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Effect of Intense Exercise on Inflammatory Cytokines and Growth Mediators in Adolescent Boys Dan Nemet, Youngman Oh, Ho-Seong Kim

, MaryAnn Hill and Dan M. Cooper Pediatrics 2002;110;681 DOI: 10.1542/peds.110.4.681

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2002 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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This might explain the development of what seems to be a paradoxical catabolic state in the initial phases of exercise training programs. We found significant decreases in anabolic mediators: total IGF-I ( 11. Vo2. This is important for a number of reasons that. University of California. enzyme-linked immunosorbent assay. Exercise can enhance growth and development in children. IGFBP-3 proteolysis. a period of rapid fluctuation in circulating levels of anabolic hormones. PhD*. fat.C.5-hour wrestling practice session. interleukin [IL]-6. heart rate. Results. MD‡. IL-1 . As an extreme example of this paradigm.edu PEDIATRICS (ISSN 0031 4005).13 but hormonal markers of adequate levels of physical activity in this age group have yet to be determined. Portland. bound IGF-I ( 11. Received for publication Mar 28. Oregon Health Sciences University. IGFBP. adolescents. Evidence for compensatory mechanisms to counter the antianabolic inflammatory response to acute exercise were also noted: IL-1ra increased (80 20%) and IGF-binding protein-3 proteolysis (which can maintain unbound. 2011 . However. reduced GH binding protein and IGF-I). in children with systemic inflammatory diseases. Oregon. beats per minute. MD* ABSTRACT. California. Remarkable increases were found in proinflammatory cytokines IL-6 (795 156%). coefficient of variation. the early (4 –5 weeks) response to training programs in children lead to a catabolic.110:681– 689. in basal. TNF. Copyright © 2002 by the American Academy of Pediatrics. GH.aappublications. training in children initially leads to a state of GH resistance (ie.org by guest on September 16. the American Academy of Pediatrics recently highlighted the potential risks of high-intensity training and sports specialization in young athletes14 and noted. and adults. and tumor necrosis factor. resting levels of IGF-I. there is increasing evidence in both children and adults that even relatively brief periods of aerobic exercise training (5 weeks) can lead to reductions. 2001. evels of physical activity during childhood can influence growth and development of muscle. as in adults. Bldg 25. receptor antagonist.M. fitness.7. proinflammatory cytokines. ABBREVIATIONS. 1. ELISA. IGF-binding protein. IL-1 .1% Tween-20. sports. performed a single. but recent investigations have revealed an intriguing paradox. adolescence. tumor necrosis factor.4%). seem to involve either too much or too little physical activity during childhood.2 2. These data demonstrate that an intense exercise bout in male adolescents leads to reductions in anabolic mediators and profound increases in inflammatory cytokines. and IL-1 (286 129%) and in IGF-binding protein-1 (835 234%).12. Namely.9 –11 chronically elevated IL-6 leads to reduced basal IGF-I and impaired somatic growth.2 2. From the *Center for the Study of Health Effects of Exercise in Children.Effect of Intense Exercise on Inflammatory Cytokines and Growth Mediators in Adolescent Boys Dan Nemet.2. ZOT 4094-03. 110 No.1–3 Paradoxically.(30 12%). bpm. 4 October 2002 Downloaded from pediatrics. ra. 2002. Orange. Cooper. The cumulative effect of these individual exercise perturbations would be to lower basal levels of IGF-I. Tris-buffered saline with 0.8 stimulate proinflammatory cytokines known to inhibit directly anabolic activity of the GH3 IGF-1 axis (namely. and insulin ( 42 10%. and potential compensatory mechanisms in childhood or adolescence. volume of oxygen uptake. E-mail: dcooper@uci. interleukin. Orange. obesity. may be involved. Blood was sampled before and after the session. Conclusions. Recent data suggest that exercise alteration of the growth hormone (GH)3insulin-like growth factor-I (IGF-I) axis (GH3 IGF-I). “Although many concerns surround intense sports competition 681 L PEDIATRICS Vol.5 years. and Dan M. each of which has been shown previously in adults to be increased with exercise). rather than expected increases. age 14 to 18.4. Irvine. insulin-like growth factor. body mass in˙ dex.6 