New insights in paediatric exercise metabolism

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Journal of Sport and Health Science 1 (2012) 18e26

www.jshs.org.cn

Review

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

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

Abstract

Research in paediatric exercise metabolism has been constrained by being unable to interrogate muscle in vivo. Conventionally, research hasbeen limited to the estimation of muscle metabolism from observations of blood and respiratory gases during maximal or steady state exerciseand 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 exercisemetabolism during growth and maturation. Methodologically robust studies using 31P-magnetic resonance spectroscopy and oxygen uptakekinetics with children are sparse and some data are in conflict. However, it can be concluded that children respond to exercise with enhancedoxygen utilization within the myocyte compared with adults and that their responses are consistent with a greater recruitment of type I musclefibres. Changes in muscle metabolism are age, maturation- and sex-related and dependent on the intensity of the exercise challenge. Theintroduction of experimental models such as “priming exercise” and “work-to-work” transitions provide intriguing avenues of research into themechanisms underpinning exercise metabolism during growth and maturation.Copyright � 2012, Shanghai University of Sport. Production and hosting by Elsevier B.V. All rights reserved.

Keywords: Children; Magnetic resonance spectroscopy; Oxygen uptake kinetics

1. Introduction

Paediatric exercise metabolism studies are normally limitedto examining blood and respiratory gas markers of maximal (orpeak) and steady state exercise metabolism. These studies haveenhanced knowledge but ethical considerations have restrictedpotentially more informative research at the level of themyocyte. The few muscle biopsy studies which have beenperformed with healthy children have focused on resting andpost-exercise measures and have generally been restrictedto small samples of predominantly male children and

* Corresponding author.

E-mail address: [email protected] (N. Armstrong)

Peer review under responsibility of Shanghai University of Sport

Production and hosting by Elsevier

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doi:10.1016/j.jshs.2011.12.001

adolescents. The emergence of non-invasive technologies suchas 31P-magnetic resonance spectroscopy (31P-MRS) andmethodologies such as breath-by-breath determination ofpulmonary oxygen uptake ðp _VO2Þ kinetics, which allow invivo investigations during exercise, therefore have the potentialto provide new insights into paediatric exercise metabolism.

This paper will briefly review what we know fromconventional indicators of exercise metabolism during growthand maturation and explore recent insights into paediatricmuscle metabolism provided by rigorous analyses of p _VO2

kinetics data and 31P-MRS spectra.

2. The contribution of conventional methodologies to theunderstanding of paediatric exercise metabolism

2.1. Aerobiceanaerobic interplay during maximalperformance

Peak _VO2 is the best single indicator of young people’saerobic fitness and data show an almost linear increase in

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Paediatric exercise metabolism 19

boys’ peak _VO2 in relation to age with girls showing a similartrend at least up to the age ofw14 years when peak _VO2 tendsto level off. Girls’ peak _VO2 values are w10% lower thanthose of boys during childhood and the sex difference reachesw35% by age 16 years. Peak _VO2 is strongly related to bodysize and in both sexes maturation exerts an additional positiveeffect on peak _VO2 independent of age and body size.1

The assessment of peak anaerobic performance has focusedon the estimation of peak power output (PPO) determinedusing the Wingate anaerobic test. Sex differences in PPOappear to be minimal until w12e13 years of age but thisfinding is confounded by the fact that few studies havesimultaneously considered chronological age and the stage ofmaturation of the participants. From w13 years there isa more marked increase in the PPO of boys in relation tochronological age so that by w16 years boys’ values exceedthose of girls by w50%.2

Both sexes experience a more marked increase in PPO thanpeak _VO2 during maturation with peak _VO2 increasing byw70% and w50% in boys and girls, respectively comparedwith PPO increases of w120% and w65% from 12 to 17years.3,4 However, although estimates of peak aerobic andanaerobic performance illustrate asynchronous, age-, sex-,growth- and maturation-related differences in exercisemetabolism they provide few insights into the aero-biceanaerobic interplay in the muscles during growth andmaturation.

