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InvitedReview
Transforminggrowthfactor-andmyostatinsignalinginskeletalmuscle
HelenD.Kollias1andJohnC.McDermott21DepartmentofNeurology,JohnsHopkinsHospital,Baltimore,Maryland;and2DepartmentofBiology,YorkUniversity,Toronto,Ontario,Canada
KolliasHD,McDermottJC.Transforminggrowthfactor-andmyostatinsignalinginskeletalmuscle.JApplPhysiol104:579–587,2008;doi:10.1152/japplphysiol.01091.2007.—Thesuperfamilyoftransforminggrowthfactor-(TGF-)cytokineshasbeenshowntohaveprofoundeffectson
深度cellularproliferation,differentiation,andgrowth.Recently,therehavebeenmajor生长advancesinourunderstandingofthesignalingpathway(s)conveyingTGF-
运送了解signalstothenucleustoultimatelycontrolgeneexpression.Onetissuethatis
最终potentlyinfluencedbyTGF-superfamilysignalingisskeletalmuscle.Skeletalmuscleontogenyandpostnatalphysiologyhaveproventobeexquisitelysensitive
个体发育totheTGF-superfamilycytokinemilieuinvariousanimalsystemsfrommicetohumans.Recently,majorstrideshavebeenmadeinunderstandingtheroleofTGF-anditscloselyrelatedfamilymember,myostatin,intheseprocesses.Inthisoverview,wewillreviewrecentadvancesinourunderstandingoftheTGF-andmyostatinsignalingpathwaysand,inparticular,focusontheimplicationsofthissignalingpathwayforskeletalmuscledevelopment,physiology,andpathology.myogenesis;Smad;MyoD
hasaremarkablemorphogenicabilitytoANOVERVIEWOFTGF-SIGNALING
原型regenerateandadapttoenvironmentalstimuli.Fundamen-TGF-1ligandisrecognizedastheprototypeofaclassof
tally,skeletalmuscleregenerationistherecapitulationof
multifunctionalgrowthfactorsthatregulatekeyeventsof更新摘要skeletalmuscledevelopmentinapostnatalcontext.Thusanmetazoandevelopment,disease,andrepair(44,45).In1981,understandingoftheregulationofdevelopmentandregen-多细胞动物TGF-effectswerefirstreportedbyRobertsandcolleagues
erationaremutuallyreinforcing.Bothregenerationand(65),whofoundthatTGF-inducedratkidneyfibroblaststodevelopmentofskeletalmuscleareprofoundlysensitivetoproliferate.Sincethen,TGF-hasbeen肾脏foundtohavea
theextracellularmilieu.Inparticular,signaltransductionplethoraofeffects,suchasregulationofcellgrowth,prolifer-pathwaysinitiatedbygrowthfactorssuchasinsulin-likeation,differentiation,adhesion,migration,andapoptosis(re-growthfactor(IGF-1),fibroblastgrowthfactor(FGF),andviewedinRefs.44,46,48).Theseeffectsarehighlycomplextransforminggrowthfactor-(TGF-)exertapotentlevelandsometimesdifficulttoreconcile;however,oneunifying
发挥ofcontrolovermusclegeneexpression.TheroleofthefeatureofTGF-signalingisthatitseffectsareprofoundlyTGF-superfamilyofgrowthfactorsisofconsiderabledependentonthecellcontext.Forexample,TGF-causesinterestsincemanyfacetsofmuscleontogenyandphysiol-increasedproliferationinfibroblasts(65)butinhibitsprolifer-ogyareregulatedbysomeoftheligandsbelongingtothisationinepithelialcells,causesdifferentiationofneuronalcells,
配体细胞活素cytokinesuperfamily.Inparticular,myostatinisofgrowingbutblocks上皮的differentiationinmesenchymalcells(2,18,19,66,
interestsinceithasbeenshowntoexertprofoundeffectson73).Inskeletalmuscle,TGF-superfamilymembershavemuscularityinmice,cattle,andhumans(seeFig.1;Refs.beenshowntohavepotenteffectsonbothmuscledevelopment52,54,68),aswellasotheranimals.TGF-superfamilyandpostnatalskeletalmusclemass.signalingreliesonarelativelyparsimoniouscanonicalpath-TheTGF-superfamilyconsistsofover50structurally
waythatinterdigitateswithparticularaspectsofthehostrelatedligands,manyofwhichfallintothreemajorsubfami-cellmachinerythroughcell-specificprotein:proteininterac-lies:TGF-,bonemorphogenicprotein(BMP),andactivin活化素机制tionsthatallowprecisecellcontext-dependentresponsesto(reviewedinRef.17).Exhaustiveworkonthemolecular
