New insights in paediatric exercise metabolism

Neil Armstrong*,Alan R.Barker

Children’s Health and Exercise Research Centre,University of Exeter,Exeter EX4 4QP,UK

New insights in paediatric exercise metabolism

Neil Armstrong*,Alan R.Barker

Children’s Health and Exercise Research Centre,University of Exeter,Exeter EX4 4QP,UK

Research in paediatric exercise metabolism has been constrained by being unable to interrogate muscle in vivo.Conventionally,research has been limited to the estimation of muscle metabolism from observations of blood and respiratory gases during maximal or steady state exercise and the analysis of a few muscle biopsies taken at rest or post-exercise.The purpose of this paper is to review how the introduction of31P-magnetic resonance spectroscopy and breath-by-breath oxygen uptake kinetics studies has contributed to current understanding of exercise metabolism during growth and maturation.Methodologically robust studies using31P-magnetic resonance spectroscopy and oxygen uptake kinetics with children are sparse and some data are in conflict.However,it can be concluded that children respond to exercise with enhanced oxygen utilization within the myocyte compared with adults and that their responses are consistentwith a greater recruitment of type Imuscle fibres.Changes in muscle metabolism are age,maturation-and sex-related and dependent on the intensity of the exercise challenge.The introduction of experimental models such as“priming exercise”and“work-to-work”transitions provide intriguing avenues of research into the mechanisms underpinning exercise metabolism during growth and maturation.

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Children;Magnetic resonance spectroscopy;Oxygen uptake kinetics

1.Introduction

Paediatric exercise metabolism studies are normally limited to examining blood and respiratory gas markers of maximal(or peak)and steady state exercise metabolism.These studies have enhanced knowledge but ethical considerations have restricted potentially more informative research at the level of the myocyte.The few muscle biopsy studies which have been performed with healthy children have focused on resting and post-exercise measures and have generally been restricted to small samples of predominantly male children andadolescents.The emergence ofnon-invasive technologies such as31P-magnetic resonance spectroscopy(31P-MRS)and methodologies such as breath-by-breath determination of pulmonary oxygen uptake（p˙VO2）kinetics,which allow in vivo investigations during exercise,therefore have the potential to provide new insights into paediatric exercise metabolism.

This paper will briefly review what we know from conventional indicators of exercise metabolism during growth and maturation and explore recent insights into paediatric muscle metabolism provided by rigorous analyses of p˙VO2kinetics data and31P-MRS spectra.

2.The contribution of conventional methodologies to the understanding of paediatric exercise metabolism

2.1.Aerobic—anaerobic interplay during maximal performance

Peak˙VO2is the best single indicator of young people’s aerobic fitness and data show an almost linear increase inboys’peak˙VO2in relation to age with girls showing a similar trend atleastup to the age of～14 years when peak˙VO2tends to level off.Girls’peak˙VO2values are～10%lower than those of boys during childhood and the sex difference reaches～35%by age 16 years.Peak˙VO2is strongly related to body size and in both sexes maturation exerts an additional positive effect on peak˙VO2independent of age and body size.1

The assessment of peak anaerobic performance has focused on the estimation of peak power output(PPO)determined using the Wingate anaerobic test.Sex differences in PPO appear to be minimal until～12—13 years of age but this finding is confounded by the fact that few studies have simultaneously considered chronologicalage and the stage of maturation of the participants.From～13 years there is a more marked increase in the PPO of boys in relation to chronological age so that by～16 years boys’values exceed those of girls by～50%.2

Both sexes experience a more marked increase in PPO than peak˙VO2during maturation with peak˙VO2increasing by～70%and～50%in boys and girls,respectively compared with PPO increases of～120%and～65%from 12 to 17 years.3,4However,although estimates of peak aerobic and anaerobic performance illustrate asynchronous,age-,sex-, growth-and maturation-related differences in exercise metabolism they provide few insights into the aerobic—anaerobic interplay in the muscles during growth and maturation.

