The endocrine response and substrate utilization during exercise in children and adolescents

Michael C. Riddell
J Appl Physiol 105:725-733, 2008. First published 17 April 2008; doi:10.1152/japplphysiol.00031.2008 You might find this additional info useful... This article cites 68 articles, 29 of which can be accessed free at: http://jap.physiology.org/content/105/2/725.full.html#ref-list-1 This article has been cited by 3 other HighWire hosted articles Twelve weeks of moderate aerobic exercise without dietary intervention or weight loss does not affect 24-h energy expenditure in lean and obese adolescents Gert-Jan van der Heijden, Pieter JJ Sauer and Agneta L Sunehag Am J Clin Nutr, March , 2010; 91 (3): 589-596. [Abstract] [Full Text] [PDF] Fat oxidation rate and the exercise intensity that elicits maximal fat oxidation decreases with pubertal status in young male subjects M. C. Riddell, V. K. Jamnik, K. E. Iscoe, Brian W. Timmons and N. Gledhill J Appl Physiol, August 1, 2008; 105 (2): 742-748. [Abstract] [Full Text] [PDF] Learning from children: the emergence of pediatric exercise science Thomas Rowland and Bengt Saltin J Appl Physiol, July 1, 2008; 105 (1): 322-324. [Full Text] [PDF] Updated information and services including high resolution figures, can be found at: http://jap.physiology.org/content/105/2/725.full.html Additional material and information about Journal of Applied Physiology can be found at: http://www.the-aps.org/publications/jappl

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Journal of Applied Physiology publishes original papers that deal with diverse areas of research in applied physiology, especially those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2008 by the American Physiological Society. ISSN: 0363-6143, ESSN: 1522-1563. Visit our website at http://www.the-aps.org/.

J Appl Physiol 105: 725733, 2008. First published April 17, 2008; doi:10.1152/japplphysiol.00031.2008.

Invited Review

HIGHLIGHTED TOPIC

Biology of Physical Activity in Youth

The endocrine response and substrate utilization during exercise in children and adolescents
Michael C. Riddell
School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada Riddell MC. The endocrine response and substrate utilization during exercise in children and adolescents. J Appl Physiol 105: 725733, 2008. First published April 17, 2008; doi:10.1152/japplphysiol.00031.2008.Adolescence is a time of rapid growth caused by signicant changes in hormone levels. For many, it is also a time of increased physical activity and sport that places a large demand on energy reserves. Exercise is known to cause perturbations in endocrine and metabolic systems in children and adolescents, yet careful characterization of these responses is only now being conducted. It does not appear that prepubertal youth have a different muscle composition than adults. However, these youth do have a lower anaerobic capacity and a greater reliance on aerobic metabolism during activity. Prepubertal adolescents may have an immature glucose regulatory system that inuences glycemic regulation at the onset of moderate exercise. During heavy exercise, muscle and blood lactate levels are lower in children than in adults and there is a greater reliance on fat as fuel. The exercise intensity that causes maximal fat oxidation rate and the relative rate of fat oxidation decreases as adolescents develop through puberty. The mechanism for the attenuated lipid utilization with the advancement of puberty, and the impact that this may have on body composition, are unknown. Surprisingly, prepubertal adolescents have relatively high rates of exogenous glucose oxidation, perhaps because of their smaller endogenous carbohydrate reserves. Further study is needed to determine the optimal exogenous carbohydrate feeding regimen for peak performance in adolescence. Studies are also needed to determine whether physical activity, at an intensity targeted to maximize fat oxidation, help to lower body adiposity in overweight youth. physical activity; metabolism; substrate oxidation; carbohydrate; lipid

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REGULAR PARTICIPATION IN PHYSICAL activity usually begins in youth, and many individuals peak in their sport performance during adolescence. Exercise causes dramatic changes in hormone concentrations and metabolites that may inuence growth and development during puberty. For some, intense training occurs in youth, and the anabolic and catabolic processes that occur with regular activity can inuence maturation and gross motor development. For nearly all children, regular participation in physical activity is healthy, promoting development of the muscular and skeletal systems, enhancing cardiovascular tness and insulin sensitivity, while reducing the likelihood of adolescent obesity, dyslipidemia, and insulin resistance. On the other hand, excessive endurance training in adolescence is associated with hypothalamic-pituitary dysfunction that can delay menarche, cause amenorrhea, and lead to immune suppression. Knowledge about specic hormonal and metabolic responses to exercise in youth is critical, therefore, to understand the physiological benets and potential risks of physical activity and sport participation. In addition, understanding the metabolic response to exercise may help to form

better physical activity and nutrient recommendations for youth of all ages. Unfortunately, despite the potential importance of studying pediatric exercise metabolism, research to date has been limited in this area, in part, because of technical and ethical conditions in studying youth. Over the last 70 years, considerable progress has been done to characterize the metabolic and hormonal responses to exercise in youth (Fig. 1). This review highlights the current state of knowledge about the hormonal and metabolic responses to acute exercise in youth and offers some potential areas of future investigation.
PUBERTY, INSULIN SENSITIVITY, AND SKELETAL MUSCLE CHARACTERISTICS

Address for reprint requests and other correspondence: M. C. Riddell, School of Kinesiology and Health Science, Faculty of Health York Univ., Toronto, ON, Canada M3J 1P3 (e-mail: mriddell@yorku.ca). http://www. jap.org

The hormones associated with pubertal development, which include growth hormone (GH), insulin-like growth factor (IGF), the sex steroids, and the catecholamines, are also hormones that can inuence energy metabolism during exercise. As such, characterizing the endocrine responses to various forms of exercise in pre- and postpubertal adolescents has long been a focus. It is well known that pubertal development is associated with a period of insulin resistance (3) and that insulin-stimulated glucose disposal at rest is lower in pubescents than in prepubertal children (3, 5). Although the cause of insulin resistance during puberty is not entirely clear, the
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Fig. 1. Time line of some of the signicant discoveries in pediatric substrate metabolism since the 1930s. RER, respiratory exchange ratio; 31P-MRS, phosphorus-31 nuclear magnetic resonance spectroscopy.

