Review 2014-11 CELL Integrative Biology of Exercise - 图文

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

Figure3.RepeatedTransientBurstsinMessengerRibonucleicAcidPrecedeIncreasesinTranscriptionalandMitochondrialProteinsinResponsetoShort-TermTraining

Subjects(n=9)completedsevensessionsofhigh-intensityintervaltrainingduringa2weekintervention.Skeletalmusclebiopsiesfromthevastuslateraliswereobtained4and24hrafterthe?rst,third,?fth,andseventhtrainingsession.PGC-1a,peroxisome-proliferator-activatedreceptorgcoactivatora;CS,citratesynthase.DataareredrawnfromPerryetal.(2010).

potentialforoxidationthatmarkedlysurpassestheaerobicca-pacityoftypeI?bersofuntrainedindividuals(Saltinetal.,1977).Indeed,theabsolutelevelfortheactivitiesofbothoxida-tiveandglycolyticenzymesinall?bertypesinhumansislargeenoughtoaccommodateasubstantialrangeofaerobicandanaerobicmetabolism.

Whetherendurance-orresistance-basedexercisetraininginhumanscanresultin?bertype‘‘reprogramming’’remainsopentodebate.Certainlyendurancetraininginduceschangesinthemetabolicpropertiesofskeletalmusclebyconferringanincreasedoxidativepro?letothetrainedmyo?bers(Saltinetal.,1977).Sucheffectsarelikelytoinvolveaplethoraofsignalingcascadesandtranscriptionfactorsincluding,butnotlimitedto,calciumsignalingpathwaysinvolvingcalcineurin,calcium-calmodulin-dependentkinase,andthetranscriptionalcofactorsperoxisomeproliferator-activatedreceptorgcoactiva-tor1a(PGC-1a)andPPARd(OlsonandWilliams2000;Linetal.,2002;Wangetal.,2004;Wuetal.,2002).However,thespeci?ctranscriptionalfactorsdirectlyinvolvedinthecontrolofthemus-clephenotypeand?ber-speci?ccontractilepropertiesremaintobefullycharacterized.

Humanskeletalmuscledisplaysremarkableplasticity,withthecapacitytoalterboththetypeandamountofproteininresponsetodisruptionsincellularhomeostasisinducedbythehabituallevelofcontractileactivity,theprevailingsubstrateavailability,andenvironmentalconditions(Hawleyetal.,2011;ZierathandHawley2004).Thoughthisphenomenonof‘‘adapta-tionplasticity’’iscommontoallvertebrates,alargevariationinthedegreeofadaptabilitybetweenhumansisevident.Thispartlyexplainsthelargeinterindividualresponsestostandardizedexercisetraininginterventionsandthestrikingdifferencesinper-formancebetweenindividuals(Bouchardetal.,2011).Thefunc-tionalconsequencesofadaptationplasticityarespeci?ctothemodeofexerciseandarein?uencedbythevolume,intensity,andfrequencyofthecontractilestimulialongwiththehalf-lifeofspeci?cexercise-inducedproteins(Hawley2002).Prolonged

endurance-basedexercisetrainingelicitschangesthatincreasethemitochondrialproteincontentandrespiratorycapacityofthetrainedmyo?bers.Theseadaptationsunderpinthealteredpat-ternsofsubstrateoxidationduringsubmaximalexercise(fromcarbohydrate-tofat-basedfuels)thatresultinlesslactatepro-ductionatagivensubmaximalpoweroutputorspeed(Holloszy1967).Incontrast,strengthandresistance-basedtrainingstimu-latesthemyo?brillarproteinsresponsibleformusclehypertro-phy,culminatinginincreasesinmaximalcontractileforceoutput(Phillips2014)withoutsubstantialchangesinfueluseduringexercise.Concomitantwiththevastlydifferentfunctionaloutcomesinducedbythesediverseexercisemodes,thege-neticandmolecularmachineryaffectingtheseadaptationsaredistinct.