全面theligand.ThisreviewwillfocusonsalientaspectsofcharacterizationoftheTGF-signaltransductionpathwayhas
显著影响TGF-superfamilysignalingthatpertainspecificallytoledtothedelineationofacanonicalsignalingpathwayforall
勾画skeletalmuscle.Informationfromavarietyofstudiesof-TGF-superfamilymembersconsistingofthreemaincompo-feringinsightsintothemoleculareventsofTGF-signalnents(74):1)theligand;2)thereceptors(serine/threonine
transduction,thefunctionofTGF-inculturedmusclekinases);and3)theintracellularmediators(Smads;seeFig.2).cells,andtheeffectsofTGF-inpostnatalskeletalmuscleFortheTGF-,Activin,andBMPsubfamiliessignaltransduc-physiology,willprovidethefoundationofthisreview.tionbeginswiththeligandbindingtoitstypeIIreceptor.The
typeIIreceptorassociateswithitscorrespondingtypeIrecep-tor,forminganactivatedheterotetramericreceptorcomplex,Addressforreprintrequestsandothercorrespondence:J.McDermott,327
Farquharson,4700KeeleSt.,Toronto,Ontario,CanadaM3J1P3(e-mail:whichtransphosphorylatesthetypeIreceptoractivatingthe
latentkinaseactivityofthereceptorcomplex.Theactivatedjmcderm@yorku.ca).
SKELETALMUSCLE
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TGF-ANDMYOSTATINSIGNALINGINSKELETALMUSCLE
Fig.1.Phenotypeofmysotatinnullvertebrates.A:upperforelimbmusclesofwild-typemouse;B:upperforelimbofmousethatismyostatinnull(52);C:bovinewithmyostatinmutation(54);DandE:humanwithmyostatinmutationasaneonate(D)andat7moofage(E;Ref.68).Copyrightpermissions:copyright1997NationalAcademyofSciencesUSA(AandB);reprintedwithpermissionfromMacmillanPublishers(C):Nature;copyright1997(D)and2004(E)MassachusettsMedicalSociety.Allrightsreserved.
receptorcomplexthenphosphorylatesareceptor-regulatedgationofmesodermalprecursorsintheparaxialregionoftheSmadproteinthatoligomerizeswithacommonSmadorembryo,whichformsomites.Thesomitesarecomposedofco-SmadtermedSmad4.TheSmadoligomertranslocatesintothenucleuswhereitinteractswithSmadbindingpartnerstopluripotentcells,ofwhichsomewillbecomemuscleprogen-regulatetranscription(27).TheseSmadbindingpartnersreg-itorcells(33).Thesemyogenicprogenitorcellsgiverisetoulate,inacelltype-specificmanner,subsetsofgenesthatareproliferatingcellsthatarecommittedtothemyogeniclineagetargetgenesofTGF-signaling.AnothergroupofSmads,termedmyoblastsandarederivedfromthemyotomecompart-inhibitorSmads(Smad6andSmad7)servetoabrogateTGF-mentofthesomite(33).Proliferatingmyoblastssubsequentlysignalingbyestablishinganautoinhibitoryfeedbackloop.
undergodifferentiation,aprocessthatincludeswithdrawalfromthecellcycle,expressionofmuscle-specificgenes,andSKELETALMUSCLEDEVELOPMENTANDREGENERATION
fusionresultingintheformationofmultinucleatedmyotubes.MyotubeseventuallygiverisetothevastarrayofmusclefibersBriefly,skeletalmuscleontogenyiscomprisedofthreethatareusedtoconstructthecomplexskeletalmusclearchi-developmentalstages:1)determination,2)differentiation,andtectureoftheanimal.Therearetwotypesofmyoblasts,3)maturation(Fig.3).Determinationbeginswiththeaggre-
embryonicandfetal.Mostembryonicmyoblastsdifferentiate
Fig.2.Overviewofthecanonicaltransforminggrowthfactor(TGF)-pathway.TheTGFsuper-familymember(ligand)bindstothetypeIIandtypeIreceptors.ThetypeIIreceptorthentransphosphorylatesandactivatesthetypeIrecep-tor.ThetypeIreceptorphosphorylatesreceptor-boundSmads(R-Smads),allowingthemtointer-actwithSmad4,andthiscomplextranslocatesintothenucleus.TheternarySmadcomplex(R-SmadsandSmad4)thencontributestohigherordercomplexeswithtranscriptionfactorsandcofactorsthatregulatetargetgenetranscriptions.AdaptedfromRef.44.