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elevation in sex steroids are thought to oppose the effects of insulin in skeletal muscle, adipose tissue, and liver (14). It has been argued that pubertal adolescents also demonstrate insulin resistance during exercise, although more work needs to be conducted in this area. For example, during 30 min of moderate cycling following glucose ingestion (0.5 g/kg body mass), peripubertal adolescents have a higher glucose-to-insulin ratio than adult male subjects (11). Although it is possible that the lower insulin sensitivity is a result of the increased levels of circulating GH, IGF-I, and catecholamines, this remains to be conrmed. Interestingly, orally ingested glucose is oxidized at a higher rate during exercise in adolescents than in adults (67), suggesting that there is not impairment in plasma glucose uptake and oxidation, per se. It may be that the recruitment of contraction-induced glucose four transporters (GLUT4) to the plasma membrane in children and in prepubertal adolescents is higher than in adults during exercise, although this requires investigation. Testosterone, which increases dramatically in adolescent boys during puberty (26), increases sarcotubular and mitochondrial enzyme content, at least when given to adult men (61). Whether the increase in testosterone at the time of puberty also increases mitochondrial content is unknown. With exercise, there is also a small but signicant increase in circulating testosterone levels in adolescent boys (26). However, a high aerobic capacity already exists in preadolescent youth compared with adults. Moreover, no evidence exists that mitochondrial content changes during puberty, although only a few studies have investigated this areas because of the need for
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muscle biopsy sampling. In one key study that used the muscle biopsy technique, Bell and colleagues (7) report similar mitochondrial volume ratios in prepubertal and adult muscle samples. It therefore remains unclear whether puberty inuences mitochondrial content and, if so, whether it has any inuence on fuel utilization during exercise. Maturation of skeletal muscle ber type at the time of puberty, specically a pattern change from slow to fast twitch, might explain some of the differences in the metabolic responses to exercise between children and adults. Compared with fast-twitch (or type 2) bers, slow-twitch red (or type 1) bers are fatigue resistant with a higher mitochondrial content that relies more on oxidative metabolism of fat and carbohydrates. The limited muscle data available for newborns and infants indicate a trend for a higher percentage of type 1 distribution in infants than in either newborns or adults (18). Evidence is lacking, however, that adolescence causes a shift in bre type composition. Examination of muscle biopsy samples taken from human diaphragm (38) and leg muscle (7) demonstrates that ber type differentiation and mitochondrial content are unchanged during adolescents. Comparison of muscle ber type among adolescence and adults is challenging, however, not only because of ethical and technical difculties in obtaining muscle biopsy samples but also because of the heterogeneous nature of muscle ber type composition is in humans. Muscle ber type composition is known to be inuenced by a number of factors, including genetic variation and differences in muscle use (30, 31). It may be difcult, therefore, to determine whether ber type changes occur with age, unless a
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relatively large longitudinal study is conducted. In one Swedish study, the muscle ber type composition was determined in 26 female subjects and 55 male subjects all at 16 yr of age and again at age 26 yr. Both sexes had 52% type 1 bers in their vastus lateralis muscles while the type 2A (a subfraction of type 2 bers with a high oxidative capacity) and 2X (a subfraction of type 2 bers with a lower oxidative capacity and a high glycolytic capacity) percentage were 33 and 15%, respectively (29). According to Saltin and Gollnick (62), this is similar to what is observed in adults and in younger children with a similar genetic background. Thus, based on the limited information available, very little muscle ber type changes occur with puberty, although it may be that motor unit recruitment patterns during exercise may change with pubertal development and that these differences might alter fuel selection. Despite similar phenotypical characteristics in muscle between adolescents and adults, their metabolic responses to exercise differ considerably. One of the rst to show that metabolic responses were unique in children was Bar-Or (6), who revealed that the anaerobic capacity, as measured by his recently developed all-out 30-s Wingate test, was lower in young children compared with adolescents and adults. Compared with adults, adolescents were also shown to have lower circulating lactate levels during exercise, suggesting that the younger individuals had a lower glycolytic capacity. The commonly held belief that children had an immature glycolytic capacity was based initially on the small number of muscle biopsy studies conducted by Eriksson and his colleagues more than 35 yr ago. In those classical studies, using muscle biopsies of a small numbers of volunteers from local schools in Sweden, Eriksson proposed that children have an inferior anaerobic (or glycolytic) capacity for supplying ATP during high-intensity exercise. This hypothesis was based principally on the observation that phosphofructokinase activity was lower in the boys compared with the men. Muscle glycogen content was also found to be 50 60% that of adults (for a review of that work see Ref. 20). Based on these ndings, it was proposed that adolescents were more oxidative and less glycolytic compared with adults. Some time later, using the phosphorus-31 