsmen.
Table 1. Descriptive characteristics of subjects
The purpose of this study was to investigate PON1 activity and antioxidant status in experienced rugby players during ME on cycle ergometer; therefore looking at different conditions than in the previously performed experiments.Citation10,Citation11 Our aim was to find whether the type and duration of training before trial affects changes in PON1 activity induced by ME. In addition, dependence on PON1 polymorphism was investigated.
Subjects and methods
Subjects
Experiments were done on 25 healthy male sportsmen, elite rugby players, ages 22.0 ± 3.71 years. They had training experience of about 7.76 ± 3.62 years. Since our subjects had a broad range of training experience (2–15 years), we stratified the subjects into two subgroups: juniors – J (2–7 years of training) and seniors – S (8–15 years of training). Calculations were performed on both subgroups and the whole group. All subjects were players from the first league Sport Club ‘Budowlani’, multi-time national champions of Poland. Their training program consisted of an average of 2.5 hours daily exercise sessions performed five to six times a week. All testing was conducted during the last preparation cycle to the starting phase of the rugby league season. Personal interviews revealed that the subjects were non-smokers and were not taking drugs affecting lipid metabolism. All volunteers signed an informed consent upon participation in the experiment. The study protocol was accepted by the Bioethics Committee of Medical University of Lodz nr RNN/163/06/KE.
Study design
All testing was done in an air-conditioned laboratory, between 9 a.m. and 1 p.m. after a 12-hour overnight fast. Before starting the exercise, selected antropometric and physiological parameters were measured as listed in . In addition, venous blood (the first sample – ‘before’) was collected from all volunteers into lithium heparin Vacutainer (Becton, Dickinson and Company, New Jersey, USA) tubes. Then the sportsmen performed their exercise test on a cycle ergometer (Ergometrics 900, Ergoline) until they reached maximal oxygen consumption (VO2max) and could no longer continue the test because of exhaustion. Plateau of VO2 curve and the value of respiratory exchange ratio (RER) >1.1 were assumed as the criterion of VO2max. During the test, the load increased by 50 W every 2 minutes starting from 150 to 200 W depending on the sportsman's weight (<72 kg − 150 W, 72–86 kg – 175 W, >86 kg – 200 W). Selected cardiorespiratory parameters were measured continuously beginning at 10 minutes before the physical activity until 10 minutes after ME as listed in . The second sample of blood (‘acute bout’) was taken at the bout, and the third (‘after’) was taken 30 minutes after completion of the exercise. The blood was centrifuged (3000 × g, 4°C, 1 minute); blood plasma was frozen and stored at −80°C for 1 year for the biochemical determinations listed in Tables and .
Table 2. Markers of physiological status measured at the bout of ME
Table 3. PON and ARE activities in plasma before, during and after (30 minutes) ME depending on PON1 polymorphism and training experience, mean ± SD
Table 4. Biochemical characteristics of plasma during ME, mean ± SD
Measurements at baseline and at ME
Baseline
Body composition (lean and percent of fat) and basal metabolic rate (BMR) were assessed with Bodystat 1500 (Bodystat Ltd, UK). Systolic and diastolic blood pressure and heart rate (HR) were measured using electronic sphygmomanometer OMRON M4-1.
Maximal exercise
Chosen cardiorespiratory parameters were monitored with the VO2000 MedGraphics Cardiorespiratory Diagnosic Systems that was compatible with the Breeze suite 6.2 A Med Graphics software. Parameters listed in were taken at the bout of ME.
Determinations in plasma
PON and ARE of PON1 were measured by an adapted procedure described by Nakanishi et al.Citation8 using paraoxon and phenyl acetate as substrates. The change of absorbance dependent upon the generated products of reaction was monitored using an Ultrospec III spectrophotometer (Pharmacia LKB, Biochrom Ltd. England) and Spectro-Konetics software. PON1 Q192R genotypes were distinguished using PON/ARE activity ratio, where QQ <5.0, QR 5.0–11.0, RR >11.08.
The process of lipid peroxidation in plasma was estimated as thiobarbituric acid reactive substances (TBARS) concentration using thiobarbituric acid as previously described;Citation12 total antioxidant activity was measured as ferric reducing activity of plasma (FRAP) according to Benzie and Strain.Citation13
Lipoproteins, uric acid (UA), and total bilirubine (TBil) concentrations were estimated in the laboratory of Military Teaching Hospital no. 2 in Lodz, Poland, by means of Olympus AU 640 autoanalyzer.