This paradox led us to the idea that single bouts of exercise in children could. College of Medicine. Methods. there was no change in unbound IGF-I. Pediatrics 2002. IGF. Basal levels of IGF-I are correlated with muscle mass and fitness in prepubertal children. Clinical Research Center.]). Eleven healthy high school–age boys. With the possible exception of GH. TBST. MaryAnn Hill. osteoporosis. CA 92868. CV. which itself is stimulated by inflammatory cytokines and is known to inhibit IGF-I. In contrast. little is known about the effects of single bouts of exercise on growth mediators. HR. BMI. This paradox led us to hypothesize that single bouts of exercise in children could stimulate proinflammatory cytokines known to inhibit directly anabolic activity of the GH3 IGF-1 axis (interleukin [IL]-6.[TNF. 101 The City Dr. cardiovascular disease) are now known to be associated with physical inactivity during childhood and adolescence. Youngman Oh. growth hormone. BMI.3%).5 Thus. and ‡Department of Pediatrics.) UCI College of Medicine. typical. Objective. PhD‡. and bone. An increasing number of common adultonset diseases and conditions (eg. a system of hormones and mediators that modulate growth in many tissues. ironically. more often associated with catabolic rather than anabolic hormonal activity. wrestling. growth hormone (GH)–resistant state rather than the expected anabolic activation of the GH3insulin-like growth factor-I (IGF-I) axis. accepted Mar 28. and tumor necrosis factor[TNF. TNF.]. biologically active IGF-I despite losses in total IGF-I) increased significantly (101 39%) as well. Reprint requests to (D. MD*. IL. Ho-Seong Kim.

6 44.5%. Eleven healthy adolescent boys participated in the study (Table 1). Clearly. We further hypothesized that factors such as increasing fitness would attenuate the catabolic response. little scientific information is available to support or refute these risks. The field study was designed to mimic a real-life exercise paradigm. Field Study The wrestling practice was held approximately 6 weeks after the end of the wrestling season. The wrestlers were instructed to have a light breakfast on the morning of the test. Each pair wrestled a full 6-minute match. Designation of iron man rotated after approximately 3 to 4 minutes. 682 EXERCISE AND GROWTH MEDIATORS IN BOYS Downloaded from pediatrics.in children.17 and the ˙ volume of oxygen uptake (Vo2) peak was determined as previously described for children and adolescents. St Louis.2–30. the interassay CV was 3. and the exercise session began at approximately noon.8%. The time interval between the end of the training session and phlebotomy was 41 4 seconds (27–70 seconds). and pin counters.to 4-month season. and insulin.org by guest on September 16. Wrestling was chosen specifically because individual practice sessions are intense and because high school wrestlers are known to develop GH resistance during the course of a standard 3. we studied the effect of a single. and TNF. and the sensitivity was 0. As is typically the case in high school wrestling practices. To accomplish this. Indicators that represent a “catabolic” response included IGFBP-1.5 75. including take-downs. such as IGFBP-3 proteolysis and IL-1 receptor antagonist (IL-1ra). OH). IL-6. Thus. suggesting an ability of growing children to adapt hormonally to repeated exercise bouts (ie. National Center for Health Statistics.and postintervention specimens were analyzed in the same batch by technicians who were blinded to the order of the samples. weight. Immediately before and after exercise. “Iron man” (15 minutes): Wrestlers were placed in groups of 5 or 6 with 1 wrestler in each group designated the “iron man. faculty/student recreation center.” We hypothesized that acute alterations in the circulating levels of the GH3 IGF-I axis and in the proinflammatory cytokines would be substantially catabolic in response to single bouts of intense exercise in adolescents.” The iron man continuously wrestled facing a new partner every 30 seconds. and Body Mass Index Measurements Standard. The practice was coached by 1 of the wrestling team coaches. University of California. Live wrestling (10 minutes): Each wrestler was paired with a partner of similar weight and ability. Height. calibrated scales and stadiometers were used to determine height. All pre. None of the participants trained during the day preceding the blood