nuclear magnetic resonance spectroscopy (31P-NMRS) technique in calf muscle, Taylor and colleagues (64) conrmed that muscle oxidative capacity was indeed higher in children and adolescents compared with young adults. In that study, children also had higher pH and ADP levels during muscular contraction and a more rapid recovery from the exercise (64), which t with the belief that children have a greater reliance on aerobic metabolism and, perhaps, an immature glycolytic capacity. One must note that other biopsy studies from maturing children have failed to conrm the relationship between maturation and glycolytic enzyme capacities (33). However, children have been reported to have 3.5-fold lower lactate dehydrogenase activity compared with adults in the obliques internus abdominis muscle in a recent study by Kaczor et al. (37). This nding of a lower lactate dehydrogenase activity in an abdominal muscle of children compared with adults conrms what had been reported previously in lower limb biopsies done on boys and adults (9, 21). The lower nonoxidative glycolytic ux though lactate dehydrogenase is thought to, at least partially, explain the considerably lower circulating lactate levels that are commonly observed during exercise in
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children compared with adults (34, 52, 58, 67). Based on the biopsy samples done by Eriksson and his colleagues (2225), muscle lactate levels after maximal exercise are also lower in adolescents than in men. The lower blood lactate concentrations in children during exhaustive exercise may be a result of a lower relative muscle mass, a higher relative total lactate water space, and/or a higher reliance on aerobic metabolism (8). Children and young adolescents clearly oxidize both fat and exogenous carbohydrate at a higher rate during exercise than adults (see SUBSTRATE UTILIZATION DURING EXERCISE below). Surprisingly, no studies have been published on the key regulatory enzyme pyruvate dehydrogenase in children. A higher activity in this key regulatory enzyme that links glycolytic ux to oxidative metabolism might help to explain the higher oxidative phosphorylation and greater exogenous glucose oxidation in youth compared with adults. Enzymes of the tricarboxylic acid cycle have been investigated in children but to a limited extent. Early studies found signicantly higher NADP-isocitrate dehydrogenase, fumarase, and malate dehydrogenase levels in skeletal muscle of pubescent children compared with adults, with no differences in citrate synthase activity (33). The activity of 2-oxoglutarate dehydrogenase (OGDH) in skeletal muscle, which is a rate-limiting enzyme in the tricarboxylic acid cycle, is similar in children and in adults (37). Thus, based on the limited muscle biopsy data in healthy children, it is unclear whether differences in enzyme content or activity explain the differences in energy metabolism during exercise between children and adults. MRS data. The use of noninvasive techniques to study substrate metabolism in children and adolescents has increased our knowledge on the topic considerably, while allowing researchers to avoid the risks associated with needle biopsy and blood sampling. In the rst study to use 31P-NMR in children to measure calf muscle Pi, PCr, and pH, Zanconato et al. (72) showed that preadolescent children (aged 710 yr) are less able than adults to generate ATP via rephosphorylation through anaerobic metabolism. Moreover, these young adolescents did not attain as low a muscle pH as the adults did during intense calf muscle contractions, supporting the notion that the children do not have the same anaerobic capacity as adults. Using the same technique, Kuno et al. (39) also published that trained and sedentary boys aged 1215 yr had reduced anaerobic capacity when compared with young men. On the other hand, no difference was found in glycolytic metabolism between prepubertal and pubertal girls using magnetic resonance spectroscopy (MRS) techniques (49). This latter study cautioned that the morphological differences in muscle size and composition between younger children, adolescents, and adults signicantly impacts on the interpretation of the MRS data (49). The work by Zanconato et al. (72) and Kuno et al. (39), cited above, is consistent with the notion that, compared with adults, children and adolescents have a higher rate of muscle oxidative phosphorylation during heavy exercise. Oxygen kinetics measured at the mouth during exercise are indeed different in children compared with adults, suggesting that children are more oxidative (4, 72, 73). As these authors point out, the greater O2 utilization during heavy exercise could result from a greater delivery of O2 to the working muscle, a greater mitochondrial content, or a great reliance on oxidative fuels, such as fat, during exercise, although these possibilities all
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require conrmation. As mentioned above, however, a higher mitochondrial capacity in youth is unlikely, at least based on the studies using the muscle biopsy technique to measure mitochondrial content and activity. Based on the available biochemical factors cited above, and the other important contributions in the eld, Inbar and Chia (35) suggest in a recent review that prepubertal adolescents are at relative disadvantage when performing short-term strenuous activities because of their immature anaerobic metabolism. Moreover, based on the limited data available (49), they conclude that the maturational changes in the anaerobic pathways may be more pronounced in male than in female subjects. Even if at a relative disadvantage, children can often be observed doing brief intense activities and then taking short breaks to recover from the activity. Whether this type of activity helps to mature the glycolytic pathways in muscle is unclear.
ENDOCRINE RESPONSES TO EXERCISE AND GLUCOSE HOMEOSTASIS