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Fig.3.Schematicdiagramdepictingthestatesofskeletalmuscledevelopmentinthemouse.Stagesofskeletalmuscledevelop-ment:1)determination;2)differentiation(embryonicandfetal);and3)maturation.Determinationendswiththeformationofthemyotomefromthedermomyotome.Embry-onicmyoblastsdifferentiateandfusetoformprimarymusclefibers.Fetalmyoblaststhenundergodifferentiationtoformsecondaryfibersthatsurroundtheprimaryfibers(13,33).Dpc,dayspostconceptioninthemouse.
andfusetoformprimarymusclefibers,butsomecontinuetorestrictedroleinskeletalmuscledevelopment,musclemassproliferateandbecomefetalmyoblasts.Thesefetalmyoblastsregulation,andadiposetissue.Theelucidationoftheroleofformsecondaryfibers,smallerthantheprimaryfibers,whichTGF-surroundtheprimaryfibers(13).Fetalmyogenesisismore1inskeletalmusclebeganinexperimentsusingculturedmusclecellsinvitro,whiletheunderstandingoftheroleofsimilartopostnatalmuscleregenerationthanembryonicmyo-myostatinbeganinvivothroughgenetargetingexperimentsingenesis.Postnatally,myotubesmatureintomusclefibers.Intheadult,skeletalmuscleregenerationbeginswithquiescentmice.Thesetwodifferentstartingpointsledtodifferentsatellitecells,locatedbetweenthebasallaminaandthesarco-insightsintotheroleoftheseinterrelatedpathways.TGF-1islemmaofthemusclefiber,thatbecomeactivatedbytrauma,bethearchetypalcytokineofthissuperfamilyandmuchoftheitmechanicalorbiological(e.g.,disease).RecentworkhasunderstandingofthecomponentsoftheTGF-signalingclassifiedsatellitecellsasaheterogeneouspopulationofcellspathwayhavebeendelineatedbythestudyofTGF-1.Con-comprisedofstemcellsandcommittedprogenitorsbasedonversely,becauseofthepervasivehypermuscularphenotypeofthecombinedPax7andMyf5statusofthecells(32).Oncemyostatinnullmice,myostatinresearchhasfocusedmoreonactivated,satellitecellsproliferate,undergodifferentiation,clinicalapplicationsinskeletalmuscleandlessonthedetailedandthenfusetoanexistingmusclefiberoralternatelycreatebiochemicaldissectionofitscognatesignalingpathway.
fibersdenovo(seereview,Refs.9,26).
Inthelate1980s,severalgroupsmadethreekeyobserva-Twofamiliesoftranscriptionalregulatoryproteinsarecrit-tionsthatenabledtheidentificationofanimportantinvivoroleicalinregulatingdevelopmentalmyogenesis:themusclereg-forTGF-inskeletalmuscledevelopment.First,TGF-isulatoryfactors(MRFs)andthemyocyteenhancerfactor2presentinlargeamountsinthelimbbud,isproducedinthe(MEF2)proteins.MRFmembersareconsideredtheprototypicectoderm,andaffectstheadjacentmesenchymalcells.Second,masterregulatorygenesinskeletalmusclebasedontheirTGF-inhibitsdifferentiationoffetal,butnotembryonic,capacitytoconvertsomenonmyogenicfibroblastcellsintoamyoblasts(80).Last,thetreatmentoflimbbudorganculturesmyogeniccellphenotype(61).MEF2familymembersfunctionwithTGF-neutralizingantibodiesresultsintheprematureasnecessarycoactivatorsfortheMRFsinanevolutionarilyappearanceoflargemyotubes(secondary;Ref.14).TheseconservedancientcodetospecifyskeletalmuscleontogenyobservationssuggestthatTGF-preventsprematuredifferen-(7).BothMRFsandMEF2membershavefunctionalcis-tiationinmigratingmyoblasts,allowingforpropermuscleelementswithinmanyskeletalmuscle-specificpromotersandformationinthedevelopingembryoniclimb.
enhancers(7).
