Review
IntegrativeBiologyofExercise
JohnA.Hawley,1,2,*MarkHargreaves,3MichaelJ.Joyner,4andJuleenR.Zierath5,6,*
LeadingEdge
&NutritionResearchGroup,SchoolofExerciseSciences,AustralianCatholicUniversity,Fitzroy,Victoria3065,AustraliaInstituteforSportandExerciseSciences,LiverpoolJohnMooresUniversity,MerseysideL35UA,UK
3DepartmentofPhysiology,TheUniversityofMelbourne,Parkville,Victoria3010,Australia4DepartmentofAnesthesiology,MayoClinic,Rochester,MN55905,USA5DepartmentofMolecularMedicine,KarolinskaInstitutet,vonEulersva¨g4a,17177Stockholm,Sweden
6TheNovoNordiskFoundationCenterforBasicMetabolicResearch,FacultyofHealthandMedicalSciences,UniversityofCopenhagen,2200Copenhagen,Denmark
*Correspondence:john.hawley@acu.edu.au(J.A.H.),juleen.zierath@ki.se(J.R.Z.)http://dx.doi.org/10.1016/j.cell.2014.10.029
2Research
1Exercise
Exerciserepresentsamajorchallengetowhole-bodyhomeostasisprovokingwidespreadpertur-bationsinnumerouscells,tissues,andorgansthatarecausedbyorarearesponsetotheincreasedmetabolicactivityofcontractingskeletalmuscles.Tomeetthischallenge,multipleintegratedandoftenredundantresponsesoperatetobluntthehomeostaticthreatsgeneratedbyexercise-inducedincreasesinmuscleenergyandoxygendemand.Theapplicationofmoleculartechniquestoexercisebiologyhasprovidedgreaterunderstandingofthemultiplicityandcomplexityofcellularnetworksinvolvedinexerciseresponses,andrecentdiscoveriesofferperspectivesonthemech-anismsbywhichmuscle‘‘communicates’’withotherorgansandmediatesthebene?cialeffectsofexerciseonhealthandperformance.
Introduction
SuperiorlocomotiveabilitywasonceessentialforhumansurvivalandafundamentalreasonthatHomosapiensevolvedandprospered.Physicalactivitywasobligatoryforevadingpredatorsandfoodprocurement.Evolutionarytheorydescribesthemechanismofnaturalselectionas‘‘survivalofthe?ttest,’’theunderlyingsuppositionbeingthatthe‘‘?t,’’asopposedtothe‘‘un?t,’’hadagreaterlikelihoodofsurvival.Moderndayhumansrunfaster,jumphigher,andarestrongerthanatanytimeinhis-tory.Yetexercise,particularlywhenundertakentoanindivid-ual’smaximum,isacomplexprocessinvolvingthesynchronizedandintegratedactivationofmultipletissuesandorgansatthecellularandsystemiclevel.Thoughthereductionistapproachofdissectingbiologicalsystemsintotheirconstituentpartshasbeenvaluableinexplainingthebasisofmanybiochemicalpro-cesses,forexercisebiologists,thisapproachhasseverelimita-tions:theintegrativebiologyofexerciseisextremelycomplexandcanbeneitherexplainednorpredictedbystudyingtheindi-vidualcomponentsofvariousentities.