Because physical activity increases some of the hormones associated with pubertal development and because other hormones that are released during exercise inuence growth and development, characterization of the hormonal responses to acute exercise in youth is important. Surprisingly, systematic characterization of the endocrine response to exercise in children and adolescents has not been done nearly as carefully as it has been studied in adults [for a historical review of the studies done in adults see Riddell et al. (57)]. One of the rst to measure hormones during exercise in children was Fahey in 1979 (26). No differences in hormonal responses to exercise were found among 27 boys at different stages of puberty, perhaps because only one type of exercise was examined and because only a few hormones were measured (testosterone, GH, and insulin). Since then, only a handful of studies have reported circulating levels of select hormones in children and adolescents, and often the responses are measured only at moderate-intensity exercise. Exercise has long been known to be a potent stimulus of the GH and IGF-i axis in children and adolescents. Indeed, physical activities that include intermittent bursts of high intensity play do cause dramatic peaks in circulating GH concentrations that add considerably to the normal circadian rhythm of this potent developmental hormone. It was thought in the 1960s by Ekblom (17) that elevations in pubertal hormones, including GH and testosterone, caused by regular exercise, contribute to increased growth and development in adolescents. This hypothesis remains to be conrmed. In adolescent boys and girls, intermittent high-intensity cycling at 80% peak oxygen con O2peak), with 1-min rest intervals every 10 min, sumption (V causes an 10-fold increase in serum GH levels, although IGF-I levels are unaffected (27). Interestingly, a high-fat meal before high-intensity intermittent exercise blunts the GH response considerably (27). Carbohydrate ingestion also blunts the GH response to exercise in boys and girls (68). Thus the timing of a nutrient-rich meal before exercise may be an important consideration in young growing adolescents. Based on a large number of sophisticated studies done in animal models and in humans conducted in the 1980s and 1990s, it is known that the main glucoregulatory hormones
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during moderate-intensity prolonged exercise are insulin and glucagon, with minimal contributions from catecholamines, GH, cortisol, and thyroid hormone (70). With increasing intensities, catecholamines are the main regulators of hepatic glucose production and glycogen utilization (43). It is unclear whether these same endocrine factors regulate substrate mobilization in a similar fashion in children, although evidence described below suggests that differences do exist. Based on a number of pediatric-focused studies, insulin levels drop during prolonged exercise in adolescent boys (27, 28, 53, 55, 66) and girls (40), similar to what is typically observed in adults during prolonged exercise. In a study by Laaneots et al. (40) in Virus laboratory, examining girls at various stages of puberty, postexercise insulin levels were shown to be highest in girls at the last stage of puberty (40), perhaps to compensate for their elevations in pubertal hormones. In contrast, a drop in insulin was observed only in mature boys but not in less mature boys in an earlier study by Fahey et al. (26). Therefore, it may be that the insulin response to exercise differs with pubertal stage and sex, although this requires conrmation. When adults perform exercise above 80% maximal oxygen O2 max), insulin levels increase after exercise to consumption (V counter the dramatic rise in catecholamines and the transient hyperglycemia that ensues (43). It is unclear whether the same endocrine responses exist in adolescents. In fact, Galassetti et al. (27) report that 30 min of heavy intermittent exercise (at O2 peak) in adolescents increases glucagon levels but fails 80% V to increase the other counterregulatory hormones. In a related study at the same relative work rates, glucagon failed to increase and a compensatory rise in insulin also failed to occur (28). In contrast, during resistance exercise, the catecholamine and cortisol response is reported to be higher in boys compared with men or women (51), suggesting that adolescents may have a higher stress response to this form of exercise. This might have implications in blood glucose homeostasis during intense exercise in youth, causing more of a transient hyperglycemia. At rest, plasma concentration of epinephrine and metanephrine decrease, whereas norepinephrine increases with advancing puberty (71). It is unclear whether these changes in baseline catecholamine levels inuence glucose homeostasis at the onset of exercise in adolescents. In a series of classic studies conducted in Germany, Lehmann and colleagues (41) reported similar catecholamine excretion between younger and older boys but found 30% lower peak norepinephrine levels in 12-yr-old boys compared with men during maximal treadmill running (42). Rowland et al. (60) found no signicant differences in norepinephrine levels during two different submaximal exercise intensities nor at maximal exercise between 10- to 12-yr-old boys and men. The catecholamine responses to 60 O2max) was also identical in pre- and min of exercise (70% V postpubertal girls, despite marked differences in energy utilization (65). Thus more research is needed to clarify whether the adrenal responses to different forms of exercise change with puberty. Regular exercise is known to inuence dehydroepiandrosterone, testosterone, progesterone, -endorphin, somatotropin as well as leptin and other adipokines, although the examination of the hormonal response to exercise in adolescence is limited. Pomerants et al. (50) found no changes in circulating leptin or ghrelin in response to 30 min of exercise performed at
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95% of the ventilatory threshold, although prepubertal children had signicantly higher basal values for serum ghrelin compared with the more mature boys. Plasma -endorphin, corticotrophin, and ACTH all increase proportional to the exercise intensity similarly in pubertal and pre pubertal adolescents, whereas the GH response is higher in pubertal vs. prepubertal adolescents in some (12) but not all (26) studies. Recently, more attention has been focused on how obesity inuences the endocrine responses to exercise in youth. Based on work in Coopers (19) laboratory, obesity blunts the GH and catecholamine responses to exercise in adolescents, whereas insulin levels are higher, suggesting that these youth are insulin resistant as expected. The attenuated GH, the attenuated catecholamine, and the failure to suppress insulin release during exercise in obese adolescents, to levels observed in nonobese youth, support the hypothesis that obesity causes impairment in the adrenergic response to exercise. Interestingly, despite the blunted counterregulatory hormone responses and the higher circulating insulin levels during exercise, obese adolescents do not develop hypoglycemia (19), suggesting that liver and/or muscle are resistant to these endocrine signals that regulate glucose balance. Future studies should focus on how age, maturation, and body adiposity inuence not only hormonal responses to exercise but also the specic tissues metabolic responses to these endocrine factors. Glycemia. In some (15, 16, 24, 55), but not all (44, 47) studies, children have been shown to have a small (11.5 mmol/l) and transient fall in blood glucose concentration during the rst few minutes after the start of aerobic exercise. The reason for the drop in blood glucose is unclear but may be a result of what Boisseau and Delamarche (10) refer to as an immature hepatic glycogenolytic system. The clinical relevance (or performance-related implications) of this small drop in glycemia is unclear, however. The decrease in glycemia at the onset of exercise in adolescent boys is not attenuated by exogenous carbohydrate intake (55). During moderate-intensity cycling, blood glucose levels and catecholamines levels are lower in adolescent girls than in adolescent boys (15), which suggests that girls either have a lower hepatic glucose production rate than boys or that girls utilize more plasma glucose during exercise than boys. Both possibilities require investigation. Although the belief that children have an immature glucoregulatory system, at least for the metabolic pathways involved at the start of exercise, remains a possibility, there is little evidence that healthy youth develop exerciseassociated hypoglycemia. It may be that the drop in glycemia at the start of exercise is caused by the increase in glucose disposal into working muscle, which is independent of insulin signaling. The effect of age, maturation, and sex on hepatic glycogen stores and on hepatic glucose production rates during exercise requires investigation, although these studies are currently challenging because of technical and ethical considerations. As pointed out in a review by Boisseau and Delamarche (10), infants have only 15 g of hepatic glycogen with the majority of that used to maintain the central nervous systems high demand for glucose. Knowledge of hepatic glycogen stores in older children and adults is scarce because of the invasiveness of these sorts of studies. If children and young adolescents have a low amount of hepatic glycogen, it would be expected
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that they would be hampered in their ability to exercise for prolonged periods because of increased risk for hypoglycemia. This is clearly not the case. Young adolescents can exercise for O2max) without at least 120 min at a high intensity (60% V developing hypoglycemia, even when they do not ingest carbohydrate before or during the activity (24, 44, 47, 5355). However, it is worth mentioning that in a majority of these studies, the participants were exercising in a fed state (i.e., within hours of a meal), rather than in a fasted state when hypoglycemia may be more likely. It is also important to note, that although orally ingested carbohydrate may not be required to prevent hypoglycemia during prolonged exercise in children and adolescents, these energy source can improve performance and contribute signicantly to the energy supply during the activity (see SUBSTRATE UTILIZATION DURING EXERCISE below).
SUBSTRATE UTILIZATION DURING EXERCISE