2.2. Recovery from high intensity exercise

The ability of young people to recover faster than adultsfollowing high intensity exercise is well documented.5e7 Thismight be explained by children and adolescents havingenhanced oxidative capacity, faster phosphocreatine (PCr) re-synthesis, better acidebase regulation, and lower productionand/or more efficient removal of metabolic by-products thanadults.8 But some researchers have critiqued the high intensityexercise models used to compare children and adults andconcluded that young people’s faster recovery is simplya direct consequence of their body size and their limitedcapacity to generate power.9

2.3. Substrate utilization

Boys have higher relative rates of fat oxidation than men ata range of exercise intensities and the exercise intensity thatelicits peak fat oxidation is higher in boys than in men.10,11 Sexdifferences in substrate utilization have been reported.12 butage-related data in females are conflicting and have beenattributed to menstrual cycle variations between girls andwomen.13,14 In boys, high rates of fat oxidation decline duringmaturation and the development of an adult fuel-utilizationprofile occurs in the transition frommid-puberty to late-pubertyand is complete on reaching adulthood.10,15 Timmons et al.12

have suggested that children have an underdeveloped depot ofintramuscular fuels rather than an underdeveloped glycolyticflux.

2.4. Muscle fibre types

Boisseau and Delmarche16 hypothesised that maturation ofskeletal muscle fibre patterns might account for the develop-ment of metabolic responses to high intensity exercise duringgrowth and maturation. The interpretation of muscle biopsystudies of young people is, however, confounded by largeinterindividual variations in fibre profiles and few, mostlymale, participants.17 Patterns which have emerged suggest thatmuscle fibre size increases linearly with age from birth toadolescence and, at least in males, into adulthood.18 Thepercentage of type I fibres decreases in healthy males from age10e35 years but clear age-related fibre type changes have notbeen consistently demonstrated in females although this mightbe a methodological artefact as few data on young females areavailable.17,19

In underpowered experimental designs, statistically signif-icant sex differences in the percentage of type I fibres have notbeen reported during childhood and adolescence. However,there is a consistent trend with adolescent boys and youngmale adults exhibiting 8%e15% more type I fibres in thevastus lateralis than similarly aged females in the samestudy.19e21 No study has reported a lower percentage of type Ifibres in boys than girls.

2.5. Muscle energy stores

In the early 1970s Eriksson et al.22e26 carried out a series ofinnovative muscle biopsy studies on small samples of 11e16years old boys which have influenced the understanding ofpaediatric exercise metabolism for almost 40 years.

Muscle biopsies from the lateral part of the quadricepsfemoris revealed resting adenosine triphosphate (ATP) storeswhich were invariant over the age range 11.6e15.5 years. ThePCr stores of the 15-year-old boys were 63% higher than thoseof the 11-year-old boys. The ATP stores at all ages and the PCrstores of the 15-year-old boys were not dissimilar to valuesothers had reported in adults. Glycogen stores at rest werereported to increase by 61% from 11 years to 15 years. Theconcentration of ATP remained virtually unchanged followingseveral bouts of submaximal exercise but minor reductionswere reported following maximal exercise. The PCr storesgradually depleted following exercise sessions of increasingintensity. Muscle glycogen stores decreased following exercisein all age groups but the depletion was three times greater inthe older boys suggesting enhanced glycolysis with age.26

2.6. Muscle enzyme activity

Eriksson et al.26 reported succinic dehydrogenase andphosphofructokinase (PFK) activity at rest in 11-year-old boysto be 20% and 50% respectively lower than they had previ-ously reported for adults.27 Haralambie28 determined theactivity of 22 enzymes involved in energy metabolism in13e15-year-old boys and girls and in adult men and womenand, in conflict with Eriksson’s observations, he found nosignificant difference in the activity of glycolytic enzymes

20 N. Armstrong and A.R. Barker

between adolescents and adults. He did, however, confirm hisearlier observation29 of greater activity of oxidative enzymesin adolescents than in adults. Subsequently, Berg et al.30,31

reported glycolytic enzymes activity to be positively corre-lated with age and oxidative enzymes activity to be negativelycorrelated with age over the age range 6e17 years, in bothmales and females. All muscle biopsies were taken at rest.