AdaptationstoExerciseTraining:TheCumulativeEffectofRepeatedExerciseBouts

Theconversionofvariouschemical,electrical,andmechanicalsignalsgeneratedduringmusclecontractiontomoleculareventspromotingphysiologicalresponsesandsubsequentadaptationsinvolvesacascadeofeventsresultinginactivationand/orrepressionofspeci?csignalingpathwaysregulatingexercise-inducedgeneexpressionandproteinsynthesis/degradation.Thesepathwaysarenumerousandhavebeenreviewedelse-where(Bassel-DubyandOlson2006;CoffeyandHawley2007;EganandZierath,2013;Hoodetal.,2006).Potentialsignalsdur-ingcontractileactivityinclude,butarenotlimitedto,increasedsarcoplasmic[Ca2+],increasedAMPand/oranincreasedADP/ATPratio,reducedcreatinephosphateandglycogenlevels,increasedfattyacidandROSlevels,acidosis,andalteredredoxstate,includingNAD/NADH,andhyperthermia(Hawleyetal.,2006).Redundancyandcompensatoryregulationarekeycharacteristicsofbiologicalsystemsthatacttopreservephysi-ologicalresponsesandadaptationstoavarietyof‘‘threats’’tocellularhomeostasis.Indeed,somegenedeletionsormutationshavelittleeffectonmetabolicadaptation,highlightingthepoten-tialcaveatsinvolvedinutilizingtransgenicorknockoutmodelstoexaminemechanismsofmuscleadaptation(McGeeetal.,2014).KeysignalingpathwaysinvolveCa2+/calmodulin-dependentki-nases(CaMK),calcineurin,AMP-activatedproteinkinase(AMPK),mitogen-activatedproteinkinases(ERK1/2,p38MAPK),andmammaliantargetofrapamycin(mTOR).Thetargetsofthesesignalingpathwaysincludemanytranscriptionfactors,coactiva-tors,andrepressors.ExerciseincreasesactivationofCaMKII(RoseandHargreaves,2003),AMPK(WinderandHardie1996;Fujiietal.,2000),andMAPKs(Widegrenetal.,1998).Aspreviouslynoted,contraction-inducedalterationsinintracellular[Ca2+]arelinkedtodistinctiveprogramsofgeneexpressionthatestablishphenotypicdiversityamongskeletalmyo?bers(Chin,2005;TaviandWesterblad,2011).Inaddition,activationofAMPKbyexer-cise-inducedalterationsinmuscleenergystatusincreasesgenetranscriptioninskeletalmuscle(McGeeandHargreaves,2010).

Adaptationstoexercisetrainingresultfromthecumulativeef-fectoftransientincreasesinmRNAtranscriptsthatencodeforvariousproteinsaftereachsuccessiveexercisebout.TheserepeatedburstsinmRNAexpressionappeartobeessentialtodrivetheintracellularadaptiveresponsetoexercisetraining(NeuferandDohm1993;Perryetal.,2010)(Figure3).Thetiming

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Figure4.SchematicoftheMajorSignalingPathwaysInvolvedintheControlofSkeletalMuscleHypertrophyandMitochondrialBiogenesis

Multipleprimarysignals,including,butnotlimitedto,mechanicalstretch,calcium,pH,redoxstate,hypoxia,andmuscleenergystatus,arealteredwithvoluntarydynamicexercise.Followinginitiationofoneormoreofthesepri-marysignals,additionalkinases/phosphatasesareactivatedtomediateaspeci?cexercise-inducedsignal.Inmammaliancells,numeroussignalingcascadesexist.Thesepathwaysareregulatedatmultiplesites,withsub-stantialcrosstalkbetweenpathwaysproducingahighlysensitive,complextransductionnetwork.

andresponsivenessofindividualmRNAspeciestodifferenttypesofcontractileactivityisvariable,butpeakinductionforboth‘‘metabolic’’and‘‘myogenic’’genesgenerallyoccur4–8hrafteranexercisebout,withmRNAlevelsreturningtopre-ex-erciselevelswithin24hr(Yangetal.,2005).AnotherlevelofregulationofmRNAandproteinabundancebyexerciseinvolves

alterationsinDNAmethylationstatus(Barre

`setal.,2012),his-tonemodi?cations(McGeeandHargreaves,2011),andmicro-RNAexpression(Zacharewiczetal.,2013).Ultimatelytheabilityofagivenmusclecelltoalterthetypeandquantityofproteinisafunctionofitshalf-life.Proteinsthatturnoverrapidlyandhavehighratesofsynthesisarecapableofattaininganewsteady-statelevelfasterthanthosethatturnoverslowlyduringadapta-tiontocontractileandotherstimuli.