Using the methods developed by Dill and colleagues at the Harvard Fatigue Laboratory, Robinson (58) was the rst to publish in 1938 that the physiological responses to treadmill walking and running differed among children and adults. In that pioneering work, Robinson suggested that a lower respiratory exchange ratio (RER) during exercise in younger adolescents compared with older adolescents and adults was the result of a diminished reserve of carbohydrates. However, he believed that the prolonged 15-h fast before the test caused a reduction in endogenous carbohydrate stores in the younger volunteers and therefore a lower RER. Follow-up studies by Morse and colleagues (46) conrmed that RER levels are lower in children than in adults and that RER increases with increasing age in adolescents. Although RER does have its limitations when used to quantify substrate utilization (36), this technique has been used extensively to characterize substrate oxidation in children and in adults. A study by Montoye (45) in the early 1980s is also of note in this context because of the large numbers of children and adolescents studied (180 examined the 10- to 14-yr age range and 190 in the 15- to 19-yr age range). Based on these, and numerous other studies to date, the general consensus is that the lower RER frequently observed in children, when compared with adults, indicates that the former utilize considerably more fat and less carbohydrate for energy at a given relative exercise intensity. This difference between boys and men also holds true for girls and women (44). As an example of the magnitude of difference, Timmons et al. (67) found that O2 peak, pre- and early perpetual boys during cycling at 70% V oxidize 70% more fat and 23% less carbohydrate compared with men (67). The higher relative contribution from fat in adolescents persists even when the exercise is performed during carbohydrate feeding. In line with the notion that maturation inuences substrate utilization are a number of studies examining children at different stages of puberty. Compared with older girls (aged 14 yr), younger girls (aged 12 yr) have a higher fat oxidation rate during moderate intensity exercise (65). Compared with older boys, younger boys have higher relative rate of fat oxidation than post pubertal boys (66). Zunquin et al. (74) also recently reported that the development of puberty reduces the ability to oxidize fat during exercise in obese boys.
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Recently, investigation on the exercise intensity that elicits peak fat oxidation has been revisited by Jeukendrups group, showing that peak fat oxidation rates occur between 40 and O2max in untrained men and women (69) and at 63% 50% of V of VO2max in well-trained athletes (1). Finding the intensity at which point maximal fat oxidation occurs in children and adolescents is important for both performance and health benet reasons. Recently, Stephens et al. (63) showed that maximal fat oxidation is higher in prepubertal boys compared with pubertal boys, and based on their RER values collected, maximal fat oxidation occurs at somewhere between 40 and O2max in prepubertal boys. Moreover, based on their 70% V ndings, these authors propose that the development of an adult-like metabolic prole occurs between mid to late puberty and is complete by the end of puberty (63). Recently, peak fat oxidation rate during cycling in boys was calculated to be 8 mg kg lean body mass1 min1, occurring at 60% O2 peak. In untrained young men, peak fat oxidation rate was V determined to be 5 mg kg lean body mass1 min1, occur O2 peak (56). In that same study of a small ring at 40% V cohort of adolescent boys, examined in a 3-yr longitudinal design, both the relative fat oxidation rate and the exercise intensity that elicited peak fat oxidation decreased as boys develop through puberty, with the most signicant changes occurring between mid- to late puberty (56). Because of the high rate of fat oxidation occurring during intense exercise, the exercise intensity at which point carbohydrate dominates as the fuel source is considerably higher in children than in adults, and this drops considerably as adolescents develop though puberty. The mechanism for the higher rate of fat oxidation in childhood compared with adulthood is unknown. During prolonged exercise, nonesteried fatty acids (NEFA) are released from triacylglycerol stores in adipose tissue and muscle. Their release during moderate exercise is regulated by the sympathetic nervous system through a gradual increase in epinephrine release and a gradual reduction in insulin release by the pancreatic beta cells. The high epinephrine-to-insulin ratio increases circulating NEFA levels severalfold, which then facilitates the amount oxidized by skeletal muscle. It is not clear, however, whether children and adolescents have higher circulating NEFAs than adults during endurance exercise. Delamarche et al. (16) indirectly reported a higher NEFA turnover in boys than what is typically reported for men; however, Martinez and Haymes (44) found no difference in plasma NEFA and glycerol levels in girls and women during a 30-min run. Interestingly, increases in circulating lactate levels during high-intensity exercise is thought to limit NEFA release by adipose tissue and children do have lower lactate production during heavy exercise compared with adults. The higher oxidation of long-chain fatty acids in the skeletal muscle mitochondria of children may play a key regulatory role in lowering carbohydrate oxidation during exercise. Long-chain fatty acids are shuttled across the mitochondrial membrane by two carnitine palmitoyltransferases (CPT I and CPT II), and these are thought to be rate limiting for fatty acid oxidation in muscle. However, there are no age-related changes in CPT activity in children compared with adults (37), and there are also no major differences in enzyme activities of fatty acid metabolism (acetoacetyl-CoA thiolase and 3-hydroxyacyl dehydrogenase) in