Exerciserepresentsamajorchallengetowhole-bodyhomeo-stasis,andinanattempttomeetthischallenge,myriadacuteandadaptiveresponsestakeplaceatthecellularandsystemiclevelsthatfunctiontominimizethesewidespreaddisruptions.Previousreviewshaveconsideredthemetabolicresponsestoexerciseandthecellularmechanismsthatunderpinskeletalmuscleadaptationtoexercisetraining(Bassel-DubyandOlson,2006;CoffeyandHawley2007;EganandZierath,2013;Hop-peleretal.,2011).Here,wehighlightthatvoluntary,dynamic,whole-bodyexerciseprovokeswidespreadchangesinnumerouscells,tissues,andorgansthatarecausedbyorarearesponsetotheincreasedmetabolicactivityofcontracting
skeletalmuscle.Tomeetthischallenge,multipleintegratedandredundantresponsesoperatetobluntthehomeostaticthreatsgeneratedbytheincreasedenergyandO2demand.Inthis‘‘muscle-centric’’viewofexercise,thesystemic(cardiovas-cular,respiratory,neural,andhormonal)responsesareviewedas‘‘servicefunctions,’’supplyingthecontractingmuscleswithfuelandO2tosustainagivenlevelofactivity.Thefundamentalpremiseisthatmultiscaleandredundantresponsessimulta-neouslyoperatetobluntthemanychallengestowhole-bodyho-meostasiscausedbythedemandsofthecontractingmuscles.Theapplicationofmolecularbiologytechniquestoexercisebiologyhasprovidedabetterunderstandingofthemultiplicityandcomplexityofcellularpathwaysinvolvedintheseexerciseresponses.Recentdiscoveriesofferperspectivesontheroleplayedbyskeletalmuscleinnumeroushomeostaticprocessesandonthemechanismsbywhichmuscle‘‘communicates’’withotherorganssuchasadiposetissue,liver,pancreas,bone,andbrain.
WhyStudyExercise?
Thereareseveralbroadreasonstostudyexercise.Hypothesesgeneratedoverthelasttwodecadesfromcomparativephysiol-ogists(Hochachkaetal.,1999)andanthropologists(BrambleandLieberman,2004)suggestthatthecombinedtraitsofsupe-riorendurancecapacityandanimpressiveabilitytothermoreg-ulatepermittedancestralhumansfromthehighplainsofEastAfricatosucceedasgamehuntersandtherebyobtainhigh-pro-teinsourcesoffoodthatwereessentialfortheemergenceoflargerbrainsandcomplexcooperativebehavior.Humanskeletalmuscles,limbs,andthesupportingventilatory,cardiovascular,andmetabolicsystemswerewellsuitedforuprightlocomotion,
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witheconomyofmovementforbipedalwalkingandrunningfarexceedingthatofotherprimates(BrambleandLieberman,2004;Brooks,2012).Atthistime,lifestyleandenergyavailabilitywereinextricablylinkedtotheperiodiccyclesoffeastsandfamines,withcertaingenesevolvingtoregulateef?cientstorageandutilizationofendogenousfuelstores,theso-called‘‘thriftygenes’’(Neel,1962).ExpandingonNeel’soriginalconcept,sur-vivalduringfeast-faminecyclesthroughoutthehunter-gathererperiodwasaccompaniedbytheselectionofgenesandtraitstosupporta‘‘physicalactivitycycle’’(Boothetal.,2002;Chak-ravarthyandBooth,2004),andundertheseconstraintsmostofthepresenthumangenomeevolved.Duringmoderntimes,thoseallelesandtraitsthatevolvedforenergystorageandlocomotionarenowexposedtoaninactivelifestyleandaccesstoenergy-densefoodsoveranextendedlifespan,therebyincreasingtheriskofchronicdisease.Therefore,the?rstreasontostudyexerciseistoprovideinsightintothepathogenicpro-cessesunderpinningthenumerouscontemporaryphysicalinactivity-mediateddisorders.
Therecentemergenceofnoncommunicablediseasesasma-jorkillersinindustrializednations(Baueretal.,2014)andtheroleofphysicalactivityinpreventingand/ortreatingtheseconditionsisasecondreasontostudyexercise.Asedentarylifeisnowsoprevalentthatithasbecomecommontorefertoexerciseashav-ing‘‘healthybene?ts’’eventhoughtheexercise-trainedstateisthebiologicallynormalcondition.Itisalackofexercisethatisabnormalandcarrieshealthrisks(BoothandLees,2006).Phys-icalinactivityincreasestheincidenceofatleast17unhealthyconditionsandrelatedchronicdiseases(Boothetal.,2000),whereasalowexercisecapacityisanindependentpredictorofall-causemortality(Blairetal.,1996;Myersetal.,2002)andmorbidity(Willisetal.,2012).Yetexerciseinbothbiologicalresearchandasprimarypreventativetherapycontinuestobeundervaluedandunderutilizedbythescienti?candmedicalcommunities.Consequently,athirdreasontostudyexerciseistodeterminetheprecisemechanismsbywhichitpromoteswhole-bodyhealthandtoestablishmolecularlinksbetweenspeci?cexerciseinterventionsanddiseaseprevention.Althoughthelastdecadehasseenmajoradvancesinunravelingthemechanism(s)bywhichcellular,molecular,andbiochemicalpathwaysareaffectedbyexercise,theunderstandingofhowtheseeffectsarelinkedtohealthbene?tsisstilllacking.Inthiscontext,epidemiologicalevidencesuggeststhatonlyhalfoftheprotectiveeffectsofexercisecanbeexplainedonthebasisoftraditionalriskfactorslikereductionsinbloodpressure(BP)andbloodlipids(JoynerandGreen,2009).
