Cytokines, Growth Mediators and Physical Activity in Children during Puberty

J. Jürimäe, A. P. Hills, T. Jürimäe

• Publisher: S. Karger
• Year: 2010
• ISBN:
  9783805595599
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Linear growth and sexual maturation are influenced by the actions of the endocrine system as well as by the nutritional status and level of physical activity of an individual. This publication focuses on the latest research regarding different physical growth and energy balance-related mediators in puberty. It summarizes the complex relationship between inflammatory mediators/cytokines, growth factors, body composition, physical fitness and physical activity of children and adolescents. Special emphasis in the book is placed on the role of various recently discovered inflammatory mediators/cytokines in the development of possible metabolic risk factors, in bone metabolism and other body composition parameters. Further, the book considers the adaptation to acute and chronic exercise in children during puberty and the development of possible menstrual irregularities.Health professionals, particularly pediatricians, exercise and sport scientists, coaches, researchers and students will find the book an excellent source of up-to-date information written by leading international experts in the field.

Jürimäe J, Hills AP, Jürimäe T (eds): Cytokines, Growth Mediators and Physical Activity in Children during Puberty.
Med Sport Sci. Basel, Karger, 2010, vol 55, pp 128-140

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Exercise Training, Physical Fitness and the Growth Hormone-Insulin-Like Growth Factor-1 Axis and Cytokine Balance

Alon Eliakim · Dan Nemet

Child Health and Sports Center, Endocrinology Clinic, Pediatric Department, Meir Medical Center, Sackler School of Medicine, Tel-Aviv University, Kfar-Saba, Israel

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Abstract

The effect of exercise training on anabolic hormones and inflammatory mediators is particularly important during childhood and puberty, since during this period there is a spontaneous increase in anabolic hormones that leads to the marked puberty-related growth spurt. Therefore, any training-associated hormonal and/or inflammatory effect during this critical period may have profound consequences on growth and development, especially if the effect is maintained for long periods. Several studies suggest the hypothesis that a sudden imposition of a training program which is associated with substantial increase in energy expenditure leads initially to an increase in pro-inflammatory cytokines, and as a consequence, to decreases in IGF-1 levels. Further, if the training adaptation is successful, the proinflammatory cytokines fall, and with that decrease, the suppression of IGF-1 diminishes, an anabolic ‘rebound’ in the GH-IGF-1 axis may ensue, and IGF-1 level exceed the pre-training level. Exactly how and when this switch takes place, and whether the initial catabolic-type stage is necessary for the ultimate anabolic adaptation remains unknown. Consistent with the two phases hypothesis, longer periods of training were indeed associated with stable or with increases in circulating GH and IGF-1 levels. Despite the early training-associated decrease in circulating IGF-1 levels, there is an increase in muscle mass and fitness may improve, suggesting that the local tissue effect of exercise on growth factors differ from systemic effects. Total caloric intake as well as macro-nutrient content, consumption and timing influence the anabolic and inflammatory response to training. Finally, changes in the balance of anabolic and catabolic hormones and inflammatory mediators during the training season may help elite athletes and their coaches in their training and preparation for competition.

Copyright © 2010 S. Karger AG, Basel

Training efficiency depends on the intensity, volume, duration, and frequency of training and on the athlete's ability to tolerate it. An imbalance between the training load and the individual's tolerance may lead to under- or overtraining. As a consequence, many efforts are made to objectively quantify the fine balance between training load and the athlete's tolerance. The endocrine system, by modulation of anabolic and catabolic processes, plays a major role in the physiological adaptation to exercise training [50]. For example, the change in the cortisol/testosterone ratio, as an indicator of the anabolic-catabolic balance, has been used with limited success to determine the physiological strain of training [18]. In recent years changes in circulating components of the growth hormone (GH) → insulin-like growth factor-1 (IGF-1) axis, a system of growth mediators that control somatic and tissue growth in many species [27], have been used to quantify the effects of training [14]. In addition, exercise is also associated with a remarkable change of inflammatory cytokines. These cytokines include both pro-inflammatory mediators [e.g. interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF- α)] and anti-inflammatory mediators [e.g. interleukin-1 receptor antagonist (IL-1ra)] and their response to exercise can be used to gauge exercise load as well. As demonstrated in the previous chapter, the effect of single exercise on these systems is relatively well studied. Surprisingly, single exercise may lead to a simultaneous increase in antagonistic mediators. On the one hand, exercise stimulates anabolic components of the GH → IGF-1 axis [43, 46], while on the other hand, exercise increases catabolic pro-inflammatory cytokines such as IL-6, IL-1 and TNF-α [29, 34, 36]. The assessment of changes in these antagonistic circulating mediators may assist in quantifying the effects of different types of prolonged exercise training and recovery modalities. However, interestingly, relatively few studies examined the levels of these anabolic/catabolic hormones in elite athletes, during different training stages throughout the competitive season, in ‘a real life’ setting.