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pubescent children compared with young adults (33). It may be that the higher fat oxidation in boys may be a default mechanism as a result of an underdeveloped glycogenolysis and/or glycolytic system as has been proposed by Timmons et al. (67), although experimental evidence to support this hypothesis is lacking. Interestingly, the CPT/OGDH ratio of enzyme activities in skeletal muscle tends to be higher (16%) in children vs. young adults (37), suggesting that there is preferential oxidation of fatty acids over other substrates such as carbohydrate in children compared with adults. The inuence of childhood disease and metabolic dysregulation on substrate metabolism has been of interest to some investigators. Adolescents with Type 1 diabetes have even higher rates of fat oxidation during moderate-intensity exercise compared with nondiabetic adolescents (53). Fat oxidation rate is correlated to the level of fat-free mass (FFM) in obese boys (13). When expressed per unit of FFM, or as a percentage of total fuel oxidation, fat utilization is lower in postpubertal than prepubertal obese boys (13). It does not appear, therefore, from this study and others that childhood obesity is caused by a reduced rate of fat oxidation during exercise. Estrogen has long been thought to explain the higher rate of fat oxidation in women compared with men. An increase in estrogen during puberty was therefore thought to increase fat oxidation rates in female subjects. As cited above, however, a more than twofold higher rate of fat oxidation occurs during exercise in 12-yr-old girls compared with 14-yr-old girls (65), despite nearly 50% higher circulating estradiol levels in the latter group. These data, along with the observation that fat oxidation rate is inversely related to estradiol concentrations in girls (65), suggest that it is likely not estrogen that is responsible for the higher rate of fat oxidation in adult women, as has been proposed by some (32). Boys and girls appear to have similar rates of fat oxidation during treadmill walking performed at the same absolute intensity, at least until the nal stages of puberty at which point RER values are slightly higher in girls than in boys (59). Despite a lower whole body rate of carbohydrate oxidation during exercise, and a much higher rate of fat oxidation, children have considerably higher rates of orally ingested glucose oxidation. During moderate to intense cycling (ranging O2 peak), orally ingested 6 8% glucose from 50 to 70% V beverage (sometimes called exogenous carbohydrate) provides between 15 and 22% of the overall energy supply in pre- and early pubertal boys (5355, 67). These values are considerably higher than what is reported for adults (48) and is counter to the widely held belief that children would not oxidize signicant amounts of exogenous carbohydrate because of their greater reliance on fat as a fuel. In the one study that compared adolescent boys with male subjects directly, pre- and early pubertal boys had a 50% higher relative contribution from exogenous carbohydrate to the total energy supply when compared with men (67). To further investigate the effects of pubertal status and age on exogenous carbohydrate utilization, Timmons et al. (66) recently took 20 boys of the same chronological age (12 yr) and divided them into three groups based on their pubertal stage (i.e., prepubertal vs. early pubertal vs. mid- to late pubertal). The boys consumed either a placebo drink or a 13 C-enriched 6% carbohydrate drink, while cycling for 60 min O2max. Interestingly, fat oxidation was similar at 70% of their V
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in all three pubertal groups, but the energy supply from exogenous carbohydrate oxidation differed. Specically, exogenous carbohydrate oxidation contributed to 30% of the total energy expenditure in the pre- and early pubertal boys, but to only 24% in mid- to late pubertal boys, identical to what was observed in a group of more mature 14-yr-old boys. Exogenous carbohydrate oxidation rate, expressed as a percentage of total energy expenditure, was inversely related to testosterone levels (r 0.51, P 0.005, n 29), suggesting that the androgen might lower the relative contribution from this important fuel source. Thus it appears that that the reliance on exogenous carbohydrate during exercise is particularly sensitive to pubertal status, with the highest oxidation rates observed in pre- and early pubertal boys and lowest in mid- to late puberty, independent of chronological age. Interestingly, relative exogenous carbohydrate oxidation rate during exercise is not different between younger (i.e., 12 yr old) and older (i.e., 14 yr old) girls despite large differences in circulating estradiol levels (65). Differences between adults and children may also exist in their ability to oxidize fructose during exercise. A beverage combining fructose and glucose has considerably less of an insulin and glucose response compared with glucose alone in adolescent boys (55). In addition, compared with glucose alone, fructose plus glucose has a similar rate of oxidation, although the former provides more of an ergogenic effect during aerobic exercise (55). Beverages containing glucose and fructose have a higher energy contribution during exercise than glucose alone in adults (2). All-out cycling sprint performance after intermittent cycling for 90 min in boys can be increased by 20 40% with a combined 6% glucose and fructose beverage, compared with either placebo or 6% glucose alone (55). Although exogenous carbohydrate intake spares endogenous carbohydrate and fat in boys, to a greater extent than in adults, the location of this spared fuel (i.e., intramuscular or extramuscular stores) is unknown.