Haralambie28,29 reported a comparison of the restingactivity of potential rate limiting enzymes of glycolysis andthe tricarboxylic acid cycle, namely, PFK and isocitric dehy-drogenase (ICDH). The ratio PFK/ICDH was reported to be93% higher in adults than in adolescents at 1.633 and 0.844,respectively. A re-calculation of Berg’s data indicateda similar relationship of glycolytic and oxidative enzymes withthe ratio of pyruvate kinase to fumarase varying from 3.585 inadults, 3.201 in adolescents to 2.257 in children.30,31

2.7. Lactate production and accumulation

Eriksson et al.25,26 reported muscle lactate accumulationfollowing exercise to increase with age and, on the basis of an‘almost significant’ relationship between lactate accumulationin the muscles and testicular volume, they hypothesiseda maturational effect on lactate production. In more recentstudies blood lactate accumulation has been used as a surro-gate of muscle lactate production and glycolytic activity.1,32

We have discussed the limitations of this extrapolationelsewhere.33

The interpretation of blood lactate accumulation is cloudedby theoretical and methodological issues and data need to beinterpreted with caution. Sex differences and maturationeffects independent of age have proved elusive to establish.However, consistent findings are that children accumulate lessblood lactate during exercise than adults and that there isa negative correlation between the exercise intensity at thelactate threshold (TLAC) and age.33 Pianosi et al.34 reportedthat the ratio lactate/pyruvate following exercise increasedwith age and concluded that this indicated an age-relatedenhanced glycolytic function. Other authors, however, havehypothesised that lower post-exercise blood lactate accumu-lation in children reflects a smaller muscle mass combinedwith a facilitated aerobic metabolism.35

3. What do we know from conventional research?

What we know about paediatric exercise metabolism fromconventional indicators is limited by ethical and methodo-logical considerations. Age-related increases in peak aerobicand anaerobic performance are asynchronous with greaterincreases observed in peak anaerobic performance than peakaerobic performance during puberty. Young people recoverfrom high intensity exercise faster than adults. Substrateutilization studies indicate an age-related effect, at least inmales, with children and adolescents relying more on lipids asan energy source than adults do during steady state exercise.Muscle biopsy data indicate an age-related decline in thepercentage of type I fibres and a trend indicating boys to have

a higher percentage of type I fibres than girls. Resting muscleconcentrations of ATP appear invariant with age but restingmuscle PCr and glycogen concentrations progressivelyincrease, at least through the teen years. Resting oxidativeenzymes activity is positively related to age and glycolyticenzymes activity might be negatively related to age. The ratioof glycolytic/oxidative enzymes activity is higher in adultsthan in adolescents or children. The balance of evidencesuggests that children are disadvantaged compared to adoles-cents who are, in turn, disadvantaged compared to adults inactivities involving high intensity exercise supportedpredominantly by anaerobic metabolism. Young people,however, appear well equipped for low-to-moderate intensityactivities supported by lipids and aerobic metabolism.

4. The contribution of new non-invasive methodologiesand technologies to understanding paediatric exercisemetabolism

4.1. Pulmonary oxygen uptake kinetics

In the laboratory p _VO2 kinetics are analysed by the use ofa step transition where a period of very low intensity exercise,such as unloaded pedalling on a cycle ergometer, is followedby a sudden increase in exercise intensity to a pre-determinedlevel. The p _VO2 kinetics response to the step change inexercise intensity is interpreted in relation to four exerciseintensity domains. The upper threshold of the moderateintensity domain is the TLAC which also serves as the lowerthreshold of the heavy exercise intensity domain. The uppermarker of the heavy exercise intensity domain is the maximallactate steady state (MLSS, the highest metabolic rate at whichexercise can be sustained without an accumulation of bloodlactate33) or, more often in young people, the critical power(CP, the highest metabolic rate at which _VO2 can be stabilisedbelow peak _VO2

36,37). Exercise above MLSS or CP but belowpeak _VO2 is in the very heavy exercise domain and exerciseabove peak _VO2 is in the severe exercise domain.38

With young participants it has been noted that small breath-to-breath variations are inherent to children’s responseprofiles.39 This reduces the confidence with which p _VO2

kinetic responses can be estimated and confidence intervals arelikely to be beyond acceptable limits unless sufficient identicaltransitions are aligned and averaged to improve the signal tonoise ratio.40 Rigorously determined and interpreted data fromyoung people are available in the moderate, heavy and veryheavy intensity exercise domains.41e43

The p _VO2 response to a step transition has three phases. Atthe onset there is an immediate increase in cardiac outputwhich occurs prior to the arrival at the lungs of venous bloodfrom the exercising muscles. This cardiodynamic phase (phaseI) which, in children, lasts w15 s is independent of _VO2 at themuscle ðm _VO2Þ and reflects an increase in pulmonary bloodflow with exercise. Phase II, the primary component, is a rapidexponential increase in p _VO2 that arises with hypoxic andhypercapnic blood from the exercising muscles arriving at thelungs. Phase II kinetics are described by the time constant (t)

