Purpose of review

It is becoming increasingly clear that physical activity in children plays a critical role in growth and development, therapy for certain chronic diseases and disabilities, and in the pediatric origins of a variety of bone, metabolic, and cardiovascular diseases. New mechanistic insights have created the opportunity for a phase shift in understanding of the links between exercise and health in the context of the growing child.

Recent findings

Exercise even in healthy children profoundly alters stress, immune, and inflammatory mediators including peripheral blood mononuclear cells and circulating pro- and anti-inflammatory cytokines (like interleukin-6). Moreover, exercise even in healthy adults stimulates the production of reactive oxygen species (ROS) and mediators that attenuate them. Oxidative stress, in turn, alters growth and stress mediators. Both ROS and stress/inflammatory factors interact with powerful growth mediators like growth hormone and insulinlike growth factor-I. These findings suggest specific ways in which the balance between pro- and anti-inflammatory, catabolic, and anabolic factors associated with exercise can influence health and growth in children.

Summary

To address the current epidemic of physical inactivity and obesity in children and to optimize the therapeutic effects of exercise in children with disease and disability will require real changes in environments (eg, schools and playgrounds); innovative approaches to rehabilitation of children with chronic disease and disability; and enlightened training of child health professionals. Identifying novel exercise mechanisms involving stress, inflammation, and growth factors will help guide these efforts.

The present study compares previous reports on the effect of "real-life" typical field individual (i.e., cross-country running and wrestling--representing combat versus noncombat sports) and team sports (i.e., volleyball and water polo-representing water and land team sports) training on GH and IGF-1, the main growth factors of the GH→IGF axis, in male and female late pubertal athletes. Cross-country running practice and volleyball practice in both males and females were associated with significant increases of circulating GH levels, while none of the practices led to a significant increase in IGF-I levels. The magnitude (percent change) of the GH response to the different practices was determined mainly by preexercise GH levels. There was no difference in the training-associated GH response between individual and team sports practices. The GH response to the different typical practices was not influenced by the practice-associated lactate change. Further studies are needed to better understand the effect of real-life typical training in prepubertal and adolescent athletes and their role in exercise adaptations.

Exercise leads to simultaneous increases in mediators signaling apparently antagonistic functional responses such as growth factors and inflammatory mediators. The aim of the present study was to demonstrate the physiological effect of IL-6 on circulating components of the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis. Twelve men (ages 26 +/- 2 yr) were divided into two groups (n = 6 in each group), receiving either albumin or recombinant human (rh) IL-6 infusion. IL-6 was infused via an antecubital vein, and a contralateral antecubital vein was used for blood sampling. The IL-6 dose was chosen to reach plasma levels of IL-6 characteristic of intense exercise (5 microg/h, for 3 h, resulting in plasma levels of 100 pg/ml). Blood samples for GH, GH binding protein, IGF-I, and IGF binding protein (IGFBP)-1 and -3 were collected at baseline, 30 min, and 1, 2, 3, 4, 5, and 8 h after the beginning of the rhIL-6 infusion. IL-6 levels increased only in the rhIL-6-infused group (P < 0.0005) and returned to baseline after the infusion was stopped. IL-6 infusion led to a significant increase in GH, peaking 1 h after the beginning of infusion (P < 0.001). A decrease in total IGF-I levels was noted only in the rhIL-6-infused group (P < 0.027). An initial decrease in IGFBP-1 levels was noted in both groups during infusion (P < 0.03). Following the initial decrease, there was a significant increase in IGFBP-1 levels only in the IL-6-infused participants, peaking at 2 after the infusion cessation (P < 0.001). IL-6 infusion had no effect on GH binding protein, IGFBP-3, and acid-labile subunit levels. rhIL-6 levels similar to the levels found after strenuous exercise induced a typical exercise-associated GH-->IGF-I axis response (increase GH, decreased IGF-I, and elevated IGFBP-1). The results suggest that IL-6 plays a role in the GH-->IGF-I response to intense exercise.

Exercise training efficiency depends on the intensity, volume, duration, and frequency of training, as well as on the athlete's ability to tolerate it. Recent efforts to quantify the effects of aerobic exercise training on hormonal response have suggested that exercise leads to simultaneous changes of antagonistic mediators. The effects of anaerobic exercise on these mediators are not known. Therefore, the aim of the present study was to evaluate the effects of a brief sprint interval session on the balance between anabolic (growth hormone [GH]--> insulin-like growth factor [IGF]-I axis) and catabolic hormones (cortisol), and circulating inflammatory cytokines such as interleukin (IL)-6. Twelve healthy elite junior handball players (17-20 years) participated in the study. Exercise consisted of a 4 x 250-m run on a treadmill, at a constant intensity of 80% of the personal maximal speed. Each run was separated by 3 minutes of rest. Blood samples were collected before, immediately after each 250-m run, and 1 hour after the last run. Exercise led to significant increases in GH (0.3 +/- 0.2 to 5.1 +/- 2.2 ngxml, p < 0.05), IGF binding protein (IGFBP)-3 (4191 +/- 2.48 to 4875 +/- 301 ngxml, p < 0.05), IL-6 (1.3 +/- 0.2 to 2.1 +/- 0.3 pgxml, p < 0.002), testosterone, and testosterone/cortisol ratio, and to a significant decrease in IGFBP-1 levels. Levels of IL-6 remained elevated 1 hour after the end of exercise. Exercise had no significant effects on IGF-I and cortisol levels. Changes in the GH-IGF-I axis and testosterone/cortisol ratio after the brief sprint interval exercise suggested exercise-related anabolic adaptations. The increase in IL-6 may indicate its important role in muscle tissue repair after anaerobic exercise. Changes in the anabolic-catabolic hormonal balance and in inflammatory mediators can be used as an objective tool to gauge the training intensity of different types of anaerobic exercises and training periods.