The effect of exercise training on these anabolic hormones and inflammatory mediators is particularly important during childhood and puberty, since during this period there is a spontaneous increase in anabolic hormones that leads to the marked puberty-related growth spurt. Therefore, any training-associated hormonal and/or inflammatory effect during this critical period may have profound consequences on growth and development, especially if the effect is maintained for long periods. This chapter will focus on the effect of exercise training on the GH-IGF-1 axis and inflammatory mediators during puberty, on differences between systemic and local (i.e. muscle) responses to exercise and on ways to use these responses to assist adolescent competitive athletes and their coaches in the evaluation of the training load.

Cross-Sectional Relationship between Fitness, Anabolic Hormones and Inflammatory Mediators

Previous studies described [10, 16] that both functional (i.e. maximal oxygen consumption, VO_2max) and structural (i.e. thigh muscle volume determined by magnetic resonance images) indices of fitness were correlated with mean overnight GH levels, GH binding protein (GHBP) and serum IGF-1 levels in pre and late pubertal girls. These cross-sectional data suggest that fitness in healthy, non-professional, pre-pubertal and adolescent females is associated with anabolic adaptations of the GH-IGF-1 system. A recent study in young adult athletes demonstrated that mean and peak GH levels were significantly higher in elite male and female athletes compared to physically active and to sedentary controls with no difference in IGF-1 levels. There was a strong correlation between GH levels and training intensity [49]. Whether the difference in the relationship between fitness and IGF level can be attributed to maturational effect, needs to be elucidated.

The significant correlation between fitness and mean overnight GH levels probably resulted from an increase in peak GH amplitude since only peak amplitude (and not peak frequency or width) correlated with mean GH. The positive correlation between GHBP and fitness is unique. GHBP is the extracellular domain of the GH receptor [41], and therefore reflect tissue GH receptor capacity. Ligand-mediated receptor regulation appears to exist for GH and GHBP in a number of situations. GHBP decreases in acromegaly [24] and during exogenous rhGH therapy [26], and is high in obesity despite low GH [21]. But ligand-mediated receptor downregulation does not appear to operate during normal growth when both GH and GHBP increase in the prepubertal years [4]. The relatively trained or fit state in prepubertal and adolescent females is another example of simultaneous increases in both GH and GHBP. The mechanism of these responses is not known, but suggests anabolic adaptations of both the ligand and receptor. Collectively, it seems that increasing levels of physical activity stimulate GH pulsatility, and, as a consequence, circulating IGF-1. It is compelling to speculate that the stimulation of the GH → IGF-1 axis by exercise contributes, along with genetic, nutritional, and other environmental factors, to an increase in muscle mass and, ultimately, to improved cardiorespiratory responses to exercise (such as peak VO₂). The data suggest that this mechanism is active both in prepubertal and adolescent girls even while spontaneous growth and natural increase in muscle mass proceeds.

Other studies in adolescent rhythmic gymnasts demonstrated no difference in circulating IGF-1 levels compared to sedentary controls despite reduced adiposity and leptin levels [6]. Since IGF-1 is affected by energy balance, reduced body weight and fat mass is often associated with decreased IGF-1 levels. Therefore, the authors suggested that exercise preserved IGF-1 levels in the rhythmic gymnasts. Consistent with these observations, a follow-up of 4 years during puberty demonstrated that while rhythmic gymnastics training was associated with delayed puberty, there was no effect on linear growth [1].

In contrast, decreased levels of salivary free IGF-1 were found in young female volleyball players compared to sedentary controls [2]. The authors suggested that this decrease could be related to greater muscle requirements. However, whether these results reflect possible different unique body compartment exercise-associated effects (muscle, circulation, saliva) needs to be evaluated.

Virtually all of the major IGF-binding proteins (1 through 6), each of which is known to influence IGF-1 bioactivity in different ways, were also related to indexes of fitness suggesting that the BPs may play a role in the interaction between fitness and exercise. With the exception of IGFBP-3, the level of IGFBPs in the circulation is low, and the exact role of these IGFBPs in the circulation has yet to be determined. Nonetheless, it is noteworthy that the cross-sectional relationships between fitness and IGFBPs were consistent with current understanding of the biological activity of IGF-1-binding proteins based on tissue studies. IGFBP-1 and IGFBP-2, known to inhibit IGF-1 function, were found to be inversely correlated with muscle mass [10, 16]. IGFBP-4, a known inhibitor of the anabolic functions of IGF-1 in bone tissue culture experiments [31], was found to be inversely correlated with muscle mass [10] and VO_2max [9]. In contrast, the IGF-1 potentiating binding protein, IGFBP-5, was positively correlated with muscle mass [15]. Accordingly, these data suggest the possibility that the generally increased IGF-1 bioactivity in fitter subjects might not be related only to changes in circulating IGF-1, but also to changes in IGFBPs.

Effect of Training

Very few longitudinal studies examined the effect of endurance training on the GH-IGF-1 axis in children. Reduced IGF-1 associated with training has been observed in high school wrestlers and in highly trained young female gymnasts [20, 40]. In these studies, the training program was accompanied by a loss of body mass providing clear evidence for a negative energy balance and catabolic state.

Recently, the effect of a brief (5 weeks) randomized, prospective endurance-type training intervention on the GH-IGF-1 axis in pre and late pubertal males and females was reported. Based on the cross-sectional data, the authors hypot...