The compounds were derived from Sigma Aldrich Chemical (St Louis, MO, USA) with the exception of Trizma base derived from Fluka (Buchs, Switzerland) and Triton X-100 derived from Serva Feinbiochemica (Heidelberg, Germany).
Statistical analysis
All analyses were carried out using Statistica Software, version 10. Results were expressed as mean ± standard deviation (SD). The differences among biochemical variables obtained before, at the bout, and 30 minutes after ME were analyzed using Friedman analysis of variance followed by Wilcoxon test for paired samples post hoc. Differences between comparison groups were estimated using U Mann–Whitney test. Pearson product-moment correlation coefficients (r) were calculated to estimate pairwise correlations and multiple correlation coefficients (R) were calculated using multiple linear regression analysis to evaluate the influence of multiple variables. All results with P < 0.05 were considered statistically significant.
Results
The results of the preliminary tests listed in show that the volunteers in our study were healthy, with cardiovascular parameters within normal range and body construction and composition typical for rugby players. The measurements performed at the bout of ME allow for an assessment of the cardiovascular and respiratory conditioning and function of the organism (). RER equal to 1.31 indicates involvement of an anaerobic metabolism due to maximal effort. VO2max equal to 46.29 ml/kg/minute, measured on cycle ergometer, is typical for well-trained rugby players.Citation14
The effect of ME on PON/ARE depending on PON1 Q192R polymorphism
For the whole group of 25 investigated subjects, PON increased substantially at the bout of ME by 19.3%, and remained elevated 30 minutes after ME (). Even a higher increase, by 37.8%, was registered for ARE. After ME, ARE returned to the basal value unlike PON. When the subjects were assigned to separate phenotype subgroups, i.e. Q subgroup (QQ) and R subgroup (including both phenotypes QR and RR), increases of PON1 activities expressed in percentage values were similar to results of the whole group. Statistical analysis of the values of these activities in each subgroup revealed that in the Q subgroup the PON increase at acute bout of ME was statistically significant. This result is similar to the results obtained in the whole group of sportsmen. However, unlike in the whole group, PON in the Q subgroup returned to the basal level 30 minutes after ME. In the R subgroup, no statistically significant increase at the bout of ME was registered for either PON or ARE. However, it should be noted that the vast majority of the subjects (21 volunteers) had QQ phenotype ().
The effect of ME on PON/ARE depending on training experience
No differences between the S and J subgroups in PON and ARE before ME were found. PON increased in both subgroups at the bout of ME (). In the J subgroup the activity increased by 15.7% and in the S subgroup by 22%. In the S subgroup, however, the rise was short-lasting since 30 minutes after ME PON returned to its basal level. While in the J subgroup, it remained at a similar level as at the bout of ME (the difference between ‘acute bout’ and ‘after’ values was not significant, P > 0.05). ARE was found to increase at the bout of ME only in the S subgroup (by 55.76%). After ME it was still elevated in comparison to before ME. In the J subgroup, no changes of ARE were observed at any examined time.
The effect of ME on PON1 activity standardized for HDL-C
In the whole group no differences were observed in PON/HDL-C ratio before, at the bout and after ME in contrast to ARE/HDL-C ratio, which increased at the bout of ME (P = 0.01) ().
Similarly, in Q subgroup PON/HDL-C ratio did not change throughout the study but ARE/HDL-C ratio was higher at the bout of ME (P = 0.004).
Stratification of the rugby players based on their training experience revealed no differences in PON/HDL-C and ARE/HDL-C ratios in both subgroups. PON/HDL-C ratio was found not to change throughout the study in either subgroup. ARE/HDL-C ratio changed in S but not in the J subgroup. In S it rose at the bout in comparison to before ME (P = 0.005). After ME it was still observed at a higher level than before ME (P = 0.02).
The effect of ME on biochemical values in the plasma
Values of all investigated parameters increased at the bout of ME, but significant increase was found only in the case of TChol – by 14.1%, TBil – by 8.4%, and ARE/HDL-C – by 31.9% (). At 30 minutes after ME, most parameters returned to the values of ‘before exercise’. A completely different pattern of change was observed for UA and FRAP, as these parameters were still increasing 30 minutes after ME, to reach levels significantly exceeding those of before ME. The value of UA increased by 22.7% and FRAP increased by 18.2% in comparison to the basal level.