Purpose

Brief periods of aerobic exercise training lead to reductions, rather then the expected increases in circulating IGF-I. We hypothesized that intense exercise training in adolescents initially leads to simultaneous increases in proinflammatory cytokines and decreases in activity of the GH/IGF-I axis; and that as exercise training proceeds, levels of proinflammatory cytokines become reduced, and a rebound in IGF-I ensues leading to the higher IGF-I levels.

Method

To test this, we evaluated the GH/IGF-I axis and levels of inflammatory cytokines (IL-6, TNF-alpha, IL-1beta, IL-1ra), body composition, and fitness in 13 healthy adolescent boys (mean age 15.9 +/- 0.3 yr) over the course of a high-school wrestling season. Subjects were tested preseason, midseason (6 wk), peak season (12-14 wk), and 4 wk postseason.

Results

No significant weight loss was noted throughout the season. During the wrestling season (mid and peak) both total (P < 0.046) and free (P < 0.002) IGF-I levels decreased, whereas proinflammatory cytokines (IL-1ra, P < 0.005; IGFBP-1, P < 0.013; and IGFBP-2, P < 0.025) increased. GHBP (P < 0.018) levels also decreased during the season. In the postseason, there were significant increases in GHBP, and free and total IGF-I, whereas proinflammatory cytokines decreased.

Conclusions

An initial catabolic-type hormonal response occurs with intense exercise training in adolescents. This is followed by a rebound in circulating growth factors when the period of heavy training ceases.

Recent studies demonstrate an unexpected reduction in circulating levels of IGF-I after 5 wk of endurance-type exercise training in adolescent boys and girls and prepubertal girls. We hypothesized that the reduction in IGF-I would be accompanied by a training-associated stimulation of proinflammatory cytokines IL-1beta, IL-6, or tumor necrosis factor-alpha (TNF-alpha), each of which can inhibit the GH-->IGF-I axis. Healthy boys (age range 9-11 y old, mean Tanner 1.7) volunteered for the study and were randomized to control (n = 14) and training groups (n = 12) for 5 wk. After the intervention, significant increase in fitness was observed in the training group but not control group. Although IGF-I was correlated at baseline to peak oxygen consumption in all subjects, there was a significant decrease in IGF-I and IGF binding protein-3 in the training subjects (-12.8 +/- 7.3% and -17.5 +/- 7%, respectively, p < 0.05). In contrast, IGF binding protein-2, known to inhibit anabolic effects of IGF-I, increased in the training subjects (27.8 +/- 11%, p < 0.02) as did IL-1beta and TNF-alpha (51.5 +/- 30.22%, p < 0.02, and 44.5 +/- 23.2%, p < 0.02, respectively). Finally, we also found that GHBP was inversely correlated with fitness, suggesting altered GH function in more-sedentary boys. Thus, these data support the hypothesis that a sustained increase in physical activity can stimulate proinflammatory cytokines, which may contribute to suppression of the GH-->IGF-I axis. Physical activity can influence growth and development through its influence on anabolic and catabolic mediators.

Objective

Exercise can enhance growth and development in children, but recent investigations have revealed an intriguing paradox. Namely, the early (4-5 weeks) response to training programs in children lead to a catabolic, growth hormone (GH)-resistant state rather than the expected anabolic activation of the GH-->insulin-like growth factor-I (IGF-I) axis. 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 GH-->IGF-1 axis (interleukin [IL]-6, IL-1beta, and tumor necrosis factor-alpha [TNF-alpha]).

Methods

Eleven healthy high school-age boys, age 14 to 18.5 years, performed a single, typical, 1.5-hour wrestling practice session. Blood was sampled before and after the session.

Results

We found significant decreases in anabolic mediators: total IGF-I (-11.2 +/- 2.3%), bound IGF-I (-11.2 +/- 2.4%), and insulin (-42 +/- 10%. However, there was no change in unbound IGF-I. Remarkable increases were found in proinflammatory cytokines IL-6 (795 +/- 156%), TNF-alpha (30 +/- 12%), and IL-1beta (286 +/- 129%) and in IGF-binding protein-1 (835 +/- 234%), which itself is stimulated by inflammatory cytokines and is known to inhibit IGF-I. 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, biologically active IGF-I despite losses in total IGF-I) increased significantly (101 +/- 39%) as well.