2.2.Recovery from high intensity exercise

The ability of young people to recover faster than adults following high intensity exercise is well documented.5—7This might be explained by children and adolescents having enhanced oxidative capacity,faster phosphocreatine(PCr)resynthesis,better acid—base regulation,and lower production and/or more efficient removal of metabolic by-products than adults.8Butsome researchers have critiqued the high intensity exercise models used to compare children and adults and concluded that young people’s faster recovery is simply a direct consequence of their body size and their limited capacity to generate power.9

2.3.Substrate utilization

Boys have higherrelative rates offatoxidation than men at a range of exercise intensities and the exercise intensity that elicits peak fatoxidation is higher in boys than in men.10,11Sex differences in substrate utilization have been reported.12but age-related data in females are conflicting and have been attributed to menstrual cycle variations between girls and women.13,14In boys,high rates offatoxidation decline during maturation and the development of an adult fuel-utilization profile occurs in the transition from mid-puberty to late-puberty and is complete on reaching adulthood.10,15Timmons et al.12have suggested that children have an underdeveloped depot of intramuscular fuels rather than an underdeveloped glycolytic flux.

2.4.Muscle fibre types

Boisseau and Delmarche16hypothesised that maturation of skeletal muscle fibre patterns might account for the development of metabolic responses to high intensity exercise during growth and maturation.The interpretation of muscle biopsy studies of young people is,however,confounded by large inter individual variations in fibre profiles and few,mostly male,participants.17Patterns which have emerged suggest that muscle fibre size increases linearly with age from birth to adolescence and,at least in males,into adulthood.18The percentage oftype Ifibres decreases in healthy males from age 10—35 years butclear age-related fibre type changes have not been consistently demonstrated in females although this might be a methodological artefactas few data on young females are available.17,19

In underpowered experimental designs,statistically significantsex differences in the percentage oftype Ifibres have not been reported during childhood and adolescence.However, there is a consistent trend with adolescent boys and young male adults exhibiting 8%—15%more type I fibres in the vastus lateralis than similarly aged females in the same study.19—21No study has reported a lowerpercentage oftype I fibres in boys than girls.

2.5.Muscle energy stores

In the early 1970s Eriksson etal.22—26carried outa series of innovative muscle biopsy studies on small samples of 11—16 years old boys which have influenced the understanding of paediatric exercise metabolism for almost 40 years.

Muscle biopsies from the lateral part of the quadriceps femoris revealed resting adenosine triphosphate(ATP)stores which were invariantoverthe age range 11.6—15.5 years.The PCrstores of the 15-year-old boys were 63%higherthan those of the 11-year-old boys.The ATP stores atallages and the PCr stores of the 15-year-old boys were not dissimilar to values others had reported in adults.Glycogen stores at rest were reported to increase by 61%from 11 years to 15 years.The concentration of ATP remained virtually unchanged following several bouts of submaximal exercise but minor reductions were reported following maximal exercise.The PCr stores gradually depleted following exercise sessions of increasing intensity.Muscle glycogen stores decreased following exercise in all age groups butthe depletion was three times greater in the older boys suggesting enhanced glycolysis with age.26

2.6.Muscle enzyme activity

Eriksson et al.26reported succinic dehydrogenase and phosphofructokinase(PFK)activity atrestin 11-year-old boys to be 20%and 50%respectively lower than they had previously reported for adults.27Haralambie28determined the activity of 22 enzymes involved in energy metabolism in 13—15-year-old boys and girls and in adult men and women and,in conflict with Eriksson’s observations,he found no significant difference in the activity of glycolytic enzymesbetween adolescents and adults.He did,however,confirm his earlier observation29of greater activity of oxidative enzymes in adolescents than in adults.Subsequently,Berg et al.30,31reported glycolytic enzymes activity to be positively correlated with age and oxidative enzymes activity to be negatively correlated with age over the age range 6—17 years,in both males and females.Allmuscle biopsies were taken atrest.