Paediatric exercise metabolism 21

which is the time taken to achieve 63% of the change in p _VO2.In phases I and II ATP re-synthesis cannot be fully supportedby oxidative phosphorylation and the additional energyrequirements of the exercise are met from body oxygen stores,PCr and glycolysis. During moderate intensity exercise withchildren p _VO2 reaches a steady state (phase III) within about2 min. In the heavy intensity exercise domain, the primaryphase II oxygen cost is similar to that observed duringmoderate intensity exercise but the overall oxygen cost ofexercise increases over time as a slow component of p _VO2 issuperimposed upon the primary component and the achieve-ment of a steady state might be delayed by w10e15 min.44 Inadults, at exercise intensities above the MLSS or CP the slowcomponent of p _VO2 rises rapidly over time and eventuallyreaches peak _VO2 but this phenomenon has not been observedin children.37,45

The mechanisms underlying the p _VO2 slow componentremain speculative but it has been established thatw86% havebeen accounted for at the contracting muscles.46 Duringexercise above the TLAC the p _VO2 slow component is asso-ciated with a progressive recruitment of additional type IImuscle fibres with the low efficiency contributing to theincreased oxygen cost of exercise.47 However, this is probablynot the whole story and fatigued fibres recruited during phaseII might also become less efficient and require greater oxygenconsumption per unit of ATP turnover and/or a greater ATPturnover per unit of power output.48 Early studies of youngpeople indicated that they did not exhibit a slow componentduring heavy exercise49 but more rigorous studies usingappropriate modelling techniques50 have observed p _VO2 slowcomponents in both pre-pubertal children51,52 andadolescents.53

Despite a temporal dissociation at the onset of exercise (thecardiodynamic phase), modelling simulations54 and directmeasurement of m _VO2 using the Fick technique duringcycling55 have demonstrated m _VO2 and phase II p _VO2

kinetics to correspond in adults within w10%. In an innova-tive study Rossiter et al.56 confirmed this relationship bysimultaneously determining adults’ p _VO2 kinetics and PCrkinetics using knee extensor exercise in a magnetic resonance(MR) scanner. This work has not been replicated with childrenas they display a lower p _VO2 amplitude than adults whichmakes the simultaneous assessment of young people’s p _VO2

and PCr kinetics in an MR scanner infeasible. However,Barker et al.57 have demonstrated a close relationship betweenchildren’s intramuscular PCr kinetics during prone quadricepsexercise in an MR scanner and p _VO2 kinetics during uprightcycling at both the onset and offset of moderate intensityexercise. In adults the recovery kinetics of muscle PCr hasbeen routinely employed as a non-invasive measure of muscleoxidative capacity.58 The close kinetic coupling between thep _VO2 and PCr kinetic profiles at the onset and offset ofexercise support the use of the phase II p _VO2 kinetics t asa proxy measure of muscle PCr kinetics. Children’s phase IIp _VO2 kinetics response to and recovery from step changes inexercise intensity therefore provide a non-invasive windowinto metabolic activity in the muscles.

4.2. Pulmonary oxygen uptake kinetics and paediatricexercise metabolism

4.2.1. Moderate intensity exerciseBreath-by-breath studies of children’s p _VO2 kinetics

response to a transition to moderate intensity exercise dateback over 25 years59 and although they present a generalconsensus that there is an age-related decline in the oxygencost of exercise there are conflicting reports regarding whetheror not p _VO2 kinetics is faster in children than in adults.However, many of the early studies have been criticised on thebasis of their lack of adequate exercise transitions, poormodelling techniques, not reporting 95% confidence intervals,and/or limitations within their participant samples.40,60 Ina more recent and rigorous study of children’s and adults’p _VO2 kinetics response during exercise below TLAC the phaseII t has been demonstrated to be faster in boys than men and ingirls than women. No differences in the p _VO2 kineticsresponse of boys compared with girls or men compared withwomen were reported.61

Children’s faster t and therefore greater aerobic contribu-tion to ATP re-synthesis suggests an enhanced oxidativecapacity which might be due to greater oxygen delivery orbetter oxygen utilization by the muscle during childhood orboth. Data are sparse but muscle blood flow and thereforeoxygen delivery during exercise has been reported to decreasein boys from age 12 to 16 years.62,63 Peak _VO2 which isprimarily dependent on oxygen delivery is not related to thephase II t during moderate intensity exercise in children61 andthere is no compelling evidence to suggest that increaseddelivery of oxygen increases the rate of p _VO2 kinetics duringmoderate intensity exercise. It is therefore likely that chil-dren’s faster phase II t reflects an enhanced capacity foroxygen utilization by the mitochondria.