Afourthreasontostudyexerciseistounderstandthecapacityofvariousmammalianspeciestofunctioninextremeenviron-mentsandtotesthypothesesaboutphysiologicalregulationundersuchconditions.Inthiscontext,humansarecompetentathletes,butourcapacityforlocomotionispaltrycomparedwiththatofotherspeciesthataremorepowerfulandfasterandpossessgreaterendurance.Withrespecttospeed,thecheetah(Acinonyxjubatus)reignssupremeamongterrestrialmammals,achievingmaximumvelocitiesof113km/hr(Sharp,1997),makingtheworld’sfastesthuman(withatopspeedof48km/hr)seemratherpedestrian.Thepronghornantelope(Anti-locapraAmericana)cansustainspeedsof>80km/hrfor4–5km,
andtheGreyhoundandsleddogaresimilarlycapableofextraor-dinaryburstsofspeed(PooleandErickson,2011).Notwith-standingsuchcomparisons,researchintothe‘‘limits’’ofathleticcapacityprovidesinsightintotherolesofvariousorgansystemsinvolvedinmaximizinghumanperformance(JoynerandCoyle,2008).Suchenquiryisnotnew.In1925,NobelLaureateA.V.Hillpublishedapaperonthephysiologicalbasisofathleticre-cords(Hill,1925)andwasthe?rsttodescribetheconceptofanindividual’smaximumoxygenuptake(VO2max)asanindexofthehighestenergydemandthatcanbemetaerobicallywhileexercising.Hillproposedthatanindividual’sVO2maxwasthesin-glebestmeasureofcardio-respiratoryperformanceandcouldbeusedforquantifyingtheadaptationofmanyorgansystemstophysicalactivityorinactivity(Bassett,2002).Perhaps?ttingly,thetestforVO2maxfortheassessmentofathleticpotentialorig-inallyproposedbyHillisnowrecognizedasabetterpredictorofmortalitythananyotherestablishedriskfactororbiomarkerforcardiovasculardisease(Myersetal.,2002).Clearlythebiologyunderlyingmaximalexerciseperformanceconfersadvantagesbeyondtheathleticarena!
VoluntaryExercise:MoreThanMuscleContractionWhatWeMeanWhenWeTalkaboutExercise
Exerciseisthevoluntaryactivationofskeletalmuscleforrecre-ational,sporting,oroccupationalactivities.Thedistinctionbe-tweenvoluntary,whole-bodyinvivoresponsestoexerciseversusthoseevokedbyotherexperimentalmodelsisimportant.Exvivoelectricalstimulationofanisolatedskeletalmuscle,forinstance,evokesanactionpotentialand‘‘contraction’’andtrig-gersintracellularpathwayswithputativerolesintrainingadapta-tion(FittsandHolloszy,1978).However,whole-body,voluntaryexerciseinducesarangeofadditionalphysiologicalresponsesthatarecriticalformuscleperformance(andmovement).Accordingly,manyeffectsobservedinanimalsandisolatedsys-temsfrequentlydifferfromthoseseeninhumansinvivo,andcareshouldbetakenwhenextrapolatingresponsesfromonesetofconditionsoragivenexperimentalmodeltoanother(SchlegelandStainier,2007).