Haralambie28,29reported a comparison of the resting activity of potential rate limiting enzymes of glycolysis and the tricarboxylic acid cycle,namely,PFK and isocitric dehydrogenase(ICDH).The ratio PFK/ICDH was reported to be 93%higher in adults than in adolescents at 1.633 and 0.844, respectively.A re-calculation of Berg’s data indicated a similar relationship of glycolytic and oxidative enzymes with the ratio of pyruvate kinase to fumarase varying from 3.585 in adults,3.201 in adolescents to 2.257 in children.30,31

2.7.Lactate production and accumulation

Eriksson et al.25,26reported muscle lactate accumulation following exercise to increase with age and,on the basis of an‘almost significant’relationship between lactate accumulation in the muscles and testicular volume,they hypothesised a maturational effect on lactate production.In more recent studies blood lactate accumulation has been used as a surrogate of muscle lactate production and glycolytic activity.1,32We have discussed the limitations of this extrapolation elsewhere.33

The interpretation of blood lactate accumulation is clouded by theoretical and methodological issues and data need to be interpreted with caution.Sex differences and maturation effects independent of age have proved elusive to establish. However,consistent findings are that children accumulate less blood lactate during exercise than adults and that there is a negative correlation between the exercise intensity at the lactate threshold(TLAC)and age.33Pianosi et al.34reported that the ratio lactate/pyruvate following exercise increased with age and concluded that this indicated an age-related enhanced glycolytic function.Other authors,however,have hypothesised that lower post-exercise blood lactate accumulation in children reflects a smaller muscle mass combined with a facilitated aerobic metabolism.35

3.What do we know from conventional research?

What we know about paediatric exercise metabolism from conventional indicators is limited by ethical and methodological considerations.Age-related increases in peak aerobic and anaerobic performance are asynchronous with greater increases observed in peak anaerobic performance than peak aerobic performance during puberty.Young people recover from high intensity exercise faster than adults.Substrate utilization studies indicate an age-related effect,at least in males,with children and adolescents relying more on lipids as an energy source than adults do during steady state exercise. Muscle biopsy data indicate an age-related decline in the percentage of type Ifibres and a trend indicating boys to have a higher percentage of type Ifibres than girls.Resting muscle concentrations of ATP appear invariant with age but resting muscle PCr and glycogen concentrations progressively increase,at least through the teen years.Resting oxidative enzymes activity is positively related to age and glycolytic enzymes activity might be negatively related to age.The ratio of glycolytic/oxidative enzymes activity is higher in adults than in adolescents or children.The balance of evidence suggests that children are disadvantaged compared to adolescents who are,in turn,disadvantaged compared to adults in activities involving high intensity exercise supported predominantly by anaerobic metabolism.Young people, however,appear well equipped for low-to-moderate intensity activities supported by lipids and aerobic metabolism.

4.The contribution of new non-invasive methodologies and technologies to understanding paediatric exercise metabolism

4.1.Pulmonary oxygen uptake kinetics

In the laboratory p˙VO2kinetics are analysed by the use of a step transition where a period of very low intensity exercise, such as unloaded pedalling on a cycle ergometer,is followed by a sudden increase in exercise intensity to a pre-determined level.The p˙VO2kinetics response to the step change in exercise intensity is interpreted in relation to four exercise intensity domains.The upper threshold of the moderate intensity domain is the TLACwhich also serves as the lower threshold of the heavy exercise intensity domain.The upper marker of the heavy exercise intensity domain is the maximal lactate steady state(MLSS,the highestmetabolic rate atwhich exercise can be sustained without an accumulation of blood lactate33)or,more often in young people,the critical power (CP,the highestmetabolic rate atwhich˙VO2can be stabilised below peak˙VO236,37).Exercise above MLSS or CP butbelow peak˙VO2is in the very heavy exercise domain and exercise above peak˙VO2is in the severe exercise domain.38

With young participants it has been noted that small breathto-breath variations are inherent to children’s response profiles.39This reduces the confidence with which p˙VO2kinetic responses can be estimated and confidence intervals are likely to be beyond acceptable limits unless sufficientidentical transitions are aligned and averaged to improve the signal to noise ratio.40Rigorously determined and interpreted data from young people are available in the moderate,heavy and very heavy intensity exercise domains.41—43