4.2.2. Heavy intensity exerciseIn a series of studies of pre-pubertal children’s p _VO2

kinetics response to a transition to exercise above the TLAC,Fawkner and Armstrong51 observed that girls were charac-terised by a slower phase II t and a greater relative contri-bution of the p _VO2 slow component to the end-exercise p _VO2.In a subsequent study they monitored changes in the p _VO2

kinetics response to a transition to heavy intensity exerciseover a 2-year period and noted that the phase II t slowed andthe p _VO2 slow component increased with age. Despite anincrease in the p _VO2 slow component the overall oxygen costat the end of the exercise was equal on test occasions 2 yearsapart suggesting that the phosphate turnover required tosustain the exercise was independent of age and that the olderchildren achieved a lower proportion of their end exercisepVO2 during phase II.52 The same group reported similarfindings in a 2-year longitudinal study of boys who were 14years old at the first test occasion.53 In accord with exercise inthe moderate intensity domain, peak _VO2 was not related tothe phase II t during heavy intensity exercise.51e53

The slowing of the phase II t with age might be related tochanges in oxygen delivery but as indicated in the previous

22 N. Armstrong and A.R. Barker

section this is not supported by compelling evidence. It hasbeen argued that the rate of p _VO2 kinetics at the onset ofexercise is regulated by the exchange of intramuscular phos-phates between the splitting of ATP and its subsequent re-synthesis from PCr.64 Furthermore, it has been reported inadults that there exists a dynamic symmetry between the rateof PCr breakdown and the phase II t at the onset of highintensity exercise.56 This suggests that the faster phase II t inchildren might be due to an age-dependent effect on theputative phosphate linked controller(s) of mitochondrialoxidative phosphorylation. A phenomenon which might bepartially explained by children’s enhanced aerobic enzymeprofile and/or reduced resting total creatine concentration (asinferred from muscle PCr stores) compared to adults.

As the mechanisms underlying the p _VO2 slow componentreside in the muscles, the increase in the magnitude of thep _VO2 slow component with age is likely to be related tochanges in muscle fibre recruitment patterns. If oxidativecapacity is negatively related to age then the greater glycogendepletion of type I fibres and the enhanced recruitment of typeII fibres by adults will contribute to an elevated p _VO2 slowcomponent. The data are consistent with children havinga higher percentage of type I muscle fibres than adults and thereported sex differences are in accord with girls having a lowerpercentage of type I muscle fibres than similarly aged boys.

4.2.3. Very heavy intensity exerciseResearch in the very heavy exercise domain has been

characterised by experimental manipulation of pedalrate during exercise and metabolic rate prior to exercise.Breese et al.65 combined measurements of the integratedelectromyogram (iEMG) with a “work-to-work” modelinvolving step changes from unloaded pedalling to very heavyintensity exercise (U-VH), unloaded pedalling to moderateintensity exercise (U-M), and moderate to very heavy intensityexercise (M-VH). They reported that the phase II t in boys inresponse to the U-VH protocol was significantly faster than inmen. Men exhibited a relatively greater p _VO2 slow componentthan the boys and this was accompanied by an increased rateof change in iEMG activity of the vastus lateralis in men only.The M-VH protocol resulted in a similar relative slowing ofthe phase II t in both boys and men although the boys stilldemonstrated a faster t than the men and the overall oxygencost was increased in men only.

In addition to p _VO2 kinetics heart rate (HR) kinetics werealso monitored during each protocol in order to provide anestimate of cardiac output dynamics and they were notsignificantly different in boys and men during either U-VH orM-VH protocols.65 The HR kinetics data support the view thatage-related differences in the phase II t are not primarilyinfluenced by oxygen delivery. Breese et al.’s65 observationsare wholly consistent with the view that age-related differ-ences in the magnitude of the p _VO2 slow component arelinked to changes in muscle fibre recruitment following theonset of very heavy intensity exercise.