SUMMARY AND IMPLICATIONS

During play and structured sport, young people derive energy from the interplay between anaerobic and aerobic metabolism, with a greater reliance on aerobic metabolism as fuel compared with adults. In the resting state, adolescents developing through puberty have some degree of insulin resistance that carries over during exercise. Compared with adults, adolescents have lower circulating lactate levels likely because of a reduced activity of the enzyme pyruvate dehydrogenase, a lower lactate production rate, a higher rate of oxidative phosphorylation, and a great reliance on lipid as an energy source. Glucose production at the onset of exercise may be inadequate to prevent a transient drop in glycemia, although the likelihood of the development of hypoglycemia in healthy adolescents even during long-duration exercise seems remote. Throughout a wide range of exercise intensities, lipid utilization is considerably higher in childhood than in adult hood, and adolescents have attenuated rates of lipid oxidation as they develop through puberty. The greatest change in substrate utilization in boys and girls occurs during the nal stages of puberty. Despite a higher rate of lipid utilization compared with adults, adolescent boys oxidize exogenous carbohydrate at a higher relative rate, perhaps because of their lower endogenous carbohydrate stores. As a result, endogenous energy sources are spared with carbohydrate intake and exercise performance may be enhanced. In young prepubertal female subjects, exogenous carbohydrate intake reduces the high rate of lipid oxidation during exercise, although this effect is lost as girls develop through puberty. A schematic summary of the major fuel uxes during prolonged exercise in youth and the possible mechanisms for the observed higher reliance on lipid and exogenous carbohydrate as a fuel source during exercise is shown in Fig. 2. Because considerable differences exist in the mix of fuels used during exercise between children and adults, one wonders

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Fig. 2. Substrate ux during prolonged moderate-intensity exercise in youth. Fuel utilization during exercise differs in children compared with adults. Before puberty, youth rely less on carbohydrate and more on lipid as a fuel source. When carbohydrate intake (i.e., exogenous carbohydrate) occurs during exercise, prepubertal children have a higher relative rate of exogenous carbohydrate oxidation compared with adults. As children develop through puberty, the greater reliance on lipid and exogenous carbohydrate as the 2 main fuel sources during exercise is lost. The possible mechanisms for the unique patterns of fuel utilization in youth may include 1) a greater provision of nonesteried fatty acids (NEFA) and a reduced provision of hepatic-derived glucose into the circulation, 2) a greater reliance on intramyocellular lipids for oxidation, 3) a reduced muscle glycogen content, 4) reductions in key glycolytic enzymes in skeletal muscle, or 5) increased fatty acid transport into mitochondria.