The p˙VO2response to a step transition has three phases.At the onset there is an immediate increase in cardiac output which occurs prior to the arrivalat the lungs of venous blood from the exercising muscles.This cardiodynamic phase(phase I)which,in children,lasts～15 s is independent of˙VO2at the muscle（m˙VO2）and reflects an increase in pulmonary blood flow with exercise.Phase II,the primary component,is a rapid exponential increase in p˙VO2that arises with hypoxic and hypercapnic blood from the exercising muscles arriving at the lungs.Phase IIkinetics are described by the time constant(τ)which is the time taken to achieve 63%of the change in p˙VO2. In phases Iand IIATP re-synthesis cannot be fully supported by oxidative phosphorylation and the additional energy requirements of the exercise are metfrom body oxygen stores, PCr and glycolysis.During moderate intensity exercise with children p˙VO2reaches a steady state(phase III)within about 2 min.In the heavy intensity exercise domain,the primary phase II oxygen cost is similar to that observed during moderate intensity exercise but the overall oxygen cost of exercise increases over time as a slow component of p˙VO2is superimposed upon the primary component and the achievement of a steady state might be delayed by～10—15 min.44In adults,atexercise intensities above the MLSS or CP the slow component of p˙VO2rises rapidly over time and eventually reaches peak˙VO2but this phenomenon has not been observed in children.37,45

The mechanisms underlying the p˙VO2slow component remain speculative butithas been established that～86%have been accounted for at the contracting muscles.46During exercise above the TLACthe p˙VO2slow component is associated with a progressive recruitment of additional type II muscle fibres with the low efficiency contributing to the increased oxygen cost of exercise.47However,this is probably not the whole story and fatigued fibres recruited during phase II might also become less efficient and require greater oxygen consumption per unit of ATP turnover and/or a greater ATP turnover per unit of power output.48Early studies of young people indicated that they did not exhibit a slow component during heavy exercise49but more rigorous studies using appropriate modelling techniques50have observed p˙VO2slow components in both pre-pubertal children51,52and adolescents.53

Despite a temporal dissociation at the onset of exercise (thecardiodynamic phase), modelling simulations54and direct measurement of m˙VO2using the Fick technique during cycling55have demonstrated m˙VO2and phase II p˙VO2kinetics to correspond in adults within～10%.In an innovative study Rossiter et al.56confi rmed this relationship by simultaneously determining adults’p˙VO2kinetics and PCr kinetics using knee extensor exercise in a magnetic resonance (MR)scanner.This work has notbeen replicated with children as they display a lower p˙VO2amplitude than adults which makes the simultaneous assessment of young people’s p˙VO2and PCr kinetics in an MR scanner infeasible.However, Barkeretal.57have demonstrated a close relationship between children’s intramuscular PCr kinetics during prone quadriceps exercise in an MR scanner and p˙VO2kinetics during upright cycling at both the onset and offset of moderate intensity exercise.In adults the recovery kinetics of muscle PCr has been routinely employed as a non-invasive measure of muscle oxidative capacity.58The close kinetic coupling between the p˙VO2and PCr kinetic profiles at the onset and offset of exercise support the use of the phase II p˙VO2kineticsτas a proxy measure of muscle PCr kinetics.Children’s phase II p˙VO2kinetics response to and recovery from step changes in exercise intensity therefore provide a non-invasive window into metabolic activity in the muscles.

4.2.Pulmonary oxygen uptake kinetics and paediatric exercise metabolism

4.2.1.Moderate intensity exercise

Breath-by-breath studies of children’s p˙VO2kinetics response to a transition to moderate intensity exercise date back over 25 years59and although they present a general consensus that there is an age-related decline in the oxygen cost of exercise there are conflicting reports regarding whether or not p˙VO2kinetics is faster in children than in adults. However,many of the early studies have been criticised on the basis of their lack of adequate exercise transitions,poor modelling techniques,notreporting 95%confidence intervals, and/or limitations within their participant samples.40,60In a more recent and rigorous study of children’s and adults’p˙VO2kinetics response during exercise below TLACthe phase IIτhasbeen demonstrated to be fasterin boys than men and in girls than women.No differences in the p˙VO2kinetics response of boys compared with girls or men compared with women were reported.61

Children’s fasterτand therefore greater aerobic contribution to ATP re-synthesis suggests an enhanced oxidative capacity which might be due to greater oxygen delivery or better oxygen utilization by the muscle during childhood or both.Data are sparse but muscle blood flow and therefore oxygen delivery during exercise has been reported to decrease in boys from age 12 to 16 years.62,63Peak˙VO2which is primarily dependent on oxygen delivery is not related to the phase IIτduring moderate intensity exercise in children61and there is no compelling evidence to suggest that increased delivery of oxygen increases the rate of p˙VO2kinetics during moderate intensity exercise.It is therefore likely that children’s faster phase IIτreflects an enhanced capacity for oxygen utilization by the mitochondria.