Voluntaryexerciseencompassesmanyelementsbeyondsimplemusclecontraction.Volitionaleffortgeneratedinthemo-torcortexofthebraindrivesthespinalcordtorecruitmotorunits,resultinginspeci?cmovementpatterns.Inparallelwithneuralsignalstoskeletalmuscle,therearealsopowerfulneuralfeedforwardsignalstothecardiovascular,respiratory,andmetabolicandhormonalsystems,alongwithneuralfeedbackfromthecontractingskeletalmuscles,thatgenerallypermitmetabolicdemandstobemetwithlimiteddisruptionofhomeo-stasis(Figure1).
Numerousissuesrelatingtothespeed,force,duration,andin-tensityofmusclecontractions,alongwiththetotalmusclemassengagedintheactivity,areimportantforacompleteunderstand-ingofthephysiologicalresponsestoexercise.Anisometricorstaticcontractionofhighforcebutshortdurationcompressesbloodvesselsinthecontractingmusculatureandlimitsblood?owandO2deliverytothosemuscleswhilesimultaneouslyincreasingBP.Incontrast,duringsustainedrhythmicexerciselikecyclingorrunning,thecontractiontimesareshort,thereislittledisruptionofmuscleblood?ow,andperturbationsinBP
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Figure1.ThePhysiologicalResponsestoVoluntary,DynamicExercise
Multipleorgansystemsareaffectedbyexercise,initiatingdiversehomeostaticresponses.
areminimized.Themusclemassengagedinexerciseiscritical,asitdeterminesboththeabsoluteO2?uxandtotalfuelrequire-ments.Formostaerobic-basedactivities,suchasrunningorcycling,activemusclemassamountsto??15kgina70kgathlete(Coyleetal.,1991),althoughforrowingandcross-countryskiing(forwhichtheathleteissubstantiallytallerandheavier),thisismarkedlyhigher(Hagerman1984).Thenomenclaturerelatingtothequanti?cationofexerciseintensityisalsorelevantbecausetheprevailingworkrateexertsamajorroleindeterminingtheoverallphysiologicalresponsestoexercise.Forexerciselasting>5min,intensityistypicallyexpressedasapercentageofanin-dividual’sVO2max.Low-,moderate-,andhigh-intensityexercisecorrespondto<45%,45%–75%,and>75%ofindividualVO2max,respectively.
SkeletalMuscleEnergyMetabolism
ATPisrequiredtofuelthecellularprocessessupportingmusclecontraction.Theseincludethemaintenanceofsarcolemmalexcitability(Na+/K+ATPase),reuptakeofCa2+intothesarco-plasmicreticulum(Ca2+ATPase),andforcegenerationviaactin-myosincross-bridgecycling(myosinATPase).Intramus-cular[ATP]isremarkablywellmaintainedoverawiderangeofexerciseintensitiesanddurations,andwhile[ATP]declinesundercertainexerciseand/orenvironmentalconditions,themagnitudeofchangeissmallwhenconsideredagainstthetotalturnoverofATPwithinactivemyocytes.Duringsprintexercise,ATPturnovercanincrease100-foldaboverest(Gaitanosetal.,1993;Parolinetal.,1999),arangeofmetabolicactivityexceedingthatinallothertissuesandonethatposesamajorenergeticchallengetothecontractingmyo?bers.Giventhatintramuscular[ATP]isrelativelysmall,metabolicpathwaysresponsibleforATPresynthesisarerapidlyactivated.Duringshort-term(??30–60s)maximalexercise,thisisachievedprimar-ilythroughsubstrate-levelphosphorylationviathebreakdownofcreatinephosphateandduringtheconversionofglucoseunits,derivedalmostentirelyfromintramuscularglycogen,tolactate(Gaitanosetal.,1993;Parolinetal.,1999).Themobilizationofextramuscularsubstratesisalsocriticaltomaintainskeletalmusclemetabolismduringprolongedexercise(vanLoonetal.,2005;Wasserman,2009).Thus,theliverincreasestherelease
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ofglucoseintothecirculation(initiallyderivedfromglycogenolysisandlaterfromgluconeogenesis),andtheadipo-cyteincreasesthehydrolysisofitstriglyc-eridestoresandthereleaseoflong-chainnonesteri?edfattyacidsintotheblood-stream.