MitochondrialBiogenesisandEnduranceTrainingAdaptation

Mitochondrialbiogenesisrequiresthecoordinationofmultiplecellularevents,includingtranscriptionoftwogenomes,synthe-744Cell159,November6,2014a2014ElsevierInc.

sisoflipidsandproteins,andthestoichiometricassemblyofmultisubunitproteincomplexesintoafunctionalrespiratorychain(Hoodetal.,2006).Impairmentsatanystepcanleadtodefectiveelectrontransport,failureofATPproduction,andaninabilitytomaintainenergyhomeostasis.SincetheseminalworkofHolloszy(1967),whodiscoveredthatmusclesoftread-mill-trainedratsexhibitedhigherlevelsofmitochondrialproteinsthanthoseofuntrainedanimals,majorbreakthroughsinunravel-ingthecellulareventscontrollingskeletalmusclemitochondrialbiogenesishaveoccurred.Severaltranscriptionfactorsthatregulatetheexpressionofthenucleargenesencodingmito-chondrialproteinswerediscovered(Scarpulla2006).Theseincludenuclearrespiratoryfactors1and2(NRF-1,NRF-2)thatbindtothepromotersandactivatetranscriptionofgenesthatencodemitochondrialrespiratorychainproteins(KellyandScar-pulla2004).NRF-1alsoactivatesexpressionofthenucleargenethatencodesmitochondrialtranscriptionfactorA(TFAM),whichmovestothemitochondriaandregulatestranscriptionofthemitochondrialDNA(i.e.,themitochondrialgenome).BecausenotallpromotersofgenestranscribingmitochondrialproteinshaveNRF-1-bindingsites,othertranscriptionfactorsareinvolvedincontractile-modulatedmitochondrialbiogenesis,includingtheestrogen-receptor-relatedreceptors(ERR)aanddandtheperoxisomeproliferator-activatedreceptorcoactiva-tors(PPARs),whichregulateexpressionofthemitochondrialfattyacidoxidativeenzymes(KellyandScarpulla,2004;Scar-pulla,2006).

AnothermajorbreakthroughinunravelingthecellulareventsthatpromotemitochondrialbiogenesiswasthediscoveryofPGC-1a,aninduciblecoactivatorthatregulatesthecoordinatedexpressionofmitochondrialproteinsencodedinthenuclearandmitochondrialgenomes(Linetal.,2005).AcriticalfeatureofthePGC-1coactivatorsisthattheyarehighlyversatileandinteractwithmanydifferenttranscriptionfactorstoactivatedistinctbio-logicalprogramsindifferenttissues(Linetal.,2005).Inskeletalmuscle,PGC-1ahasemergedasakeyregulatorofmitochon-drialbiogenesisthatrespondstoneuromuscularinputandtheprevailingcontractileactivity.Asingleboutofenduranceexer-ciseinducesarapidandsustainedincreaseinPGC-1ageneandproteininskeletalmuscle(Mathaietal.,2008),whereasmuscle-speci?coverexpressionofPGC-1aresultsinalargein-creaseinfunctionalmitochondria(Linetal.,2002),improve-mentsinwhole-bodyVO2max,ashiftfromcarbohydratetofatfuelsduringsubmaximalexercise,andimprovedenduranceper-formance(Calvoetal.,2008).Gain-of-functionstudiesrevealthatexpressionofPGC-1aatornearphysiologicallevelsleadstoactivationofgeneticprogramscharacteristicofslow-twitchmuscle?bers(Linetal.,2002),withthemusclesofthesetrans-genicmiceresistanttocontraction-inducedfatigue.LossoffunctionstudieschallengetheabsoluterequirementofPGC-1aforexercisetraining-inducedchangesinmusclemitochondrialbiogenesis,angiogenesis,and?bertypechanges(Gengetal.,2010;Roweetal.,2012).Onbalance,currentobservationsplacePGC-1aasacentralplayerinorchestratingmanyoftheoxidativeadaptationstoexercise.