Correlations between PON/ARE and other variables
Correlation with antropometric parameters resulted in a negative correlation between age and ARE tested before ME (r = −0.570, P = 0.003). ARE increment at the bout of ME was found to correlate with the training experience of rugby players (r = 0.45, P = 0.023). No association was found between PON/ARE and aerobic endurance indices of subjects such as VO2max or VO2 at aerobic threshold or HRmax. However, a positive correlation was found between HR at rest and PON increment at the bout of ME (r = 0.6, P = 0.002). Multiple linear regression analysis revealed an association between ARE after ME and the combination of body fat, weight and lean (RCitation2 = 0.36, F = 5.02, P < 0.009).
Correlation with blood biochemical data showed a moderate positive correlation between PON and HDL-C: before (r = 0.491, P = 0.020), at the bout (r = 0.448, P = 0.036), and after ME (r = 0.493, P = 0.019). Moderate positive correlation was also seen between PON and FRAP: before (r = 0.438, P = 0.032), at the bout (r = 0.446, P = 0.029), and after ME (r = 0.462, P = 0.023). Significantly stronger correlation was found between UA and FRAP: before (r = 0.639, P = 0.001), at the bout (r = 0.496, P = 0.019), and after ME (r = 0.687, P < 0.001). In addition, the correlations between the increments of PON/ARE activities from the basal values to those obtained at the bout of ME with other registered data were examined. It was found that ARE increment was negatively correlated with ARE before ME (r = −0.504, P = 0.01) and PON increment was negatively correlated with FRAP level before ME (r = −0.804, P = 0.01).
Discussion
The effect exerted by a single bout of strenuous exercise on the components of antioxidant capacity of plasma and lipoprotein content is controversial. Our study focused on a group of elite rugby players. We chose this group of subjects to find whether ME would cause different changes in the biochemical composition of the blood in professional sportsmen after training at intensities often requiring anaerobic energy production as opposed to changes found in young sportsmen after typical aerobic training, which we described previously.Citation10
Many lifestyle factors such as the intensity, frequency, and type of physical activity are known to modify cardiovascular risk factors. One of these factors, which depends on lifestyle, is the lipid and lipoprotein profile in plasma. Publications show ambiguous results of the effect of intensive exercise on the concentration of TChol and its fractions.Citation15 The effect depends on the physical fitness of subjects, their lifestyle, the basal, pre-exercise concentrations of these lipids as well as the duration and intensity of the physical exercise.Citation15 PON1 activity changes induced by physical activity may, in parallel to lipid concentration changes, be expected as PON1 is an enzyme associated with the HDL particle. There is no concordance among the researchers as to the influence of HDL-C concentration on PON1 activity. Both positive correlationCitation16 and lack of associationCitation17 were observed. In our study on elite rugby players regularly practicing aerobic and intensive anaerobic physical activity for a relatively long time, we observed a significant increase in TChol concentration in plasma during ME with accompanying but not significant increment of HDL-C. At the same time both PON and ARE increased significantly. It was found that there is a positive correlation between PON and HDL-C before, at the bout, and after exercise. These observations are very similar to those previously obtained in young sportsmen.Citation10 A similar relationship between PON/ARE activity and HDL-C concentration was found, in Tsakiris et al.'sCitation16 study of very well-trained male basketball players, all members of a champion team; but this relationship was seen before physical activity. Therefore, it may be presumed that the rise in PON1 activity during physical exercise was due to the increase in the concentration of the enzyme as a consequence of the increase of HDL-C concentration. Indeed, after standardizing PON1 activity for HDL concentration (PON/HDL-C) no changes in PON were found. However, an increase in ARE and ARE/HDL-C was still observed at the bout of ME. Therefore, this change in ARE activity of PON1 could not have been a simple consequence of the increase in the number of the protein molecules associated with HDL particles. We hypothesize that it was rather influenced by the changes in the properties of HDL particles, which in certain conditions can even render proinflammatory (dysfunctional HDL).Citation18 Qualitative changes of HDL particles depend mainly on alterations in the susceptibility to oxidation of unsaturated fatty acids found in phospholipids, triglicerides, and apolipoprotein A-I (Apo A-I).Citation19 Phospholipids and Apo A-I are necessary to preserve PON1 stability and may indeed modify the enzyme's activity.Citation20
In our study, we found that ARE was associated with the combination of body fat, weight, and lean. Our results confirm our previous finding that PON1 activity in sportsmen is related to body composition.Citation10 Indeed, it was repeatedly observed that PON1 activity may depend on body weight or BMI. In most studies, obese subjects were found to have lower PON1 levels in comparison to subjects with normal weight;Citation21,Citation22 though decrease in PON1 activity after weight reduction was also found.Citation23 Moreover, we observed that ARE was higher in younger subjects, which is in concordance with other studies.Citation24 Decrease of PON1 activity with age is probably due to a lower number of the enzyme particles with a free sulfydryl group at Cys284.Citation25