sampling. Participants were vigorously encouraged during the high-intensity phases of the exercise proTABLE 1.8 (range: 161–178) 0. Participant Characteristics (n 16.15 The complexity of anabolic and catabolic responses to exercise has become increasingly apparent in recent years.5) 2. MO).16 Weight was measured before and at the end of the practice.aappublications. weight/ height2). IGF-binding protein-3 (IGFBP-3). we also tested for evidence of compensatory mechanisms that might mitigate the catabolic response. METHODS Sample Population The study was approved by the Institutional Review Board. Finally. Irvine. The practice consisted of the following: Warm-up (20 minutes): Jogging and “stretch” exercise with sports-specific calisthenics such as push-ups and sit-ups. Intra- standard error of the mean..3) 1. and 80 minutes) during the practice. Because BMI changes with age. Webster. HR was measured by individual palpation at baseline and at 3 time points (20. and mean respiratory exchange ratio peak was 1. Samples were placed in ice bath and were immediately taken to centrifugation. training).18 Mean heart rate (HR) peak was 184 4 bpm.01. Specific wrestling positions were assigned. IL-1 . Irvine.9 (range: 59. Situation wrestling (15 minutes): The participants were paired or placed in groups of 3. No participants were on any medications at the time of the study. Measurement of Cardiorespiratory Fitness On a separate day.4 171. The technique drills involved high-intensity exercise of short duration (6 –10 seconds). blood samples were obtained by standard phlebotomy. participants were permitted free access to water and encouraged to drink when thirsty and rest briefly when excessively fatigued. Albumin Albumin levels were determined by colorimetric determination by the use of the Sigma BCP albumin procedure #256 (Sigma Diagnostic.5 11) Serum Measurements Lactate Lactate was measured with the use of YSI lactate analyzer (YSI 1500. Likely indicators of an “anabolic” response included free and bound IGF. Irvine. in the present investigation. measurement of individual mediators can no longer suffice to gain insight into mechanisms of growth regulation. Technique drills (20 minutes): The participants performed typical wrestling skills. Each participant performed a ramp-type progressive exercise test on a cycle ergometer in which the participant exercised to the limit of his tolerance. The study took place at the wrestling facility of the University of California. Each wrestler was the iron man at least once during this drill. Weight. we arranged a 1. TX). Wrestling practice involves both aerobic and anaerobic exercise and both concentric and eccentric types of movements. and body mass index (BMI. 50. we focused on both well-studied and novel mediators that are influenced by exercise and act in concert to regulate growth.8 25. and informed consent as well as assent were obtained. The intra-assay coefficient of variation (CV) was 2. Aliquots of the resulting plasma were stored at 80°C until analyzed.5–92. we calculated BMI percentile for each child using the recently published standards from the Centers for Disease Control and Prevention.5 83. within 1 week of the wrestling practice. tocol. Age (y) Weight (kg) Height (cm) BMI (kg/m2) BMI percentile Peak Vo2 (ml/min/kg) Data presented as mean 0.5 (range: 14–18.2 mg/dL. pin combinations. high school wrestling practice session. Yellow Springs.5-hour wrestling practice modeled after typical sessions of this sport.8) 4 (range: 49–98) 2 (range: 37–54) GH GH serum concentrations were determined by enzyme-linked immunosorbent assay (ELISA) with the use of the DSL-10-1900 Active kit (Diagnostic System Laboratories.8 (range: 22. escapes. To test these hypotheses. Urine samples were collected immediately before and after exercise into sterile specimen cups and were placed on ice until the aliquot was frozen at 80°C. suggesting that close-to-maximal values likely were achieved. and participants wrestled from the given situation practicing a specific move and its counters. such as encountered in the daily activities of these adolescents. This involved exercise at maximal effort in bursts of 15 to 20 seconds. each participant performed standard measurements of cardiorespiratory fitness. 2011 . Gas exchange was measured breath by breath. typical. Participants were admitted to the General Clinical Research Center at the University of California.14 0.