In a subsequent study from the same research group, it washypothesised that, based on skeletal muscle powerevelocity

relationships, the recruitment of type II muscle fibres would beenhanced for the same external power output by increasingpedal rate. The effect of different pedal cadences (50 and115 rev/min) at the same external power output on p _VO2

kinetics at the onset of very heavy exercise in trained anduntrained, teenage, male cyclists was investigated. The trainedboys showed no change in the phase II t or the p _VO2 slowcomponent with a change in pedal rate whereas the untrainedboys’ exhibited a slowing of the phase II t and an increase inthe magnitude of the p _VO2 slow component. The authorsproposed that these findings might be accounted for by alter-ations in muscle fibre recruitment and/or enhancement in theoxidative capacity of recruited muscle fibres due to eithergenetic or training influences.66

To elevate muscle oxygen availability prior to a step changeto very heavy intensity exercise Barker et al.67 used a “primingexercise” model with 9- to 13-year-old boys. This consisted ofa U-VH step change sustained for 6 min (the priming exer-cise), followed by an unloaded 6-min recovery cycle followedby another U-VH step change which was sustained for 6 min.In addition to respiratory gases, beat-by-beat HR, strokevolume and cardiac output were monitored using thoracicimpedance, and changes in the concentrations of oxy-[HbþMb] and deoxy-[HbþMb] haemoglobin/myoglobinwere estimated using near-infra red spectroscopy. The phase IIt in the second U-VH bout was unchanged by the primingexercise but the priming exercise resulted in an increase in thephase II p _VO2 amplitude and a reduction in the p _VO2 slowcomponent.

Despite greater availability of oxygen to the contractingmuscles in the second step change the phase II t was unalteredthus supporting the notion that the phase II t in young peopleis dependent on oxygen utilization by the muscle rather thanoxygen delivery. The elevated phase II _VO2 amplitude andreduced p _VO2 slow component are consistent with greaterrecruitment of type II muscle fibres. However, as the deoxy-[HbþMb], and therefore muscles’ fractional oxygen utiliza-tion was unaltered following priming exercise and there wasan elevated cardiac output/ _VO2 at the end of exercise theauthors suggested that the altered _VO2 amplitudes might berelated to an enhanced oxygen delivery.67

4.3. Magnetic resonance spectroscopy

31P-MRS is a non-invasive technique that provides in vivoa window through which muscle can be interrogated duringexercise. We have discussed the theoretical principles under-pinning 31P-MRS elsewhere. In brief, 31P-MRS allows themonitoring of the molecules which play a central role inexercise metabolism, namely ATP, PCr and inorganic phos-phate (Pi). The chemical shift of the Pi spectral peak relativeto the PCr peak reflects the acidification of the muscle andenables the determination of pH. The change in pH duringexercise provides an indication of muscle glycolytic activitybut is not a direct measure of glycolysis.68

During progressive, incremental exercise non-linearchanges in the ratio Pi/PCr plotted against power output and in

Paediatric exercise metabolism 23

pH plotted against power output occur. As power outputincreases an initial shallow slope is followed by a steeper slopeand the transition point is known as the intracellular threshold(IT). The Pi/PCr and pH ITs generally occur at the same timeand are analogous to other metabolic thresholds such as TLAC

and ventilation threshold.5731P-MRS studies are constrained by exercising within

a small bore tube with the need to synchronize the acquisitionof data with the rate of muscle contraction and this is chal-lenging for young people. We have described elsewheretechniques used in our laboratory to habituate children toexercise in an MR scanner and demonstrated that during kneeextensor exercise to exhaustion, the end-exercise pH and ITpH

and ITPi/PCr demonstrate good reliability and thus stablemeasures for the study of developmental musclemetabolism.69

4.4. 31P-MRS and paediatric exercise metabolism

4.4.1. Incremental exerciseThe first 31P-MRS study to include children was reported

by Zanconato et al.70 who compared the responses of 10 pre-pubertal children and eight adults during incremental calfmuscle exercise to exhaustion in an MR scanner. Theyobserved an increase in Pi/PCr and a decrease in pH in bothchildren and adults with increasing exercise intensity. Nodifferences were noted in the initial slope of either Pi/PCr orpH but above the ITs children were characterised by a lowerincrease in Pi/PCr and decrease in pH for a given increase inpower output compared with adults. The change in pH fromrest to end-exercise was significantly greater in adults than inchildren whose end-exercise Pi/PCr was only 27% of adultvalues. The authors interpreted their data as reflecting age-related differences in exercise metabolism with childrenrelying less on anaerobic metabolism during heavy intensityexercise than adults.