Therelativecontributionofcarbohy-drateandlipidtooxidativemetabolismisdeterminedprimarilybytheprevailingexerciseintensity(Romijnetal.,1993)andisin?uencedbypriordiet,trainingstatus,sex,andenvironmentalcondi-tions(Jeukendrup2003).Thecontributionfromtheoxidationofcarbohydrate-basedfuelsriseswithincreasingexerciseinten-sity,withaconcomitantreductioninlipidoxidation.Conversely,duringprolongedexerciseata?xedlevelofmoderateintensity,ratesofcarbohydrateoxidationdeclineaslipolysisandfatoxidationincrease.Theregulationoffuelmobilizationandutiliza-tioninvolvesacombinationoflocalfactorssuchassarcoplasmic[Ca2+],intramuscularlevelsofATPbreakdownproducts(ADP,AMP,IMP,Pi),andmuscletemperatureandintramuscularsub-strateavailability,aswellassystemicfactorssuchastheplasmalevelofkeyhormones(epinephrine,insulin,andglucagon)andcirculatingmetabolites(Hawleyetal.,2006).Thesefactorsarenotonlyinvolvedinmediatingtheacuteresponsetoexercise,butalsoactivatesignalingpathwayscriticalformanyofthechronicadaptationstoregularexercisetraining.Recentreviewshavesummarizedthevariouscellularandmolecularfactorsinvolvedintheregulationofskeletalmusclecarbohydrate(Jen-senandRichter,2012;RichterandHargreaves,2013)andlipid(JeppesenandKiens,2012)metabolismduringexercise,aswellastheinteractionsbetweenthem(Spriet,2014).OxygenTransportSystem
Atrest,whole-bodyO2consumptioninhealthy,young,adulthumansaveragesabout3.5ml/kg/min,with??20%–25%ofthisusedbyrestingskeletalmuscle.Thus,fora70kgperson,restingO2consumptionis??250ml/min,with50ml/mintakenupbyskeletalmuscle.Inlean,healthy,untrainedadults,VO2maxistypically10–15timesrestingvalues.Ineliteendurance-trainedathletes,VO2maxvaluescanexceed85ml/kg/min(Saltinand?strand,1967).ThoughO2?uxesinhumansarehigh,theyareA
marginalcomparedtovaluesachievedbyeliteracehorseswithVO2maxvaluesof110l/min,equatingto220ml/kg/min(PooleandErickson,2011).
VO2maxisdeterminedbythecombinedcapacitiesofthecen-tralnervoussystemtorecruitmotorunits,thepulmonaryandcardiovascularsystemstodeliverO2tocontractingskeletalmuscles,andtheabilityofthosemusclestoconsumeO2intheoxidative,metabolicpathways.AssociatedwithlargeincreasesinO2consumptionduringmaximalexerciseinhumansarepeakvaluesforcardiacoutput(Q)andventilationof40and200l/min,
Figure2.ComplexandRedundantPhysio-logicalControlMechanismsduringVolun-tary,DynamicExercise
Motorcorticaldriveleadstoskeletalmusclecontraction,aswellasparallelactivation(‘‘centralcommand’’)ofkeyneuro-endocrineresponses,fuelmobilization,andsupportsystemsthatin-creaseoxygenandsubstratedeliverytocon-tractingskeletalmuscle.Theintegratedresponseis?ne-tunedbyafferentfeedback,involvingme-chano-andchemo-sensitivetypeIIIandIVaffer-entsinactiveskeletalmuscle,butalsobycriticalsensorsthatmonitorvariousparameters,includingmeanarterialbloodpressure(MAP),bloodglucoseconcentration,oxygenandcarbondioxidelevels,bodytemperature,andbloodvolume.
representing8-and20-foldincreases,respectively,aboverest.Inaddition,blood?owtoactiveskeletalmusclecanincrease??100timesabovebasallevels,accountingforupto80%–90%ofQ.Notably,thereisonlyamodest(??20%)increaseinmeanarterialbloodpressure(MAP),whereasvaluesforarterialPO2,PCO2,andpHremainessentiallyidenticaltorestuntilmaximalexerciseintensitiesarereached.