AMPKandp38MAPKaretwoimportantsignalingcascadesthatconvergeupontheregulationofPGC-1aandconsequentlytheregulationofmitochondrialbiogenesis(Figure4).AMPK

inducesmitochondrialbiogenesispartlybydirectlyphosphory-latingandactivatingPGC-1a(Ja

¨geretal.,2007),butalsobyphosphorylatingthetranscriptionalrepressorHDAC5,whichrelievesinhibitionofthetranscriptionfactormyocyteenhancerfactor2(MEF2),aknownregulatorofPGC-1a(McGeeandHar-greaves,2010).Ofnote,MEF2activationisassociatedwithincreasedmuscleoxidativecapacityandrunningendurance(Potthoffetal.,2007).p38MAPKphosphorylatesandactivatesPGC-1a(Puigserveretal.,2001)andalsoincreasesPGC-1aexpressionbyphosphorylatingthetranscriptionfactorATF-2,whichinturnincreasesPGC-1aproteinabundancebybindingtoandactivatingtheCREBsiteonthePGC-1apromoter(Aki-motoetal.,2005).Thetumorsuppressorproteinp53,presum-ablyactivatedbyAMPKand/orp38MAPK,isemergingasanothertranscriptionfactorinvolvedinexercise-inducedmito-chondrialbiogenesisinskeletalmuscle.p53knockoutmicedisplayreducedenduranceexercisecapacitycomparedwithwild-typemice,alongwithreducedsubsarcolemmalandinter-myo?brillarmitochondrialcontentandPGC-1aexpression.p53mayregulateexercise-inducedmitochondrialbiogenesisthroughinteractionswithTFAMinthemitochondria,whereitfunctionstoco-ordinateregulationofthemitochondrialgenome(Bartlettetal.,2014).

MuscleHypertrophyandMyogenicPathways

Strengthtrainingincreasesmuscle?bersize(hypertrophy)andmaximaltensionoutput.Theseadaptationsareattainedbypos-itivemuscleproteinbalanceandsatellitecelladditiontopre-ex-isting?bers.Positivemuscleproteinbalanceoccurswhentherateofnewmuscleproteinsynthesisexceedsthatofbreakdown.Althoughresistanceexerciseandpostprandialhyper-aminoaci-demiabothstimulatemuscleproteinsynthesis,itisthroughthesynergisticeffectsofthesestimulithatanetgaininmusclepro-teinoccursand?berhypertrophytakesplace(Phillips2014).ActivationofmTORappearstobeimportantforcontraction-inducedincreasesinmuscleproteinsynthesis(Drummondetal.,2009).Onceactivated,mTORexistsastwodistinctcomplexes,mTORcomplex1(TORC1)andmTORcomplex2(TORC2).TORC1ischaracterizedbythepresenceofregulato-ry-associatedproteinofmTOR(RAPTOR),whereasTORC2bindsrapamycin-insensitivecompanionofmTOR(RICTOR).Thesetwoproteincomplexessensediversesignalsandproduceamultitudeofresponses,includingmRNAtranslation,ribosomalbiogenesis,andnutrientmetabolism(CoffeyandHawley2007;EgermanandGlass,2014).IGF-1haslongbeenconsideredakeyupstreamregulatorofmTOR.SignalingactivatedbyIGF-1positivelyregulatesskeletalmusclemassviainductionofproteinsynthesisdownstreamofproteinkinaseB/AktandthemTORpathway(Bodineetal.,2001).IGF-1transmitssignalingalongthePI3K/Aktpathway(Figure4),resultingintheparallelactiva-tionofthemTORpathway,producingamultitudeofresponses,includingmRNAtranslation,ribosomalbiogenesis,andnutrientmetabolism(CoffeyandHawley2007).Growth-factor-indepen-dent,mechanosensitiveactivationofmTORalsocontributestomuscleproteinsynthesis(Philpetal.,2011).

Themostwell-de?nedeffectorsofmTORsignalingarepro-teinsimplicatedintranslationalcontrol:ribosomalproteinS6ki-nase(p70S6K)andeukaryoticinitiationfactor4E-bindingprotein(4E-BP1).Indeed,afteractivationbyAkt,TORC1controlspro-teinsynthesisbyphosphorylatingp70S6kinase1andthe4E-BP1,andtheTORC2multiproteincomplexcontributestotheprolongedactivationofAkt.Phosphorylationofp70S6KandsubsequentactivationofribosomalproteinS6enhancestransla-tionofmRNAs,encodingelongationfactorsandribosomalproteinsandtherebyincreasingtranslationalcapacity.p70S6Kplaysafundamentalroleinskeletalmusclehypertrophy(Liuetal.,2002).Asingleboutofresistanceexerciseinhumansleadstoincreasesinp70S6Kphosphorylation,whichiscorrelatedwiththechronicincreaseinmusclemassandstrengthobservedafterchronicresistancetraining.Thus,theacuteresponsestoexer-cise,includingdynamicchangesinmuscleproteinturnoverandtheearlyactivationofsignalingproteins,mayactassurro-gatesoflong-termphenotypicchangesinmusclemassandstrength.