Zanconato et al.’s70 pioneering study characterised theinterpretation of 31P-MRS studies with reference to paediatricexercise metabolism for 15 years. But, Barker and Arm-strong68 identified a number of methodological flaws in thestudy design including the use of mixed sex groups, inade-quate habitation to exercise in the MR scanner, no descriptionof criteria for maximal effort, and large increments in exerciseintensity resulting in only 50% of children and 75% of adultsexhibiting ITs. In particular, the difference in calf muscle sizebetween adults and children is likely to result in dispropor-tionate sampling of the gastrocnemius and soleus muscles suchthat the soleus represents a greater portion of the 31P-MRSsignal in children. As the soleus is composed mainly of type Imuscle fibres and the gastrocnemius type II fibres interroga-tion of the calf might have biased Zanconato et al.’s results andtheir interpretation.70

Barker et al.71 therefore investigated the responses toincremental quadriceps exercise to exhaustion of well-habit-uated 9e12-year-old children (15 boys, 18 girls) and 16 adults(8 men, 8 women). MR imaging scans were used to quantifythe participants’ quadriceps muscle mass in order to normalize

power output measures using allometric models. The nor-malised power output and the cellular energetic state at themetabolic ITs were similar in children and adults and betweensexes. Above the ITPi/PCr adults displayed a steeper Pi/PCrslope than children which was also the case for girls comparedwith boys. Above the ITpH the change in pH against normal-ised power output was lower in boys compared with men butno differences were observed between girls and women. Atexhaustion, both age- and sex-related differences in Pi/PCrwere apparent but pH was independent of age and sex. Takentogether these results demonstrate an age- and sex-relatedmodulation of muscle metabolism during exercise above butnot below the IT with the anaerobic energy contribution fora given increase in normalised power lower in 9e12-year-oldchildren than in adults and in boys compared with girls. Ingirls only, significant relationships between maturity andindices of anaerobic metabolism were noted. The lack ofrelationship in the boys is likely to have been due to the boysbeing pre-pubertal or early pubertal.

Kuno et al.72 studied the responses of 12e15-year-old boysand adults to quadriceps exercise to exhaustion and duringrecovery. They reported higher values of PCr/(PCrþ Pi) andpH at exhaustion in the boys than in the men and concludedthat both the trained and untrained boys had, “less glycolyticability during exercise than adults”. During recovery the PCrkinetics t was shown to be invariant with age indicatingsimilar oxidative capacity in boys and men.73 In conflict withthese findings Taylor et al.74 reported a faster re-synthesis ofPCr in children during recovery from calf muscle exercise toexhaustion and concluded that the oxidative capacity of skel-etal muscle is highest in children. However, the interpretationof recovery data from both of these studies is confounded bythe reported low muscle pH values with adult pH valuessignificantly lower than those of children. In a more recentstudy involving finger flexion exercise, Ratel et al.75 reportedsimilar end-exercise pH values in adults and 11-year-old boysbut a faster PCr t in the boys during recovery. In accord withTaylor they concluded that their results clearly illustrateda greater mitochondrial oxidative capacity in the boys than inthe men.

4.4.2. Constant work rate exerciseThe effects of maturation on exercise metabolism were

investigated by Petersen et al.76 who evaluated the responsesof nine pre-pubertal and nine pubertal swimmers to 2 min ofcalf exercise at 40% of pre-determined maximal work capacity(MWC) followed by 2 min at 140% of MWC. At end-exercisethe Pi/PCr was higher and the pH lower in the pubertal girlsbut the differences were not statistically significant. Thisinferred that glycolytic metabolism was not age or maturitydependent but this conclusion needs to be interpretedcautiously as the difference between the two groups in Pi/PCrat end-exercise was 66% and the high individual variabilityand small sample size suggest that this might have biologicalsignificance.

Using an experimental design in which seven pre-pubertalboys and 10 men performed finger flexion exercise against

24 N. Armstrong and A.R. Barker

a resistance of 15% of maximal voluntary strength,Tonson et al.77 investigated muscle energetic changes withmaturation. They observed the total energy cost to be similarin both groups but the interplay of metabolic pathways to bedifferent. At the onset of exercise the boys exhibited a higheroxidative contribution to ATP re-synthesis and a lower PCrbreakdown than the men. The authors concluded that thisphenomenon could be explained by a greater oxidativecapacity during childhood and speculated that it might belinked to a higher percentage of type I muscle fibres.