Thecardiovascularadjustmentstoexerciserequireanintactautonomicnervoussystemandaredrivenbythreesignals:(1)feedforward‘‘centralcommand’’relatedtomotoroutput,whichactivateselectedareasinthebrainstemcardiovascular(andres-piratory)centerstostimulateincreasesinheartrate(HR),BP,andventilation;(2)afferentfeedbackfromthinlymyelinatedandunmyelinatedtypeIIIandIVafferentsincontractingmusclesthatincreasesympatheticactivation;and(3)baroreceptorsinthecarotidsinusandaorticarchthatprovidefeedbackonBPtothebrainstemcardiovascularcenters.TheHRresponsetoex-erciseisdrivenprimarilybycentralcommand-mediatedvagalwithdrawalandactivationofsympatheticout?owtotheheart.Bothfactorsalsoaugmentcardiacstrokevolume,andtheactionoftheso-called‘‘musclepump’’ensuresthatvenousreturnfromtheactivemusclevasculaturemaintainsdiastolic?llingandstrokevolume(SV).Thecentralmotordriveandcentralcom-mandaresubjectto‘‘?ne-tuning’’viafeedbacksignalsthatmonitorsubstratelevels,MAP,bloodgasesandpH,?uidstatus,andbodytemperaturedespitethemarkedho-meostaticchallengesassociatedwithhigh-intensityexercise(Figure2).
Theprimarymechanismresponsibleforskeletalmusclehy-peremiaduringexerciseisvasodilationintheactiveskeletalmuscle,mostnotablyinthesmallarterioles.Mechanical,neu-ral,andhumoralfactors,includingthosereleasedfromcon-tractingskeletalmuscle,havebeenimplicatedinthisresponse.Becausetheriseinmuscleblood?owiscloselycoupledtometabolicrate,vasodilatingsignal(s)releasedfromcontractingskeletalmusclesroughlyinproportiontotheirO2demandis(are)responsible(Hellstenetal.,2012).Candidatedilatorsub-stancesandmechanismsincludeinwardrectifyingK+chan-nels,adenosine,ATPfromvarioussources,productsofskeletalmusclemetabolism,andreactiveO2species.However,nosin-glesubstancecanfullyaccountfortheincreasesinmuscleblood?ow,andthemolecularidentityofoneormoreofthesesignalsisunknown.
Blood?owisredistributedawayfromthekidney,liver,othervisceralorgans,andinactivemuscleviavasoconstrictioninthesevascularbeds,secondarytoincreasedsympatheticactiv-ityduringexercise.ThispermitsahigherfractionofQtobedeliv-eredtoactiveskeletalmuscleandpartiallyoffsetsthefallintotalperipheralresistanceasaresultofskeletalmusclevasodilation.Blood?owtothecentralnervoussystemremainseitherun-changedorincreasesslightly,andcoronaryblood?owin-creases.Becauseevaporationofsweatisthemajormechanismfordissipationofheatduringexercise,especiallyathigherenvi-ronmentaltemperatures,thereisanincreaseinskinblood?ow
′lez-Alonsoandsweating-induced?uidlosswithexercise(Gonza
etal.,2008).Withincreasedexerciseintensity,theskinbecomesatargetforvasoconstrictionasskeletalmuscleblood?owin-creasesdespiteincreasedmetabolicheatproduction.Tomain-tainMAP,skeletalmuscletakespriorityoverskinblood?ow.AsexerciseapproachesVO2max,the?nitecardiacpumpingcapac-itymeansthatactiveskeletalmuscleisalsosubjecttovasocon-striction(Calbetetal.,2004).Withincreasedenvironmentalstress,thecombinationofprogressivehyperthermiaanddehy-drationfurtherchallengesthecardiovascularsystemduringpro-′lez-Alonsoetal.,2008).longed,strenuousexercise(Gonza
ThecriticalfunctionsofthepulmonarysystemaretomaintainarterialoxygenationandtofacilitatetheremovalofCO2producedduringoxidativemetabolism.Thisisachievedbyincreasedventilationinproportiontoexerciseintensity,andarte-rialPO2andPCO2aregenerallymaintainedatrestinglevelsuntilheavyexercise.ThefactorsresponsibleforthemarkedincreaseinventilationincludedescendingcentralcommandinparallelwithmotorcorticalactivationofskeletalmusclethatstimulatesthebrainstemrespiratorycentersandfeedbackstimulationfromtypeIIIandIVafferents(Dempseyetal.,2014).Inmosthealthyindividualsexercisingatsealevel,arterialoxyhemo-globinsaturation(SaO2)iswellmaintained.However,insomehighlytrainedenduranceathletes,high-intensityexerciseresultsinasigni?cantdropinSaO2thatimpairsO2deliverytocontract-ingskeletalmuscleandresultsinimpairedexercisecapacity(Amannetal.,2006).AnotherthreattolocomotormuscleO2de-liveryandperformanceduringhigh-intensityexerciseisre?ex
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sympatheticvasoconstrictionofthelimbskeletalmusclevascu-lature,secondarytoactivationoftypeIIIandIVafferentsinrespiratorymuscles(Dempseyetal.,2002).Increasesinrespira-torymuscleworkduringheavyexerciseresultinincreasedmetaboliteaccumulationandactivationoftheseafferents.Thisre?exservestodirectagreaterproportionofthelimitedQtotherespiratorymusclesbutattheexpenseofthelocomotormusclesandexerciseperformance.