PGC-1a4,atranscriptfromthePGC-1agene,isabundantlyexpressedinskeletalmuscleandappearstoplayaroleintheadaptiveresponsetoexercise,particularlyinthesettingofresis-tancetraining(Ruasetal.,2012).ThisproteindoesnotappeartoregulatethesamesetofoxidativegenesinducedbyPGC-1abut,rather,activatestheexpressionofIGF-1whileconcomi-tantlysuppressingmyostatin(aninhibitorofmusclecelldifferen-tiationandgrowth)pathways.Aftertrainingconsistingofeitherenduranceexercise,resistanceexercise,oracombinationofbothenduranceandresistanceexercise,increasesinPGC-1a4werecon?nedtoresistance-onlyandcombinedexercisetrainingprograms,withnochangesinthistranscriptafterendur-ance-onlytraining(Ruasetal.,2012).Thoughtheseresultsarenotable,theproposalthatskeletalmusclehypertrophyfollowingresistanceexerciseismediatedthroughPGC-1a4remainsamatterofdebate.

Skeletalmusclefromendurance-andstrength-trainedindivid-ualsrepresentsdiverseadaptivestates(Figure4).Thus,itishardlysurprisinglythatsimultaneouslytrainingforbothenduranceandstrengthresultsinacompromisedadaptationcomparedwithtrainingforeitherexercisemodalityalone(Hick-son1980),aphenomemonknownasthe‘‘interferenceeffect.’’Theseobservationsmademorethan30yearsago(Hickson1980)raisedthepossibilitythatthegeneticandmolecularmechanismsofadaptationinducedbyenduranceandresis-tancetrainingaredistinct,witheachmodeofexerciseactivatingand/orrepressingspeci?csubsetsofgenesandcellularsignalingpathways.Preliminaryevidenceforselectiveactivationand/ordownregulationoftheAMPK-PGC-1aorAkt-mTORsignalingpathwayswasreportedinrodentskeletalmuscleinresponsetoeitherlow-frequency(tomimicendurancetraining)orhigh-frequency(tomimicresistancetraining)electricalstimu-lationinvitro(Athertonetal.,2005).However,inwell-trainedhu-mans,littleevidenceexistsforanAMPK-Akt‘‘masterswitch.’’Usinghighlytrainedathleteswithahistoryofeitherenduranceorstrengthtrainingwhoperformedbothanacuteboutofexerciseintheirspecializeddisciplineandthen‘‘crossedover’’andundertookaboutofunfamiliarexercise,ahighdegreeof‘‘responseplasticity’’isconservedatoppositeendsoftheendurance-hypertrophicadaptationcontinuum(Coffeyetal.,2006).Giventhatgenotypeswereoriginallyselectedtosupportdiversephysicalactivitypatternsobligatoryforhumansurvivalandthatmoderndaysuccessinmanysportingendeavors

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requiresahighendurancecapacitycoupledwithsuperiorexplo-sivepower,theconservationofmultiplesignalingnetworkstomeetdivergentphysiologicaldemandsseemstomakesoundevolutionaryandbiologicalsense!

SpreadingtheMessage:SkeletalMuscleCrosstalk

Morethan50yearsago,Goldsteinproposedthatskeletalmus-clecellspossesseda‘‘humoral’’factorthatcontributedtothemaintenanceofglucosehomeostasisduringexercise(Gold-stein,1961).Duringthepastdecade,skeletalmusclehasbeencon?rmedasanendocrineorgan.Cytokinesandotherpeptidesthatareexpressed,produced,expressed,and/orreleasedbymuscle?bersandexerttheirautocrine,paracrine,orendocrineeffectsarenowclassi?edas‘‘myokines’’(Pedersenetal.,2003).The?ndingofmuscle‘‘crosstalk’’withotherorgans,includingadiposetissue,liver,pancreas,bone,andthebrain,providesaframeworkforunderstandinghowexercisemediatesmanyofitsbene?cial‘‘whole-body’’effects.Althoughsomemy-okinesexerttheiractionsonotherorgansinanendocrinefashion,manyoperatelocallyonskeletalmuscleandtherebyprovideafeedbackloopforthemuscletoregulateitsowngrowthandregenerationforadaptationtoexercisetraining.The?rstcytokinefoundtobereleasedintothebloodstreaminresponsetomusclecontractionwasinterleukin6(IL-6).HumanskeletalmuscleisuniqueinthatitcanproduceIL-6duringexer-ciseindependentlyoftumornecrosisfactor,suggestingthatmuscle-derivedIL-6hasaroleinmetabolismratherthaninin?ammation.IL-6increasesbothmuscleandwhole-bodyratesoflipidoxidation(possiblythoughactivationofAMPK)andalsocontributestohepaticglucoseproductionduringexercise.