Barker et al.78 compared the PCr kinetics of children andadults during constant work rate exercise below the ITPi/PCr.Eight male and 10 female 9e10-year-olds and eight adult menand eight adult women completed 4e10 repeat and averagedquadriceps exercise transitions to 80% of their previouslydetermined ITPi/PCr. No age- or sex-related differences in PCrkinetics at the onset or offset of exercise were observed andthe authors concluded that in accord with their previous 31P-MRS data from incremental exercise71 but in conflict with thep _VO2 kinetics data of Fawkner et al.,61 their data wereconsistent with a comparable capacity for oxidative metabo-lism during moderate intensity exercise in child and adultmuscle.

The same research group compared the PCr kineticsresponse to the onset of exercise at 20% of the differencebetween the previously determined maximum power outputand the power output at the ITPi/PCr (heavy intensity exercise)in adults and 13-year-olds In conflict with their data from 31P-MRS incremental exercise studies71 and p _VO2 kineticstudies,52,53 they noted no significant sex- or age-relateddifferences in the t of PCr kinetics which suggests that skel-etal muscle metabolism at the onset of exercise is adult-like in13-year-old children. However, it is noteworthy that there wasa 42% difference in the PCr kinetics of boys and men which,while not statistically significant (large standard deviationsand small sample sizes (n¼ 6)), infers possible biologicalsignificance and a potential age-related difference in musclemetabolism.79 Furthermore unpublished data from anotherstudy in Willcocks’ PhD thesis, demonstrate that at the onsetof exercise at 60% of the difference between maximal poweroutput and the power output at the ITPi/PCr (very heavyintensity exercise) boys have significantly faster PCr kineticsthan men.80

5. What is new?

Pulmonary _VO2 kinetic responses to step changes inexercise intensity provide a non-invasive in vivo window intomuscle metabolism. Children are characterised by a fasterphase II t for moderate, heavy and very heavy exercisecompared to adolescents and adults. An age-related modula-tion of the putative metabolic feedback controllers of oxidativephosphorylation underlies the faster phase II p _VO2 kinetics inchildren. A reasonable explanation is that the faster phase II tin young people is due to a lower breakdown of muscle PCrwhich is related to higher oxidative enzymes activity and/ora reduced concentration of creatine in the muscle cells

compared to adults. During exercise above TLAC the magni-tude of the p _VO2 slow component is reduced and the oxygencost during phase II is higher in young people than adults butthe end-exercise total oxygen cost is similar to that of adults.These observations are consistent with an age-related declinein % of type I muscle fibres and the noted sex differences arein accord with boys having a higher % of type I fibres thansimilarly aged girls.

There are few rigorous 31P-MRS studies of healthy youngpeople but current data indicate that age- and sex-relateddifferences in muscle metabolism are dependent on theintensity of the imposed exercise. During moderate intensityexercise no age- or sex-related differences in metabolism havebeen observed but during exercise above the ITPi/PCr theanaerobic energy contribution for a given increase in nor-malised power has been demonstrated to be lower in childrenthan adults and in boys compared to girls. In females theincreased glycolytic activity has been related to stage ofmaturation. The lower accumulation of Pi and fall in pH andPCr are consistent with a greater recruitment of type I musclefibres in children compared to adults and in boys compared togirls.

6. Conclusion

The development and application of non-invasive technol-ogies and methodologies such as 31P-MRS and breath-by-breath p _VO2 kinetics to interrogate muscles in vivo hasenhanced our understanding of paediatric exercise metabolismand provided new insights into data obtained from conven-tional techniques. Rigorously designed, executed, and inter-preted 31P-MRS studies with children are sparse and moststudies are limited by small sample sizes but initial researchhas clearly indicated the huge untapped potential of thistechnique. 31P-MRS studies are costly and the close relation-ship between PCr kinetics and p _VO2 kinetics encourages theuse of more child-friendly and less expensive p _VO2 kineticswith young people. Appropriate data collection, modelling andanalysis techniques using p _VO2 kinetics with children are nowwell-established and the recent introduction of the use ofexperimental models such as priming exercise, work to worktransitions, and manipulation of pedal rates provide intriguingavenues for future research into paediatric exercisemetabolism.

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