Theacutecardiovascularadaptationstobothdynamicandisometricexerciseleadtopatternsoflong-termremodelingandadaptationsthatincreaseVO2maxandminimizedisruptionsinwhole-bodyhomeostasis.Theautonomicandsensoryfeed-backsystemsdescribedpreviouslyaresubjecttochronicreset-tingsothat,duringdynamicexercise,somewhatlowerBPsaretolerated,thuspermittinggreaterincreasesinskeletalmuscleblood?ow.Thisisaccompaniedbycellularchangesinthebrain-stemcardiovascularcenterthattendtobepro-vagalandsym-pathoinhibitory.ThesechangespartlyexplainwhyexerciseatanygivensubmaximalworkrateaftertrainingisaccompaniedbyalowerHRandBP.TheyalsocontributetothechronicBPloweringeffectsofexerciseingeneral.Adaptationstoresistancetrainingarelesswellcharacterized.However,duringmaximalweightlifting,BPcanexceed480/350mmHg(MacDougalletal.,1985),consistentwiththeideathatcompressionofthebloodvesselsinthecontractingskeletalmusclesevokesre-sponsesdesignedtoovercome‘‘underperfusion’’bysubstan-tiallyincreasingBP.
Withdynamicexercise,thereisconsiderableremodelingofthevascularsystem,especiallyintheskeletalmusclessubjectedtotraining,includinganincreaseinthediameteroflargecon-ductingvesselslikethefemoralarteryforlegexercise(Greenetal.,2012).Thereisalsoanincreaseinthenumberofarteriolesandincreasedcapillarydensityinthetrainedmusculature.ThisstructuralremodelingisdrivenbyacomplexandredundantsequenceofeventsthatincludesNO,prostaglandins,andvascularendothelialgrowthfactor(VEGF)signalingpathways(HoierandHellsten,2014).Thetimecourseofremodelingalsovariesbybloodvesselsize.Earlyinexercisetraining,thereisamarkedincreaseinnitricoxidesynthase(NOS)expressioninthelargeconductingvesselsinresponsetoincreasedshearstress.However,asthecaliberofthevesselincreaseswithtraining,theshearstressnormalizesandNOSexpressionreturnstobaselinevalues.Thoughmanyoftheseadaptationsarerestrictedtothevascularbedsoftheworkingmuscle,improvedendothelialfunctionappearstobeawhole-bodyresponsetoexercisetraining.