Myostatinwasdiscoveredduringascreenfornovelmam-malianmembersoftheTGF-superfamily(54).ExpressionofROLEOFTGF-ANDMYOSTATININSKELETALmyostatinmRNAisfirstseenatembryonicday9.5postMUSCLEDEVELOPMENT
conceptioninthemyotomeofdevelopingsomitesandcontin-uesthroughoutmuscledevelopment.ThemyostatingeneisSinceitwouldbeuntenabletoconsiderallTGF-ligands,expressedinadultskeletalmuscle,heart,andadiposetissuewewillfocusontheprotypicalTGF-1andmyostatinligands(69).Inadditiontoitsrestrictedpatternofexpression,micebecauseoftheirpotentroleinskeletalmuscle(35,37,38,47).homozygousnullforthemyostatingenearetwotothreetimesTGF-1andmyostatinsignalinginskeletalmuscleinvolvetwolargerinmassthanthewildtypeduetoanenhancedmassofstrikinglysimilarpathways,whichmediatesomeoverlappingthemusculature(Fig.1,AandB).Theincreaseinskeletalandalsomutuallyexclusiveeffects.TGF-1playsanimpor-musclemassisattributedtobothhyperplasia(increaseintantroleinskeletalmuscledevelopmentbutalsoinfluencesmusclefibernumber)andhypertrophy(increaseinmusclefiberdifferenttissuesproducingaplethoraofoutcomes.TGF-1size).Myostatinhomozygousnullmicealsohavereducedactivityisveryspecifictothecellularcontext,thatis,itsstoresofadiposetissue(53,54).Furthermore,heterozygoussignalingoutcomeisdeterminedbytheintracellularmilieuof(ϩ/Ϫ)myostatinmicehavea25%increaseinbodyweight,thecell.ThisduplicitousnatureofTGF-1provestobewhichisalessereffectthanthatseeninthehomozygousnecessaryforitsinvivofunctionsinceitregulatesmanytissues(Ϫ/Ϫ)mice,suggestingadose-dependenteffectofmyostatinandprocesses.Conversely,myostatinplaysamuchmore
proteinlevelsonskeletalmusclemass.Naturallyoccurring
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myostatinmutationsincattle(BelgianBlue,Piedmontese,andleagues(8)showedthatTGF-inhibitedthetranscriptionalMarchigiana)andinhumanshavesubsequentlybeenshownactivityofmyogeninwithoutaffectingitsDNAbindingaffin-alsotoleadtopronouncedhypermuscularity(28,42,54,68;ity.Furthermore,ithasbeenshownthatTGF-Fig.1,C-E).Theconsistencyofthehypermuscularphenotype1targetsthecorrespondingtomyostatinnullmutationacrossspeciesisbasichelix-loop-helix(bHLH)regionofallMRFs,decreasingconsistentwiththeevolutionaryconservationofthemyostatintheirDNAtranscriptionalactivitywithoutaffectingtheirbind-geneandproteinproductbetweenhumans,mice,rats,pigs,ingproperties(43).NotonlydoesTGF-1inhibitthetran-cows,chickens,andturkeys.
scriptionalactivityoftheMyoDproteinitalsoinhibitstheSincebothTGF-transcriptionoftheMyoDgene,thusreducingbothlevelsand1andmyostatinhavebeenshowntoregulatemyogenesisandpostnatalmusclephysiology,acom-activity(76).