Our next step was to find whether the period of training of professional rugby players would influence the activity of the enzyme. Although no differences were found when comparing PON1 activities before exercise, we observed a different effect of ME on ARE depending on the period of training of rugby players. The increment of ARE at the bout of ME was higher in sportsmen who had a longer training period. When the subjects were divided into two subgroups, it was found that the increase in ARE was actually observed only in the S subgroup, while ME had no effect on ARE in the J subgroup. It is often stressed that there is a progressive improvement in the physiological capacities of rugby league players as playing experience increases.Citation14 We suggest that the antioxidant protection offered by PON1 during exercise may be yet another of these compensational mechanisms, which are developed with training experience. Sportsmen practicing typical aerobic physical activity receive PON1 protection during ME much sooner, evident after 3 years of regular training.Citation10 When physically active and sedentary subjects were compared, even basal PON1 activity was higher in subjects practicing sports.Citation26 In young sportsmen after aerobic training, a weak association was found between PON1 activity and physical fitness indices.Citation10
Another purpose of our study was to determine whether the changes in PON1 activity during physical exercise depend on Q192R polymorphism of the enzyme. We measured PON1 phenotype as it was found to be more relevant than genotype in assessing PON1 antioxidant activity.Citation27 We observed a significant increase in PON and ARE at the bout of ME only in the Q subgroup but not in the R subgroup. But it must be stressed that these results are most probably influenced by a drastically uneven number of subjects in both of these subgroups: 21 in Q subgroup and only 4 in R subgroup. This distribution of PON1 Q192R phenotype/genotype with significantly lower frequency of R allele is typical for the Caucasian race, especially in comparison to African race.Citation28 Considering the uneven PON1 Q192R allele distribution in our study, our observations only suggest but do not have essential power to prove the relationship between PON1 polymorphism and exercise-induced PON1 activity changes. To our knowledge, the only report on the impact of PON1 polymorphism on its enzymatic activity assayed in connection to acute exercise was published by Tomas et al.Citation17 However, unlike us, the authors determined PON1 genotype, not phenotype. Similar to Tomas et al.'s study, in our study a faster return of PON to its basal value was observed in the Q subgroup in comparison to the whole group. This return was registered already 30 minutes after exercise. This may suggest a lower antioxidant effectiveness of PON in Q subgroup and a faster consumption of the enzyme under conditions of oxidative stress, which certainly is taking place during ME at the level of RER equal to 1.31. These results are not in accordance with Aviram et al.'s observations.Citation29 Their in vitro study showed that antioxidant protection of Q alloenzyme is more efficient than R and during oxidation its activity is maintained for a longer time.
Certain discrepancies in PON and ARE activity changes influenced by ME were observed. Unlike PON, ARE returned to the basal level 30 minutes after ME (). The increment of PON and ARE activities at the bout of exercise, expressed in percentages, is also different (higher for ARE) and correlates with different blood biochemical parameters. PON (but not ARE) increment correlates negatively with FRAP before exercise and ARE increment correlates negatively with the value of ARE before exercise. A similar discrepancy of PON and ARE activities was observed by Hungarian researchers in obese children after a 2-week-long supervised diet and aerobic exercise program.Citation30 These discrepancies may result from the presence of separate active centers responsible for the enzyme hydrolytic activities toward paraoxon and phenyl acetateCitation31 as well as different reactions of these centers to molecular changes induced by oxidative stress during ME. The changes in oxidative-reductive balance in response to ME were substantial enough to cause a significant increase in the antioxidant defense measured as FRAP even 30 minutes after ME. Our observations indicate that beside UA and TBil PON1 can be an active element of antioxidant defense during physical activity and within 30 minutes of restitution after exercise.
Comparison of the results of PON1 activity changes induced by exercise in our previous study on young sportsmen, who had undergone a shorter but typical aerobic training, and this study on rugby players, with many years of aerobic and anaerobic training experience, resulted in the observation that ME similarly influenced PON1 activity in both studies. Similar changes in other parameters of plasma oxidative–reductive balance were found. The different types of tests performed in both experiments (treadmill or cycle ergometer) did not influence the course of PON1 activity changes at physical exercise. However, we found that in rugby players the antioxidant protection offered by PON1 in response to ME depends on training experience.
Acknowledgements
This research was supported by grant no. 503/0-079-02/503-01. The authors would like to thank Dr Wiesław Chudzik, the president of the Sport Club ‘Budowlani’ for his help in organizing the study and the rugby players for their active participation in the experiments.
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