Conclusions

These data demonstrate that an intense exercise bout in male adolescents leads to reductions in anabolic mediators and profound increases in inflammatory cytokines. This might explain the development of what seems to be a paradoxical catabolic state in the initial phases of exercise training programs.

Background

Obesity modifies inflammatory mediators, but little is known about how obesity modifies the inflammatory responses of exercising children. This study assessed the acute effect of exercise on inflammatory mediators in overweight children.

Methods

Twenty-eight overweight (OW) youth (body mass index > 85%) and 30 normal-weight (NW) controls of the same proportions of age and gender performed 10 2-minute bouts of cycle ergometry exercise above the anaerobic threshold, with 1-minute rest intervals between bouts. Pre- and postexercise blood samples were collected for white blood cell subpopulation and inflammatory cytokines.

Results

Baseline leukocyte populations were higher in OW youth (p < .05). Exercise increased most leukocyte subtypes for both groups (p < .05). Granulocytes remained elevated 2 hours postexercise (p < .05) for both groups, whereas monocytes remained elevated 2 hours postexercise for the OW children. Natural killer (NK) cells dropped below baseline 2 hours postexercise. Exercise significantly decreased CD4 and CD8 cells, which remained depressed 2 hours postexercise in the OW children. Baseline levels of interleukin (IL)-6 were congruent approximately 64% higher in OW children (p < .001). Exercise increased IL-6 in both groups (p < .001), which further increased 2 hours postexercise (p < .05). Tumor necrosis factor alpha, IL-1beta, and IL-1 receptor antagonist did not change with exercise.

Conclusions

Elevated baseline leukocyte subtypes and IL-6 levels in OW children suggest that childhood obesity is associated with a chronic low-grade inflammatory state. The acute inflammatory response to intense exercise appears to be similar between NW and OW children for most markers, but the depression of NK, CD4, and CD8 cells 2 hours postexercise suggests that an acute risk of mitogen-induced inflammation may exist in OW children after high-intensity exercise.

Recent evidence suggests a role for adipose derived cytokines (adipocytokines) such as tumor necrosis factor-alpha (TNF-alpha), IL-6, and the recently discovered adiponectin in the mechanism of impaired glucose regulation and atherosclerosis in adults. However, the relationship between adipocytokines and body composition, fasting insulin, and fitness is virtually unknown children. Fasting blood sampling was performed in 30 healthy, predominately Hispanic- and Asian-American children (16 boys, mean age 12.7 +/- 0.1 y old) from a lower socioeconomic area in Los Angeles. Adiposity was measured by dual x-ray absorptiometry (DEXA); and peak oxygen uptake using cycle ergometry. Adiponectin (mean 10.8 +/- 0.8 micro g/mL) was inversely correlated with body mass index (BMI, as percentile by age) (r = -0.48, p = 0.011) and fat mass (r = -0.43, p = 0.03). In contrast, TNF-alpha and IL-6 were both positively correlated with BMI and fat mass. Adiponectin was inversely correlated with fasting insulin (r = -0.52, p = 0.006), but no correlations were found for insulin and either TNF-alpha or IL-6. Adiponectin was correlated with HDL (r = 0.448, p = 0.019). Paradoxically, peak oxygen consumption (an indicator of fitness) was negatively correlated with adiponectin levels (r = -0.471, p = 0.013) and positively correlated with TNF-alpha (r = 0.560, p = 0.002). In children, adipocytokines are correlated with fat mass, insulin sensitivity, and cardiovascular risk factors in a manner that is qualitatively similar to relationships recently observed in adults. In more obese children, the mass of fat tissue may attenuate potentially positive effects of fitness on circulating levels of adiponectin and TNF-alpha. The novel data on adiponectin suggest that deleterious dysregulation of adipocytokines associated with obesity may occur relatively early in life.

We evaluated the effect of cold ice-pack application following a brief sprint-interval training on the balance between anabolic mediators [growth hormone (GH), insulin-like growth factor-I (IGF-I), testosterone], catabolic markers (cortisol, IGFBP-1), and circulating pro [Interlukin-6 (IL-6) and IL-1β]- and anti-inflammatory cytokines [IL-1 receptor antagonist (IL-1ra)]. Twelve males, elite junior handball players performed 4 × 250 m treadmill run, at 80% of each individual’s maximal speed, followed by a rest period with and without local cold-pack application. Pre, immediately post, and 60-min post-exercise blood samples were drawn. Exercise was associated with a significant increase in IL-6, GH, IGFBP-3, and testosterone levels. Local cold-pack application was associated with significant decreases in IL-1β, IL-1ra, IGF-I, and IGFBP-3 and a greater increase of IGFBP-1 during recovery. Local ice therapy immediately following sprint-interval training was associated with greater decreases in both pro- and anti-inflammatory cytokines and anabolic hormones supporting some clinical evidence for possible negative effects on athletic performance.