parativeanalysisofthetwomayprovideusefulinsightsintoHowdoesTGF-1inhibitmyogenesis?WhatroledoSmad2thecommonanddivergentaspectsoftheintracellularsignalingandSmad3haveinmyogenesis?Inrecentyearsseveralstudiesofthesepathways.TGF-havebeguntoelucidatetheroleofSmad2andSmad3during1signaltransductionbeginswiththeactiveligandbindingtotheTGF-typeIIreceptor(TRII)TGF-1-mediatedmyogenicinhibitionandin“normal”differ-andeitherALK-1(activinlikekinase-1)orTRI/ALK-5entiation(39,62).IthasbeenshownthatSmad3isthekey(TGF-typeIreceptor)receptors.MyostatinsignalingbeginsmediatorofTGF-inhibitionofmyogenesis.Liuandcol-withtheactivemyostatinligandbindingtoeitheractivinleagues(39)showedthatSmad3alone,andnotSmad2,viareceptortypeIIA(ActR-IIA)orActR-IIBandeitherTRI/MyoDinhibitioniscriticalinTGF-signalinginmyoblasts.ALK-5orALK-4,typeIreceptors(63).ThemyostatinligandSmad3wasfoundtophysicallyinteractwithMyoD,inhibitinghasahigheraffinityforActR-IIBinvitro(36,63).BoththetransactivationpropertiesofMyoD.Furthermore,Smad3pathwaysconvergeintheactivationofSmad2andSmad3wasalsoshowntophysicallyinteractwithMEF2Candde-followedbyoligomerizationwithSmad4.Next,theSmadcreaseitstranscriptionalactivity(40).However,therelevancecomplextranslocatesintothenucleus,whereitregulatestran-ofthisbiochemicalinteractioninvivoiscontroversialbecausescriptionofgenessuchasMyoD(39,64).Additionalnon-theMEF2CgeneisnotexpressedinmyoblastsendogenouslySmad-dependentsignalinghasalsobeenimplicatedinTGF-(50),althoughMEF2Cdoesplayaroleinthelatestagesof1effects,althoughthisissofarlesswellcharacterized(51).TodifferentiationandconditionaldeletioninskeletalmusclecounteractTGF-affectssarcomereintegrity(60).
1/myostatinsignaling,repressionofthesig-nalcanbeachievedbytheI-Smads,Smad6andSmad7,oraTheroleofSmad2inTGF-inhibitionofmyogenesisislessubiquitin-mediatedproteasomaldegradationpathwaymediatedclear.UsingmyoblastsDeAngelisetal.(15)reportedthatMEF2,bytheSmad-ubiquitinregulatoryfactors(SMURFS;Ref.5).normallyfoundinthenucleus,translocatestothecytoplasmuponSmad7hasbeenpreviouslyshowntoinhibitbothTGF-TGF-treatment.ForcedexpressionofMEF2CrescuedTGF-1andmyostatinsignaling(31,82).Furthermore,Smad7mayhaveinhibitionbymaintainingapoolofMEF2Cinthenucleus.additionalpro-myogenicfunctions.ArecentstudyfromourFurthermore,endogenousSmad2andMEF2arecomplexedgroup(31)hasshownadramaticenhancementofskeletaltogetherinthenucleiofdifferentiatingmyotubes,butnotinmuscledifferentiationandgrowthbythemyostatinsignalingmyoblasts,whereSmad2iscytoplasmicandwhereMEF2AinhibitorSmad7,whichinteractswithandpotentiatesMyoDand2Carenothighlyexpressed(62).Thusthelinkbetweentranscriptionalactivity.However,althoughSmad7isabletoMEF2andSmad2proteiniscomplexandmaydependontheinhibitTGF-1signaling,asassessedbyaTGF-responsivedifferentiationstatusofthecells.Together,thesedatasuggestpromoter(3TP-lux),itwasnotabletorescueTGF--mediatedthatSmad2isanimportantcomponentofTGF--mediatedinhibitionofmyogenesis.Therefore,considerationofhowtherepressionofdifferentiationinmyoblasts,althoughthepreciseTGF-1/myostatindownstreameffectorsintegratewithmechanismmediatingthiseffectstillrequiresfurthercharac-skeletalmuscle-specifictranscriptionalregulatorstocontrolterization(60).
geneexpressionwillbeparamountinunderstandinghowTGF-inskeletalmuscle:aroleinvivo.Recently,aninthesegrowthfactorsmodulatethemusclephenotypeduringvivoroleforTGF-1inskeletalmuscleregenerationwasdevelopmentandregeneration.