Dynamicexercisetrainingisassociatedwithanincreaseincardiacchambersize,butnotwallthickness,thatfacilitatestheincreaseinSVcausedbythismodeoftraining.Endurancetrainingpromotesvolumehypertrophy,whereasresistancetrainingdoesnotcausemajorchangesinthethicknessofcardiacmuscle.Thestimulusforcardiacvolumehypertrophywithdynamicexercisetrainingisstretchoftheventriclecausedbytheincreasedvenousreturnfromtheperiphery.Thisstretchisfacilitatedbytraining-inducedincreasesinbloodvolumeandcatecholamineconcentrations.Thecellularmechanismsresponsibleforcardiachypertrophywithexercisetraininginvolveactivationofanumberofpathways,includingtheinsu-742Cell159,November6,2014a2014ElsevierInc.
lin-likegrowthfactor1(IGF-1)-phosphatidylinositide3-kinase(PI3K)-Akt/proteinkinaseBaxis(Ellisonetal.,2012),inparticularPI3K(p110a).DownstreamofAkt,exercise-inducedcardiomyo-cytehypertrophyandproliferationappearstobeassociatedwithreducedC/EBPbexpressionandaconcomitantincreasein
CITED4expression(Bostro
¨metal.,2010).Cardiachypertrophyalsoinvolvesdenovocardiomyocyteformationbyactivationofbothcirculatingandtissue-speci?ccardiacprogenitorcells.Inhighlymotivatedyoung,healthyindividuals,VO2maxdoesnotappeartobelimitedbymusclemitochondrialoxidativecapacity(Bousheletal.,2011).Rather,O2deliverytoskeletalmuscleisratelimiting,andalthoughthisisdeterminedbybothconvectiveanddiffusivemechanisms,centralcardiovascularfunctionandtheabilitytoincreaseactiveskeletalmuscleblood
?owappeartobecritical(Gonza
′lez-AlonsoandCalbet,2003).However,musclemitochondrialoxidativecapacitydoesappeartobeanimportantdeterminantofenduranceexerciseperfor-mance(JoynerandCoyle,2008).Thus,treadmillrunningtimeatsubmaximalexerciseintensityisusedasaphysiologicalcorrelateoftransgenicinterventionsthatimpactmuscleoxida-tivecapacity(Potthoffetal.,2007;Wangetal.,2004).
SkeletalMuscleMatters
SkeletalMuscleFiberTypeandAdaptationPlasticity
Theapplicationofsurgicaltechniquestoexercisebiochemistry
inthe1960s(Bergstro
¨mandHultman1966)madeitpossibletoobtainsmall(100–150mg)samplesofhumanskeletalmuscleforhistologicalandbiochemicalstudiestoidentifyspeci?cmorphological,contractile,andmetabolicproperties.Usingtheseapproaches,different?bertypeshavebeenidenti?edalongwiththeircontractilecharacteristics,andthesehavebeenrelatedtofunctionalandmetabolicpropertiesofskeletalmuscleduringexercise(Saltinetal.,1977).Themetabolicpoten-tialofmusclehasalsobeenevaluatedbydeterminingdifferentsubstrateandenzymeactivities.Comprehensivediscussionofskeletalmuscle?bertypesandthegeneprogramsresponsiblefor?ber-speci?cpropertiesarebeyondthescopeofthisReviewandhavebeensummarizedelsewhere(Bassel-DubyandOlson2006;Saltinetal.,1977;Schiaf?noandReggiani1996;ZierathandHawley2004).However,abriefoverviewoftheclassi?cationofhumanmuscle?bertypesandtheirmetabolicpotentialiswarranted.
Histologically,skeletalmuscleappearsuniformbutiscomprisedofmyo?bersthatareheterogeneouswithrespecttosize,metabolism,andcontractilefunction.Onthebasisofspe-ci?cmyosinheavy-chainisoformexpression,myo?berscanbeclassi?edintotypeI,typeIIa,typeIId/x,andtypeIIb?bers,withtypesIandIIaexhibitinghighoxidativepotentialandcapil-larysupplyandwithtypesIIxandIIb?berbeingprimarilyglyco-lytic(PetteandStaron2000;Saltinetal.,1977;Schiaf?noandReggiani1996).TypeImyo?bersaretypicallyreferredtoas‘‘slow-twitch?bers’’becausetheyexertslowcontractiontimetopeaktension,owingtotheATPaseactivityassociatedwiththetypeImyosin,whereastypeII?bersaretermed‘fast-twitch’myo?bersandhavequickercontractiontimebutarapidfatiguepro?le(Bassel-DubyandOlson2006;Saltinetal.,1977).Withendurancetraining,theenhancementoftheoxidativepotentialoftypeIIxandIIb?bersismarkedlyincreased,resultingina