In the serum. IGFBP-3 Proteolysis IGFBP-3 proteolysis was determined by Western immunoblot analysis.5%.9 kg to 74.4%.2%. Mean baseline HR was 74 2 bpm.059 pg/mL. Correlation and linear regression analyses were computed among growth factors. and incubated with primary antibody diluted in TBST (1:3000) for 2 hours at room temperature or overnight at 4°C. then incubated with horseradish peroxidase– conjugated secondary antibody (Southern Biotechnology Associates. 2011 .74% to 4. Assay sensitivity is 0. and the sensitivity was 0.33 ng/mL (results for IGFBP-1 were not obtainable for 1 participant).3% to 6. IL-6 concentrations were also measured in the urine using these techniques.1% to 22.assay CV was 3. Membranes were washed in TBST. The membranes were blocked in 5% nonfat dry milk in Tris-buffered saline with 0. The decrease ARTICLES 683 Downloaded from pediatrics. There was a small but significant decrease in the level of total IGF-I and bound IGF-I.8 ng/mL.2% to 6. interassay CV was 5.5-hour practice. Statistical Analysis Paired t tests were used to determine before versus after exercise differences.47 0. NY).4 2. Insulin Insulin serum levels were determined by ELISA with the use of the DSL-10-1600 Active kit.2% to 11. and intra-assay CV was 1.3% to 2. and the sensitivity was 0.2%. BMI. for 1 hour at room temperature. P . Lactate increased by 441 67% (P . Intra-assay CV was 1.24 A number of investigators have used albumin specifically to adjust for vascular water changes in IGF-I or BP-3 with exercise because these molecules approximate the size of albumin.1% to 29.7% to 6.7% to 14.04 ng/mL. 5.9 kg.6% to 4. Albumin TNFTNF.1% Tween-20 (TBST).serum levels were determined by ELISA with the use of the R&D Systems Quantikine High Sensitivity kit (R&D Systems.21 IL-1 IL-1 serum levels were determined by ELISA with the use of the R&D Systems Quantikine High Sensitivity kit.3%.015 ng/mL. Although it is clear that shifts in plasma water occur immediately with heavy exercise.1 g/dL. IGFBP-3 serum concentrations were determined by ELISA with the use of the DSL-10-6600 Active kit (Diagnostic System Laboratories).3% to 9.6%.org by guest on September 16. and the sensitivity was 0. Weight. we present the mean and standard error of the mean of the percentage changes found in each participant.5%.1% to 6. Statistical analysis of growth factors and cytokines was performed using before and after concentration values as shown in Tables 1 and 2. and the sensitivity was 0. VA). was 3. Urine IGFBP-3 fragment concentrations were normalized to creatinine. Cardiorespiratory Effects of the Wrestling Practice All 11 participants completed the 1. Intra-assay CV was 8. interassay CV was 6.2%.5% to 3. and 6. RESULTS Height. In Figs 1. interassay CV was 8. and indexes of fitness. P .7 2. Serum (1 L) or urine (60 L) from the participants was fractionated by 12. and 163 3 bpm. Intra-assay CV A mean increase of 821 452% in circulating GH levels was found.aappublications.8%. Mean HR at 3 measurement points during the practice (20.2% to 11. BMI. MN). Glucose Serum glucose levels were determined by quantitative enzymatic measurements with the use of Sigma diagnostic kit #510 (Sigma Diagnostics). Birmingham. Assay sensitivity was 0.7%.0094 pg/mL.05. There was a significant change in albumin levels after the exercise (from 4. interassay CV was 5. Effect of Wrestling Practice on Anabolic Mediators IL-1ra IL-1ra serum levels were determined by ELISA with the use of the R&D Systems Quantikine High Sensitivity kit. IGF-I interassay CV was 3.20. Intra-assay CV was 7.19 Serum IGF-I concentrations were determined by a 2-site immunoradiometric assay using the DSL-5600 Active kit (Diagnostic System Laboratories). Weight decreased significantly after the practice (75. AL).96 0.0%. interassay CV was 7. IL-6 IL-6 serum levels were determined by ELISA with the use of the R&D Systems Quantikine High Sensitivity kit. we expressed IGFBP-3 proteolysis first as a percentage of intact IGFBP-3 and second as the relative concentration of the IGFBP-3 fragments normalized to serum albumin. diluted 