4.2.2.Heavy intensity exercise

In a series of studies of pre-pubertal children’s p˙VO2kinetics response to a transition to exercise above the TLAC, Fawkner and Armstrong51observed that girls were characterised by a slower phase IIτand a greater relative contribution of the p˙VO2slow component to the end-exercise p˙VO2. In a subsequent study they monitored changes in the p˙VO2kinetics response to a transition to heavy intensity exercise over a 2-year period and noted that the phase IIτslowed and the p˙VO2slow component increased with age.Despite an increase in the p˙VO2slow component the overalloxygen cost at the end of the exercise was equal on test occasions 2 years apart suggesting that the phosphate turnover required to sustain the exercise was independent of age and that the older children achieved a lower proportion of their end exercise pVO2during phase II.52The same group reported similar findings in a 2-year longitudinal study of boys who were 14 years old at the first test occasion.53In accord with exercise in the moderate intensity domain,peak˙VO2was not related to the phase IIτduring heavy intensity exercise.51—53

The slowing of the phase IIτwith age mightbe related to changes in oxygen delivery but as indicated in the previoussection this is not supported by compelling evidence.It has been argued that the rate of p˙VO2kinetics at the onset of exercise is regulated by the exchange of intramuscular phosphates between the splitting of ATP and its subsequent resynthesis from PCr.64Furthermore,it has been reported in adults that there exists a dynamic symmetry between the rate of PCr breakdown and the phase IIτat the onset of high intensity exercise.56This suggests thatthe faster phase IIτin children might be due to an age-dependent effect on the putative phosphate linked controller(s)of mitochondrial oxidative phosphorylation.A phenomenon which might be partially explained by children’s enhanced aerobic enzyme profile and/or reduced resting total creatine concentration(as inferred from muscle PCr stores)compared to adults.

As the mechanisms underlying the p˙VO2slow component reside in the muscles,the increase in the magnitude of the p˙VO2slow component with age is likely to be related to changes in muscle fibre recruitment patterns.If oxidative capacity is negatively related to age then the greater glycogen depletion of type Ifibres and the enhanced recruitmentof type II fibres by adults will contribute to an elevated p˙VO2slow component.The data are consistent with children having a higherpercentage of type I muscle fibres than adults and the reported sex differences are in accord with girls having a lower percentage of type I muscle fibres than similarly aged boys.

4.2.3.Very heavy intensity exercise

Research in the very heavy exercise domain has been characterised by experimental manipulation of pedal rate during exercise and metabolic rate prior to exercise. Breese et al.65combined measurements of the integrated electromyogram(iEMG)with a“work-to-work”model involving step changes from unloaded pedalling to very heavy intensity exercise(U-VH),unloaded pedalling to moderate intensity exercise(U-M),and moderate to very heavy intensity exercise(M-VH).They reported thatthe phase IIτin boys in response to the U-VH protocol was significantly faster than in men.Men exhibited a relatively greater p˙VO2slow component than the boys and this was accompanied by an increased rate of change in iEMG activity of the vastus lateralis in men only. The M-VH protocol resulted in a similar relative slowing of the phase IIτin both boys and men although the boys still demonstrated a fasterτthan the men and the overall oxygen cost was increased in men only.

In addition to p˙VO2kinetics heart rate(HR)kinetics were also monitored during each protocol in order to provide an estimate of cardiac output dynamics and they were not significantly different in boys and men during either U-VH or M-VH protocols.65The HR kinetics data supportthe view that age-related differences in the phase IIτare not primarily influenced by oxygen delivery.Breese et al.’s65observations are wholly consistent with the view that age-related differences in the magnitude of the p˙VO2slow component are linked to changes in muscle fibre recruitment following the onset of very heavy intensity exercise.