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METABOLIC RESPONSES TO EXERCISE IN YOUTH 5. Arslanian SA, Kalhan SC. Correlations between fatty acid and glucose metabolism. Potential explanation of insulin resistance of puberty. Diabetes 43: 908 914, 1994. 6. Bar-Or O. Pediatric Sports Medicine for the Practitioner: From Physiologic Principles to Clinical Applications. New York: Sponger-Verlag, 1983. 7. Bell RD, MacDougall JD, Billeter R, Howald H. Muscle ber types and morphometric analysis of skeletal muscle in six-year-old children. Med Sci Sports Exerc 12: 28 31, 1980. 8. Beneke R, Hutler M, Jung M, Leithauser RM. Modeling the blood lactate kinetics at maximal short-term exercise conditions in children, adolescents, and adults. J Appl Physiol 99: 499 504, 2005. 9. Berg A, Kim SS, Keul J. Skeletal muscle enzyme activities in healthy young subjects. Int J Sports Med 7: 236 239, 1986. 10. Boisseau N, Delamarche P. Metabolic and hormonal responses to exercise in children and adolescents. Sports Med 30: 405 422, 2000. 11. Boisseau N, Rannou F, Delemarche P, Monnier M, Delamarche AG. Peripubertal period decreases insulin sensitivity and glucose utilization during exercise. In: Children and Exercise XIX, edited by Armstrong N, Kirby B, and Welsman J. London: Spon, 1997, p. 412 417. 12. Bouix O, Brun JF, Fedou C, Raynaud E, Kerdelhue B, Lenoir V, Orsetti A. Plasma beta-endorphin, corticotrophin and growth hormone responses to exercise in pubertal and prepubertal children. Horm Metab Res 26: 195199, 1994. 13. Brandou F, Savy-Pacaux AM, Marie J, Brun JF, Mercier J. Comparison of the type of substrate oxidation during exercise between pre and post pubertal markedly obese boys. Int J Sports Med 27: 407 414, 2006. 14. Caprio S, Amiel SA, Merkel P, Tamborlane WV. Insulin-resistant syndromes in children. Horm Res 39, Suppl 3: 112114, 1993. 15. Delamarche P, Gratas-Delamarche A, Monnier M, Mayet MH, Koubi HE, Favier R. Glucoregulation and hormonal changes during prolonged exercise in boys and girls. Eur J Appl Physiol Occup Physiol 68: 3 8, 1994. 16. Delamarche P, Monnier M, Gratas-Delamarche A, Koubi HE, Mayet MH, Favier R. Glucose and free fatty acid utilization during prolonged exercise in prepubertal boys in relation to catecholamine responses. Eur J Appl Physiol Occup Physiol 65: 66 72, 1992. 17. Ekblom B. Effect of physical training in adolescent boys. J Appl Physiol 27: 350 355, 1969. 18. Elder GC, Kakulas BA. Histochemical and contractile property changes during human muscle development. Muscle Nerve 16: 1246 1253, 1993. 19. Eliakim A, Nemet D, Zaldivar F, McMurray RG, Culler FL, Galassetti P, Cooper DM. Reduced exercise-associated response of the GH-IGF-I axis and catecholamines in obese children and adolescents. J Appl Physiol 100: 1630 1637, 2006. 20. Eriksson BO. Muscle metabolism in childrena review. Acta Paediatr Scand Suppl 283: 20 28, 1980. 21. Eriksson BO. Physical training, oxygen supply and muscle metabolism in 1113-year old boys. Acta Physiol Scand Suppl 384: 1 48, 1972. 22. Eriksson BO, Gollnick PD, Saltin B. The effect of physical training on muscle enzyme activities and ber composition in 11-year-old boys. Acta Paediatr Belg Suppl 28: 245252, 1974. 23. Eriksson BO, Gollnick PD, Saltin B. Muscle metabolism and enzyme activities after training in boys 1113 years old. Acta Physiol Scand 87: 485 497, 1973. 24. Eriksson BO, Karlsson J, Saltin B. Muscle metabolites during exercise in pubertal boys. Acta Paediatr Scand Suppl 217: 154 157, 1971. 25. Eriksson BO, Saltin B. Muscle metabolism during exercise in boys aged 11 to 16 years compared to adults. Acta Paediatr Belg 28, Suppl: 257265, 1974. 26. Fahey TD, Del Valle-Zuris A, Oehlsen G, Trieb M, Seymour J. Pubertal stage differences in hormonal and hematological responses to maximal exercise in males. J Appl Physiol 46: 823 827, 1979. 27. Galassetti P, Larson J, Iwanaga K, Salsberg SL, Eliakim A, Pontello A. Effect of a high-fat meal on the growth hormone response to exercise in children. J Pediatr Endocrinol Metab 19: 777786, 2006. 28. Galassetti PR, Iwanaga K, Crisostomo M, Zaldivar FP, Larson J, Pescatello A. Inammatory cytokine, growth factor and counterregulatory responses to exercise in children with type 1 diabetes and healthy controls. Pediatr Diabetes 7: 16 24, 2006. 29. Glenmark B, Hedberg G, Kaijser L, Jansson E. Muscle strength from adolescence to adulthoodrelationship to muscle bre types. Eur J Appl Physiol Occup Physiol 68: 9 19, 1994. www.jap.org

whether their might be some performance or health related implications. A greater proportional reliance on exogenous carbohydrate as fuel during exercise, in addition to a greater utilization of endogenous fat, leads one to conclude that they may be developed in a way that protects endogenous substrates for growth and development of the musculoskeletal and the central nervous systems. Further investigation is required to determine whether the unique metabolic responses to exercise in youth confer any performance or health-related advantages, however. First, the lower lactate and H production and a greater reliance on aerobic metabolism may favor activities that are more aerobic in nature rather than those that are of a higher intensity and for a brief duration. For this reason, consideration should be given to develop exercise recommendations for the type, intensity, and duration of physical activity for healthy growing youth. Second, work is needed to determine whether the greater reliance on fat as fuel during prolonged activities helps to advantage children for activities of longer duration, while helping to protect precious carbohydrate stores for the developing central nervous system. Third, because it appears that children have already in place many of the metabolic advantages of a well-trained athlete, more research is needed to determine whether there may be an optimal training regime (frequency, duration, intensity) for the maintenance of this apparent metabolic advantage though development into adulthood. Finally, consideration should be given as to what are the appropriate preexercise nutritional requirements of growing youth based on their unique metabolic prole. Future investigations, using minimally invasive techniques, are needed to determine the mechanisms for the altered substrate utilization during exercise in adolescents. Specically, the various components of macronutrient oxidation during exercise require investigation, with techniques developed that can compartmentalize the sources of fat and carbohydrate utilized during a variety of exercise intensities and durations. Moreover, protein oxidation during exercise in youth and the inuence of protein utilization on growth and development requires investigation. Finally, more work needs to be done to clarify whether adolescence causes altered endocrine responses to prolonged moderate intensity exercise and heavy exercise.
ACKNOWLEDGMENTS I would acknowledge the contributions of Dr. Oded Bar-Or (deceased) for his work in pediatric exercise physiology and substrate metabolism. I thank Anna Standish for her artwork in Fig. 2 and Dr. Brian Timmons for review of the manuscript. GRANTS M. C. Riddell is supported by the National Science and Engineering Council of Canada and the Canadian Foundation for Innovation. REFERENCES 1. Achten J, Jeukendrup AE. Maximal fat oxidation during exercise in trained men. Int J Sports Med 24: 603 608, 2003. 2. Adopo E, Peronnet F, Massicotte D, Brisson GR, Hillaire-Marcel C. Respective oxidation of exogenous glucose and fructose given in the same drink during exercise. J Appl Physiol 76: 1014 1019, 1994. 3. Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane WV. Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes. N Engl J Med 315: 215 219, 1986. 4. Armon Y, Cooper DM, Flores R, Zanconato S, Barstow TJ. Oxygen uptake dynamics during high-intensity exercise in children and adults. J Appl Physiol 70: 841 848, 1991. J Appl Physiol VOL

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