1:7000. and Fitness Level Participant characteristics are presented in Table 1. IGFBPs IGFBP-1 was measured by coated-tube immunoradiometric assays with the use of the DSL-10-7800 Active kit. Melville. cytokines. Data were normalized to urine creatinine measured by standard techniques as previously described. Intra-assay CV was 3.005).03 ng/mL. respectively. All experiments were conducted at least 3 times. interassay CV was 16.4%. and the sensitivity was 22 pg/mL. Data are presented as mean standard error of the mean.22 Using hematocrit alone (as suggested by Dill and Costill in 197423) is not sufficient because it is documented that exercise-associated splenic transfusion of highly concentrated blood into the central circulation may have a measurable effect on hematocrit.4% to 6. and the sensitivity was 0. The latter value is not identical with the percentage change that would be calculated using the mean before and after values of the whole group. Boston. Monoclonal antibody against IGFBP-3 was provided by Diagnostic Systems Laboratories. Immunoreactive proteins were detected using the Renaissance Western Blot Chemiluminescence reagents (NEN. IGF-I IGF-I was extracted from IGFBPs using the acid-ethanol extraction method.5% sodium dodecyl sulfate–polyacrylamide gel electrophoresis under nonreducing conditions.6%.1 g/dL to 4.005). consequently. Minneapolis. but this was not statistically significant.7% and intra-assay CV was 2% to 4%.8%. For IGFBP-1. interassay CV was 4. 160 4 bpm.25 We used this approach in the present study.3% to 9. Densitometric measurement of immunoblots was performed using a Bio-Rad GS-670 Imaging densitometer (BioRad.7% to 8. Intra-assay CV was 3.6%. MA). Arlington. Free IGF-I was determined by ELISA with the use of the DSL-10-9400 Active kit (Diagnostic System Laboratories).018). concentrations of catabolic and anabolic mediators in the circulation are expressed as their ratio to albumin levels. Fractionated proteins were electrotransferred onto Hybond-ECL nitrocellulose (Amersham Pharmacia.18 pg/mL. interassay CV was 6.1%.8% to 11.26 IU/mL. and the sensitivity was 0. 2. and 80 minutes) was 163 3 bpm. was set at 0. Intra-assay CV was 1. 50.1%. a standardized approach toward adjusting solute concentrations has not been universally accepted.0%. interassay CV was 1. and the sensitivity was 0.3% to 4.

Table 2).037). BMI percentile was positively correlated with the increase in IGFBP-1 (r 0.2 IU/mL (349 99 IU/g albumin) Data presented as mean standard error of the mean.74.335 pg/mg creatinine 425 40 pg/mL (8506 726 pg/g albumin) 4.77. 2011 . Effect of wrestling practice on the likely anabolic mediators: total IGF-I.TABLE 2.002) and for insulin (P .65 ng/mL (87 37 ng/g albumin) 480 36 ng/mL (10855 936 ng/g albumin) 476 36 ng/mL (10769 927 ng/g albumin) 3.(r 0. and insulin. TNF. P 0. Finally.3 2.. Although representing an intense level of physical activity.05. * Values corrected for albumin: increase with exercise. Correlation Among Fitness.8 mg/dL (308 21 mg/g albumin) 1. No significant change was found for free IGF.5% of intact IGFBP-3 at baseline to 16.7 0.2% of intact IGFBP-3 at the end of exercise (P . and simultaneous catabolic and anabolic responses to exercise in a population of healthy male adolescents.3 pg/mL (31 6 pg/g albumin) 0.6 ng/g albumin) 0.2 4. Table 2). Similarly.67.I.2 0.* GH Total IGF-I† Bound IGF-I† Free IGF-I IL1.037).2 ng/g albumin) 0.002) in IGFBP-3 proteolysis when analyzed as concentration 684 ˙ We found no correlation among fitness (peak Vo2/ kg) and the magnitude of change in any of the catabolic or anabolic mediators except for IGFBP-1 (Fig 5). Individual cytokine data are presented in Fig 3. P .7 ng/mL (69. substantial. of IGFBP-3 fragments normalized to urine creatinine (Fig 4). P 0.138 pg/mg creatinine 221 14 pg/mL (4965 310 pg/g albumin) 3. in unbound IGF-I was not statistically significant (Fig 1.061 0.4 0. Effect on Catabolic Mediators Significant increases where noted in circulating IL-6.62 1.6 2.6 pg/g albumin) 96 19 ng/mL (1919 351 ng/g albumin) 3821 283 ng/mL (77366 6018 ng/g albumin) 