In a subsequent study from the same research group,it was hypothesised that,based on skeletal muscle power—velocity relationships,the recruitment of type IImuscle fibres would be enhanced for the same external power output by increasing pedal rate.The effect of different pedal cadences(50 and 115 rev/min)at the same external power output on p˙VO2kinetics at the onset of very heavy exercise in trained and untrained,teenage,male cyclists was investigated.The trained boys showed no change in the phase IIτor the p˙VO2slow componentwith a change in pedal rate whereas the untrained boys’exhibited a slowing of the phase IIτand an increase in the magnitude of the p˙VO2slow component.The authors proposed that these findings might be accounted for by alterations in muscle fibre recruitment and/or enhancement in the oxidative capacity of recruited muscle fibres due to either genetic or training influences.66

To elevate muscle oxygen availability prior to a step change to very heavy intensity exercise Barker etal.67used a“priming exercise”modelwith 9-to 13-year-old boys.This consisted of a U-VH step change sustained for 6 min(the priming exercise),followed by an unloaded 6-min recovery cycle followed by another U-VH step change which was sustained for 6 min. In addition to respiratory gases,beat-by-beat HR,stroke volume and cardiac output were monitored using thoracic impedance,and changes in the concentrations of oxy-[Hb+Mb]and deoxy-[Hb+Mb]haemoglobin/myoglobin were estimated using near-infra red spectroscopy.The phase II τin the second U-VH bout was unchanged by the priming exercise butthe priming exercise resulted in an increase in the phase II p˙VO2amplitude and a reduction in the p˙VO2slow component.

Despite greater availability of oxygen to the contracting muscles in the second step change the phase IIτwas unaltered thus supporting the notion that the phase IIτin young people is dependent on oxygen utilization by the muscle rather than oxygen delivery.The elevated phase II˙VO2amplitude and reduced p˙VO2slow component are consistent with greater recruitment of type II muscle fibres.However,as the deoxy-[Hb+Mb],and therefore muscles’fractional oxygen utilization was unaltered following priming exercise and there was an elevated cardiac output/˙VO2at the end of exercise the authors suggested that the altered˙VO2amplitudes might be related to an enhanced oxygen delivery.67

4.3.Magnetic resonance spectroscopy

31P-MRS is a non-invasive technique that provides in vivo a window through which muscle can be interrogated during exercise.We have discussed the theoretical principles underpinning31P-MRS elsewhere.In brief,31P-MRS allows the monitoring of the molecules which play a central role in exercise metabolism,namely ATP,PCr and inorganic phosphate(Pi).The chemicalshift of the Pi spectralpeak relative to the PCr peak reflects the acidification of the muscle and enables the determination of pH.The change in pH during exercise provides an indication of muscle glycolytic activity but is not a direct measure of glycolysis.68

During progressive,incremental exercise non-linear changes in the ratio Pi/PCrplotted against power output and inpH plotted against power output occur.As power output increases an initial shallow slope is followed by a steeperslope and the transition pointis known as the intracellular threshold (IT).The Pi/PCr and pH ITs generally occur at the same time and are analogous to other metabolic thresholds such as TLACand ventilation threshold.5731P-MRS studies are constrained by exercising within a smallbore tube with the need to synchronize the acquisition of data with the rate of muscle contraction and this is challenging for young people.We have described elsewhere techniques used in our laboratory to habituate children to exercise in an MR scanner and demonstrated thatduring knee extensorexercise to exhaustion,the end-exercise pH and ITpHand ITPi/PCrdemonstrate good reliability and thus stable measures for the study of developmental muscle metabolism.69

4.4.31P-MRS and paediatric exercise metabolism

4.4.1.Incrementalexercise

The first31P-MRS study to include children was reported by Zanconato et al.70who compared the responses of 10 prepubertal children and eight adults during incremental calf muscle exercise to exhaustion in an MR scanner.They observed an increase in Pi/PCr and a decrease in pH in both children and adults with increasing exercise intensity.No differences were noted in the initial slope of either Pi/PCr or pH but above the ITs children were characterised by a lower increase in Pi/PCr and decrease in pH for a given increase in power output compared with adults.The change in pH from restto end-exercise was significantly greater in adults than in children whose end-exercise Pi/PCr was only 27%of adult values.The authors interpreted their data as reflecting agerelated differences in exercise metabolism with children relying less on anaerobic metabolism during heavy intensity exercise than adults.