Contractingmuscle?bersproducemanycirculatingfactors.ThecurrentlistofpotentialmyokinesincludesbutisnotlimitedtoIL-8,IL-15,decorin,follistatin-like1,?broblastgrowthfac-tor-21(FGF21),irisin,chemokineCXCmotifligand-1(CXCL-1)alsoknownasKC(keratinocyte-derivedchemokine),andmete-orin-like(Metrnl)(Bostro

¨metal.,2012;Raoetal.,2014;Pedersenetal.,2012;Wrannetal.,2013).Asmall-moleculemyokine,b-aminoisobutyricacid(BAIBA),witheffectsonadiposetissueandliver,hasalsobeendescribed(Robertsetal.,2014).Mostrecently,exercise-inducedalterationsinkynureninemetabolism,mediatedviaincreasedskeletalmusclePGC-1a1expression,in-creaseresiliencetostress-induceddepressioninmice(Agudeloetal.,2014).Althoughthepotentialtherapeuticbene?tsofmus-cle-derivedmoleculesfortreatingobesityandotherinactivity-relateddisordersareappealing,thereislittleclinicalevidenceinhumanstodate.

Can‘‘ExerciseMimetics’’EverReplaceExercise?

Manyoftheadaptiveresponsesofskeletalmuscletoexercisetrainingcanbemimickedbygeneticmanipulationand/ordrugtreatment,atleastinanimalmodels(Narkaretal.,2008).Conse-quently,giventhenumerousbene?tsofexerciseongeneralhealth,ithasbeenstatedthat‘‘theidenti?cationofgeneticand/ororallyactiveagentsthatmimicorpotentiatetheeffectsofenduranceexerciseisalongstandingalbeitelusivemedicalgoal’’(Narkaretal.,2008).Recognizingtheprovenbene?tsofexercisetrainingonhealthoutcomesandthetrendtowardincreasinginactivityatthepopulationlevel,effortsareunderwaytodiscoverorallyactivecompoundsthatmimicorpotentiatetheeffectsofexercisetraining,so-called‘‘exercisemimetics.’’

746Cell159,November6,2014a2014ElsevierInc.

Althoughtheconceptoftakingapilltoobtainthebene?tsofexercisewithoutactuallyexpendinganyenergyhasmassap-pealforalargemajorityofsedentaryindividuals,suchanapproachislikelytofail.Exercisetrainingprovokeswidespreadperturbationsinnumerouscells,tissues,andorgan,conferringmultiplehealth-promotingbene?ts,anditisthemultiplicityandcomplexityoftheseresponsesandadaptationsthatmakeithighlyimprobablethatanysinglepharmacologicalapproachcouldevermimicsuchwide-rangingeffects.Thougha‘‘polypill’’containingseveralagonistsaimedatselectedexercise-inducedtargetsisapossibility,suchanapproachislikelytobeassoci-atedwithmultipleoff-targetandpotentialdeleterioussideeffects.Amoreachievablegoalwillbetoidentifytissue-speci?ctargetsthroughadeeperunderstandingofthemolecularpath-waysactivatedbyexerciseinvariousorgansystems,enablinglimitedaspectsoftheexerciseresponsetobepharmacologi-callymimicked.Althoughsuchagentsmaybeusefuladjuvantsinsomesettings,exerciseitselfremainsthebest‘‘polypill’’toimprovehealthandwellbeing(Fiuza-Lucesetal.,2013).Inouropinion,?ndingwaystomotivatepeopletoadoptandmaintainaphysicallyactivelifestylewillhaveagreaterimpactonindivid-ualandpopulationhealththansearchingforpotentialpharmaco-logicaltreatments.If?ndingorallyactiveexercisemimeticsisreallya‘‘longstanding’’medicalgoal,webelieveitwillcontinuetobeelusiveforreasonsevidentinthisReview.