87 11 mg/dL (1770 250 mg/g albumin) 7. the wrestling prac- EXERCISE AND GROWTH MEDIATORS IN BOYS Downloaded from pediatrics. The wrestling practice was followed by a 42 10% decrease in insulin (P . Fig 6).002) and bound IGF-I (P . exercise-associated increases in lactate were significantly correlated with the increases in IL-6 (r 0.515 0. A substantial increase in the level of IGFBP-1 was also observed.6 0. DISCUSSION This study presents the first data demonstrating immediate.83 1.73. Effect of Exercise on Cytokines and Growth Factors Before Exercise After Exercise 81. but no change in glucose levels was noted. † Values corrected for albumin: decrease with exercise. BMI.3 13. P . P . free and bound IGF-I.9 1.66. Fig 4). Numbers in parentheses are concentrations divided by albumin.01.05. and Increase in Lactate Levels With Mediator Responses to the Wrestling Practice Fig 1.136 0.03).* IGFBP-1* IGFBP-3 Glucose Insulin† 13.6 mg/dL (1660 252 mg/g albumin) 10.01).35 0. IGFBP-3 proteolysis in the serum increased from 11. A significant decrease was noted for total (P .024 pg/mL (1.7 ng/mL (85.33 0. P . ‡ Corrected to urine creatinine levels.044).25 pg/mL (67 5 pg/g albumin) 3.76 0. Serum IGFBP-3 did not significantly change.aappublications.6 2.1 0.org by guest on September 16.4 pg/ml (219 28 pg/g albumin) 1. Urine IL-6 also increased significantly with exercise.031 pg/mL (2. IL-1 .033).03.4 pg/mL (86 9 pg/g albumin) 5. However. there was an overall increase of 101 39% (P . and IL-1ra (Fig 2. P .5 11. Fitness was inversely correlated with the magnitude of the IGFBP-1 response (r 0.2 IU/mL (149 46 IU /g albumin) Lactate* Serum IL-6* Urine IL-6*‡ IL-1ra* TNF.01). When analyzed as concentration of IGFBP-3 fragments in the serum (normalized to serum albumin).623 0. TNF.62 ng/mL (116 35 ng/g albumin) 474 39 ng/mL (9648 854 ng/g albumin) 471 39 ng/mL (9579 841 ng/g albumin) 3. in the urine there was a significant increase (120 33%.5 pg/g albumin) 24 14 ng/mL (516 291 ng/g albumin) 3694 290 ng/mL (83581 7472 ng/g albumin) 81 6 mg/dL (1833 165 mg/g albumin) 15. P .5 18. and IL-1 (r 0.

We speculate that the reduction in total and bound IGF-I accompanying heavy exercise in male adolescents may be compensated.5 hours (the time elapsed between our before and after blood sampling).(P . IGF-I levels fall. it seems that immediate changes in IGF-I are not influenced by the typical exercise-associated increase in GH. pregnancy. but by the end of the exercise period. Substantial elevations in IGFBP-1 (P . P .27 Previous studies. but at approximately 1 order of magnitude less. elite rowers whose peak ARTICLES 685 Downloaded from pediatrics. GH typically increases substantially with exercise. intense bout of exercise in highly fit. and urine. IGFBP-3. Consistent with this.35 and advanced malignancies36.002) were also observed. In the present study. The bulk of circulating IGF-I is bound in a ternary complex (IGF-I.30 but the mechanisms for these immediate reductions either during exercise or in other catabolic states have yet to be elucidated. but as exercise progresses. we observed a small but significant fall in total IGF-I (Fig 1). One possibility is the proteolysis of IGFBP-3. These data suggest a mechanism that preserves circulating concentrations of the free IGF-I during exercise.001). IL-1 (P . 2011 . and ELISA may not be able to distinguish intact from all proteolyzed fragments of IGFBP-3. P . All values represent serum levels except for the additional measurement of IL-6 in the urine. we did find increased IGFBP-3 proteolytic fragments in both the serum and the urine after the wrestling practice (Fig 4). GH after exercise was elevated but not significantly. we were unable to obtain blood samples early in exercise for obvious technical reasons. the GH increase in response to exercise will typically have reached its peak and begun to return to baseline levels in most participants.33 diabetes. However. Finally.aappublications. Dall et al25 recently found no increased IGFBP-3 proteolysis with an acute. and an acid-labile sub- unit31) that is too large to