Zanconato et al.’s70pioneering study characterised the interpretation of31P-MRS studies with reference to paediatric exercise metabolism for 15 years.But,Barker and Armstrong68identified a number of methodological flaws in the study design including the use of mixed sex groups,inadequate habitation to exercise in the MR scanner,no description of criteria for maximaleffort,and large increments in exercise intensity resulting in only 50%of children and 75%of adults exhibiting ITs.In particular,the difference in calf muscle size between adults and children is likely to result in disproportionate sampling of the gastrocnemius and soleus muscles such that the soleus represents a greater portion of the31P-MRS signal in children.As the soleus is composed mainly of type I muscle fibres and the gastrocnemius type II fibres interrogation of the calfmighthave biased Zanconato etal.’s resultsand their interpretation.70

Barker et al.71therefore investigated the responses to incremental quadriceps exercise to exhaustion of well-habituated 9—12-year-old children(15 boys,18 girls)and 16 adults (8 men,8 women).MR imaging scans were used to quantify the participants’quadriceps muscle mass in orderto normalize power output measures using allometric models.The normalised power output and the cellular energetic state at the metabolic ITs were similar in children and adults and between sexes.Above the ITPi/PCradults displayed a steeper Pi/PCr slope than children which was also the case for girls compared with boys.Above the ITpHthe change in pH against normalised power outputwas lower in boys compared with men but no differences were observed between girls and women.At exhaustion,both age-and sex-related differences in Pi/PCr were apparent but pH was independent of age and sex.Taken together these results demonstrate an age-and sex-related modulation of muscle metabolism during exercise above but not below the IT with the anaerobic energy contribution for a given increase in normalised power lower in 9—12-year-old children than in adults and in boys compared with girls.In girls only,significant relationships between maturity and indices of anaerobic metabolism were noted.The lack of relationship in the boys is likely to have been due to the boys being pre-pubertal or early pubertal.

Kuno etal.72studied the responses of 12—15-year-old boys and adults to quadriceps exercise to exhaustion and during recovery.They reported higher values of PCr/(PCr+Pi)and pH at exhaustion in the boys than in the men and concluded that both the trained and untrained boys had,“less glycolytic ability during exercise than adults”.During recovery the PCr kineticsτwas shown to be invariant with age indicating similar oxidative capacity in boys and men.73In conflict with these findings Taylor et al.74reported a faster re-synthesis of PCr in children during recovery from calf muscle exercise to exhaustion and concluded that the oxidative capacity of skeletal muscle is highest in children.However,the interpretation of recovery data from both of these studies is confounded by the reported low muscle pH values with adult pH values significantly lower than those of children.In a more recent study involving finger flexion exercise,Ratel et al.75reported similar end-exercise pH values in adults and 11-year-old boys but a faster PCrτin the boys during recovery.In accord with Taylor they concluded that their results clearly illustrated a greater mitochondrial oxidative capacity in the boys than in the men.

4.4.2.Constant work rate exercise

The effects of maturation on exercise metabolism were investigated by Petersen et al.76who evaluated the responses of nine pre-pubertal and nine pubertal swimmers to 2 min of calfexercise at40%ofpre-determined maximalwork capacity (MWC)followed by 2 min at140%of MWC.Atend-exercise the Pi/PCr was higher and the pH lower in the pubertal girls but the differences were not statistically significant.This inferred that glycolytic metabolism was not age or maturity dependent but this conclusion needs to be interpreted cautiously as the difference between the two groups in Pi/PCr at end-exercise was 66%and the high individual variability and small sample size suggest that this might have biological significance.

Using an experimental design in which seven pre-pubertal boys and 10 men performed finger flexion exercise againsta resistance of 15%of maximal voluntary strength, Tonson et al.77investigated muscle energetic changes with maturation.They observed the total energy cost to be similar in both groups but the interplay of metabolic pathways to be different.At the onset of exercise the boys exhibited a higher oxidative contribution to ATP re-synthesis and a lower PCr breakdown than the men.The authors concluded that this phenomenon could be explained by a greater oxidative capacity during childhood and speculated that it might be linked to a higher percentage of type I muscle fibres.