BeyondtheFinishLine:TheNext40Years

Duringthelast40years,withtheapplicationofmoleculartech-niquestoexercisebiology,multipleandapparentlyredundantmolecularpathwaysengagedinmanykeyacuteandchronicresponsestoexercisehavebeenelucidatedinskeletalmuscleandothertissues.Althoughmajorbreakthroughsintheknowl-edgeofhowexerciseactivatesnumerouscellular,molecular,andbiochemicalpathwayshavebeenwitnessed,directevi-dencelinkingsucheffectstospeci?chealthoutcomesandun-derstandinghowtheseeffectsexerttheirbene?tsindifferentpopulationsremainselusiveandachallengeforfutureresearch.Duringthepasttwodecades,thelong-hypothesizedcrosstalkbetweenmuscleandotherorgansviathereleaseofsubstancesbythecontractingmuscleshasbeencon?rmed.However,inmanycases,normalresponsesandadaptationstobothacuteexerciseandchronicexercisetrainingcanbeseenwhenoneormorekeypathwaysareabsent,areblockedwithdrugs,orareotherwiseattenuated.Thisbiologicalredundancyindicatesthatperhapstheonlyobligatoryresponsetoexerciseisthede-fenseofhomeostasisitself.Clearlyabigchallengeforexercisebiologistsinthenext40yearswillbetoconnectdistinctsignalingcascadestode?nedmetabolicresponsesandspeci?cchangesingeneexpressioninskeletalmusclethatoccurafterexercise.Thiswillbecomplicatedbecausemanyofthesepath-waysarenotlinear,but,rather,theyconstituteacomplexnetwork,withahighdegreeofcrosstalk,feedbackregulation,andtransientactivation.Thevarious‘‘omics’’technologiesandtheapplicationofcomputationalandsystemsbiologyap-proachestoproblemsinexercisebiologyshouldfacilitatefutureprogress.

Futureresearchinthe?eldofexercisebiologyrequiresincreasinglysophisticatedapproachestounderstandthecritical

nodesofenergyhomeostasisandhowthesepathwaysaredis-ruptedinanumberofinactivity-relateddisorders.Variousstrainsofmicehavelongbeenusedtoexamineresearchquestionsinexercisebiology.Recentstudiesusingtheworm(Caenorhabdi-tiselegans),?y(Drosophilamelanogaster),andzebra?sh(Daniorerio)indicatethatthese‘‘lower’’metazoansalsopossessuniqueattributesthatcouldprovevaluableinthestudyofmeta-bolicdiseases,includingtheeffectsofexercise/musclecontrac-tion.Detailedcharacterizationoftheknownpathwaysregulatinglowermetazoanenergymetabolismmayaidinidentifyingandcharacterizingnovelcandidategenesforhumandiseasessuchasobesityandtype2diabetesmellitus,andthefunctionofsuchgenesmaybemoreamenabletostreamlinedcharacteriza-tioninlowerorganisms.Althoughtherearelimitationsofeachmodelsystemthatneedtoberecognizedwhendeployingtheseorganismsfortargetvalidationand,ultimately,translationintohumans,theabilitytoperformsophisticatedandmechanisticstudiesindicatesthatsuchanapproachcouldyieldtransforma-tiveresearchoutcomesinthecomingdecades.Inthe?nalanal-ysis,itistheorganism’sphenotypeasawholethatinteractswithandadaptstotheexternalworld.Thestudyofexercisebiologyshowsthattheneedtointegrateobservationsfromgenes,mol-ecules,andcellsinaphysiologicalcontexthasneverbeengreater.

ACKNOWLEDGMENTS

Duringourcareers,wehavebeenfortunatetoworkalongsidesomeofthepi-oneersinthe?eldofexercisebiology,includingDr.DavidL.Costill,Dr.JohnO.Holloszy,andthelateDr.BengtSaltin.WehopethatthisReview,insomesmallpart,doesjusticetoyourlegacies.Duetorestrictionsonthenumberofrefer-ences,wehavebeenunabletoincludeimportantworkbysomeofourpeers,forwhichweapologizeinadvance.

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