cross the capillary membranes. by IGFBP-3 proteolysis. in part.34 severe illness.034).05) and IL-1ra (P . which would lead to increased concentrations of free IGF-I in the circulation. IGFBP-3 proteolysis occurs in a number of conditions in which preservation of the circulating pool of IGF-I may be beneficial (eg. This is not surprising because in an interval of 1.org by guest on September 16. Although GH stimulates IGF-I production at the tissue level. although not entirely consistent. The data also show uniquely that factors such as BMI and relative fitness can influence the growth mediator response to brief periods of intense exercise.005) followed exercise. an increasing number of investigators have chosen to examine the effect of physiologic perturbations such as exercise on the bound and free IGF-I pools.26 but in the present study. factors such as relative fitness may play a role in the IGFBP-3 proteolysis response to exercise.32 Thus. For example. the half-life of bound IGF-I is in the range of 12 to 15 hours. no significant fall in free IGF-I occurred despite significant decreases in total and bound IGF-I. and IL-6 (blood.Fig 2.37). tice protocol is encountered in the lives of many adolescents and is not atypical of the intensity found in other high school–level individual and/or team sports. A small nonsignificant decrease in normalized IGFBP-3 concentration was noted. Reductions in circulating IGF-I accompany many catabolic states such as sepsis and burns. whereas the half-life of free IGF-I is on the order of 10 to 20 minutes. tend to indicate that circulating IGF-I has a biphasic response to an acute bout of exercise27–29: serum levels increase to a small but significant degree in the first 10 to 20 minutes. Indeed.0005. Effect of a wrestling practice on likely catabolic mediators. In the present study. we did not perform western ligand blot analysis specifically for intact IGFBP-3. Significant increases in TNF.

As noted. these proinflammatory cytokines are known to increase with exercise in adults. glucagon. counterregulatory hormones. prolonged hypoinsulinemia is associated with impaired growth.aappublications. consistent with previous studies in both adults38 and children.Fig 3. which antagonizes the inflammatory effects of IL-6. including catecholamines.. TNF. Insulin regulates metabolism and growth in a variety of tissues. A statistically significant increase in IGFBP-3 fragments was noted in both serum (P . ˙ Vo2/kg was 70 mL/min/kg. namely.. whereas hyperinsulinemia leads to excessive growth. was ele- EXERCISE AND GROWTH MEDIATORS IN BOYS Downloaded from pediatrics. and GH. TNF.39 The immediate reduction of insulin with heavy exercise in male adolescents 686 likely reflects increases in anti-insulin.org by guest on September 16. Effect of wrestling practice on serum cytokines (IL-6.032) and urine (P . and IL-1ra). IL-6. Insulin decreased substantially with exercise in the face of unchanging glucose concentration (Fig 1.40 The attenuation of circulating anabolic factors was accompanied by increases in mediators and cytokines usually associated with catabolic states. and IL-1 (Figs 2 and 6). IGFBP-3 proteolysis in serum and urine. Table 2). Far less is known about the long-term consequences of exercise-associated fluctuations in insulin metabolism on the process of growth and development in children. all of which optimally regulate substrate flux during exercise when skeletal muscle substrate utilization increases dramatically. typically increases in response to elevations in IL-6 itself and. and this has been shown more recently in prepubertal children as well. IL-1ra. including muscle. IL-1 .3. Before and after exercise data are presented for each participant. not surprising.21 As in our previous study in younger children. the qualitatively similar changes of IL-6 in the blood and urine (Fig 2) support the potential use of urine IL-6 to indicate exercise effects on this particular inflammatory cytokine when blood sampling is not feasible. substantially higher than the 44 mL/min/kg found in our group. Fig 4.002). 2011 .