Barker et al.78compared the PCr kinetics of children and adults during constant work rate exercise below the ITPi/PCr. Eightmale and 10 female 9—10-year-olds and eightadultmen and eight adult women completed 4—10 repeat and averaged quadriceps exercise transitions to 80%of their previously determined ITPi/PCr.No age-or sex-related differences in PCr kinetics at the onset or offset of exercise were observed and the authors concluded that in accord with their previous31PMRS data from incremental exercise71butin conflictwith the p˙VO2kinetics data of Fawkner et al.,61their data were consistent with a comparable capacity for oxidative metabolism during moderate intensity exercise in child and adult muscle.

The same research group compared the PCr kinetics response to the onset of exercise at 20%of the difference between the previously determined maximum power output and the power output at the ITPi/PCr(heavy intensity exercise) in adults and 13-year-olds In conflictwith theirdata from31PMRS incremental exercise studies71and p˙VO2kinetic studies,52,53they noted no significant sex-or age-related differences in theτof PCr kinetics which suggests that skeletalmuscle metabolism at the onset of exercise is adult-like in 13-year-old children.However,it is noteworthy that there was a 42%difference in the PCr kinetics of boys and men which, while not statistically significant(large standard deviations and small sample sizes(n=6)),infers possible biological significance and a potential age-related difference in muscle metabolism.79Furthermore unpublished data from another study in Willcocks’PhD thesis,demonstrate that at the onset of exercise at 60%of the difference between maximal power output and the power output at the ITPi/PCr(very heavy intensity exercise)boys have significantly faster PCr kinetics than men.80

5.What is new?

Pulmonary˙VO2kinetic responses to step changes in exercise intensity provide a non-invasive in vivo window into muscle metabolism.Children are characterised by a faster phase IIτfor moderate,heavy and very heavy exercise compared to adolescents and adults.An age-related modulation of the putative metabolic feedback controllers of oxidative phosphorylation underlies the faster phase II p˙VO2kinetics in children.A reasonable explanation is that the faster phase IIτ in young people is due to a lower breakdown of muscle PCr which is related to higher oxidative enzymes activity and/or a reduced concentration of creatine in the muscle cells compared to adults.During exercise above TLACthe magnitude of the p˙VO2slow componentis reduced and the oxygen costduring phase IIis higher in young people than adults but the end-exercise total oxygen cost is similar to that of adults. These observations are consistent with an age-related decline in%of type I muscle fibres and the noted sex differences are in accord with boys having a higher%of type I fibres than similarly aged girls.

There are few rigorous31P-MRS studies of healthy young people but current data indicate that age-and sex-related differences in muscle metabolism are dependent on the intensity of the imposed exercise.During moderate intensity exercise no age-orsex-related differences in metabolism have been observed but during exercise above the ITPi/PCrthe anaerobic energy contribution for a given increase in normalised power has been demonstrated to be lower in children than adults and in boys compared to girls.In females the increased glycolytic activity has been related to stage of maturation.The lower accumulation of Pi and fall in pH and PCr are consistent with a greater recruitment of type I muscle fibres in children compared to adults and in boys compared to girls.

6.Conclusion

The development and application of non-invasive technologies and methodologies such as31P-MRS and breath-bybreath p˙VO2kinetics to interrogate muscles in vivo has enhanced our under standing of paediatric exercise metabolism and provided new insights into data obtained from conventional techniques.Rigorously designed,executed,and interpreted31P-MRS studies with children are sparse and most studies are limited by small sample sizes but initial research has clearly indicated the huge untapped potential of this technique.31P-MRS studies are costly and the close relationship between PCr kinetics and p˙VO2kinetics encourages the use of more child-friendly and less expensive p˙VO2kinetics with young people.Appropriate data collection,modelling and analysis techniques using p˙VO2kinetics with children are now well-established and the recent introduction of the use of experimental models such as priming exercise,work to work transitions,and manipulation of pedal rates provide intriguing avenues for future research into paediatric exercise metabolism.

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Received 17 December 2011;revised 25 December 2011;accepted 30 December 2011

*Corresponding author.

E-mailaddress:N.Armstrong@exeter.ac.uk(N.Armstrong)

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