IGFBP-1 is known to be highly regulated by insulin. cardiomyopathy. correlation between exercise-associated increase in IGFBP-1 and BMI (expressed as BMI percentile). the present study. significant elevations in IL-1ra are typically observed in the same time that elevations in IL-6 occur after exercise.58. and acute influenza.41.and the increase in lactate (Fig 6) supports the notion that whatever its source. catabolic states such as sepsis and burns. P .55 and IL-6 is known to stimulate angiogenesis mediated by vascular growth factors (fibroblast growth factor-256 and vascular endothelial growth factor57). Top. baseline measurements (the regression equation was y 1. the exercise inflammatory response is closely tied to the degree of metabolic stress imposed. including congestive heart failure. vated after exercise in the present study. Finally.47 Thus.31 Circulating IGFBP-1 is elevated in pathologic.59 The robust IGFBP-1 response to exercise in adults was noted as early as 1989. along with our recent study in prepubertal children. Data are expressed as the percentage change from preexercise. chronic idiopathic neutropenia. IL-1 .21 Thus. Thus. the increase in catabolic mediators and decrease in anabolic mediators after wrestling may be related mechanistically.49.77.8X 4830. r 0. leukemic inhibitory factor) have been shown to regulate muscle growth.74. IL-6.are known to inhibit the GH3 IGF-I system through a variety of mechanisms. correlation between exercise-associated increase in ˙ IGFBP-1 and fitness (expressed as peak Vo2/kg). the proinflammatory cytokine response to exercise ultimately may prove to play a mechanistic role in beneficial adaptive responses to exercise in healthy children. 2011 .42 demonstrating that although IL-1ra does indeed peak after IL-6. P . and TNF.033). the IGFBP-1 response to acute exercise seems to be substantial (an increase of approximately 8-fold in the present study [Fig 2]) and reproducible in children and adolescents. IGFBP-1 is found predominately in tissues. P .60 an observation that was corroborated recently in prepubertal children as well. Fig 6.21 and this challenges the notion that during childhood proinflammatory cytokines are involved solely in pathologic conditions. although there is still controversy surrounding the source of the proinflammatory response to exercise. and TNF. Bottom. there is evidence that IGFBP-1 may actually be stimulated by IL-1 . and TNF. Elevations in IL-6 in the same range as we observed in the adolescents after exercise have been noted in a wide variety of disease states. demonstrates a robust inflammatory response to exercise in healthy children. IL-6.67.6). Fitness was inversely correlated with the magnitude of the IGFBP-1 response (the regression equation was y 97X 5182. Other members of the IL-6 family of cytokines (eg. it is likely that the increase in IGFBP-1 with exercise is caused by a variety of mechanisms related to: 1) the ARTICLES 687 Downloaded from pediatrics. r 0. and increased insulin levels are usually associated with reduced circulating IGFBP-1. suggesting.. and stimulation of IGF binding proteins that act to inhibit IGF-I function.org by guest on September 16. a rapid secretion of IGFBP-1 into the central circulation from the liver.50 the strong correlation that we observed between the increase in IL-6.aappublications.009). not in circulating blood. and acts primarily to inhibit anabolic effects of IGF-I.43– 48 Thus. Significant correlation between the increases in lactate and IL-6 in blood associated with the wrestling practice (r 0. BMI was positively correlated with the increase in IGFBP-1 (the regression equation was y 65. but a number of researchers using both human61 and animal62 models have reached the conclusion that IGFBP-1 is elevated with exercise even when insulin concentrations are constant. inhibition of IGF-I production.51–54 However. including depression of GH receptor gene expression. This finding is in agreement with the IL-1ra response after exercise seen in adults.01). The proinflammatory cytokines IL-1 .Fig 5.3. most likely. Angiogenesis and muscle hypertrophy are among the most important short-term adaptations to repeated exercise.31 Consistent with this inverse relationship was our own observation that the reduction in insulin accompanied the rise in IGFBP-1.71X 37. Finally.

An independent assessment of body composition (eg. Roemmich JN. Richter EA. 1993. Whether the increase in IGFBP-1 response to exercise in adolescents with relatively higher BMI is a function of body composition or fitness has yet to be determined. Hermann C.273:E85–E91 9. 1998. We speculate that both the short. et al. Compensatory mechanisms are also stimulated by exercise: 1) an increase in IGFBP-3 proteolysis and maintenance of the concentration of unbound IGF-I in the circulation and 2) an increase in IL-1ra. The effect of these substantial exercise-associated alterations in growth mediators on the overall process of growth and development in adolescents has yet to be determined. 1998. Johnson MD. Peak oxygen uptake. Bentham J. and it is likely that the leaner participants were relatively fitter. Hill M. J Clin Endocrinol Metab. Berman N. Sinning WE. Eliakim A. J Clin Invest. However.40(1–3): 87–91 7. IL-6.org by guest on September 16. Ross RJ. 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