confirmed.Micedeficientinfibrillin-1haveincreasedTGF-signalingactivitythatcausesafailureofskeletalmuscletoTGF-SIGNALINGINSKELETALMUSCLE
regenerate(11).ThesemiceareusedasamodelfortheMarfansyndrome(MFS)inhumans,whichiscausedbyamutationofTGF-repressesskeletalmusclespecificgeneexpressiontheFBN1genethatencodesfibrillin-1(anextracellularmatrixandhasalsobeenreportedtomodulateproliferationinsatelliteprotein).MFSsymptomsincludeboneovergrowth,ocularlenscells(3,12,19,24,47,59).Takentogether,thesestudiesdislocation,emphysema,cardiaccomplications,andaninabil-indicatethatTGF-reprogramsgeneexpressioninmuscleitytoincreaseskeletalmusclemassinresponsetoexerciseandcellsresultinginanalterationofproliferativecontrolandaotherphysiologicalsignals(16).AntagonizingTGF-signal-potentinhibitionoftheprogramofgeneexpressionunderlyingingwithaTGF-neutralizingantibodyorbylosartantreat-myogenicdifferentiation.Askeyorchestratorsofmusclegenementrescuesskeletalmuscleregenerationinthefibrillin-1-expression,theMRFswereshowntobetargetedbyTGF-deficientmice.IncreasedTGF-signalingwasalsofoundinsignaling.Therefore,logicaltargetsofTGF-1arethemyo-theskeletalmuscleofdystrophin-deficientmice,amodelofgenictranscriptionfactors,theMRFsandtheMEF2s,astheDuchennemusculardystrophy,andantagonizingTGF-sig-quintessentialregulatorsofmyogenesis.TheMRFsarecom-nalingrestoredtheregenerationprograminthesemice(11).prisedofMyoD,Myf5,myogenin,andMRF4,whereastheFurthermore,thefibrillin-1-deficientmiceexhibitedincreasedMEF2sincludeMEF2A-D.Tothatend,Brennanandcol-satellitecellnumberswhenTGF-wasantagonized.Thus
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inhibitionofTGF-signalingresultsinanimprovedskeletalincreases,thusdecreasingthetransmissionofforce,aphenom-muscleprofileinseveralgeneticallyinvokedmyopathies.enonpreviouslydescribedbyMaxwelletal.(49).WhiletheInvivostudieshavealsodocumentedthepresenceofTGF-lackofanydifferenceinthesPoofthesoleusmuscleismoreduringmuscleinjury.Muscleinjurycausedbyeccentriccon-difficulttoexplain,onetractions(6),cardiotoxininjection(22),andmusclestrain/ϪpossibilityisthatPointhesoleusmuscleoftheMstnϪcomparedwiththewildtypewasnotinjury(72)resultedinincreasedTGF-transcriptandproteinlargeenoughtoaffectthesPo.Interestingly,followingtwolevelswithin48hofinjury.However,increasesinTGF-1andlengtheningcontractions,theEDLmusclefromtheMstnϪ/ϪTGF-2precursorsdidnotcorrespondinglyleadtoanincreasemicehadagreaterforcedeficiencythanthewildtype.How-inTGF-activityfollowingmusclestrain,suggestingadelayever,nodifferenceinforceproductionwasfoundinthesoleusinTGF-activationafterinjury(72).Furthermore,TGF-muscle.MolecularanalysisrevealedthatthelevelsofActRIIBtypeIreceptorexpressionisregulatedbymyotubeexcitability.intheEDLmuscleweretwiceashighasthoseinthesoleusTRIwasdownregulatedwhenprimaryratmyotubesweremusclesuggestingthatthehigherlevelsofActRIIBintheEDLelectricallystimulatedandupregulatedinadultratmuscle72hmusclecouldprimeitforgreatersensitivitytotheligandafterdenervation(75).Thuscarefuldissectionoftheroleofcomparedwiththesoleusmuscle.
TGF-signalingintheseinvivocontextsiswarrantedtoWhileMendiasetal.(55)havefurtherunderstandtheroleplayedbytheendogenouscytokine./ϪreportedanincreaseinstrengthoftheEDLofMstnϪnullmice,thereissomeNearlythreedecadeshavepassedsincethepotenteffectsofconflictinthisareasinceanotherstudyreportedthatMstnϪ/ϪTGF-onmyogenesiswerefirstreportedandonlyrecentlyhasnullmicedonothaveincreasedPogenerationintheirEDLaninvivoroleforTGF-beguntobeelucidated.Futuremusclecomparedwithwild-typemicedespitetheirlargerstudiesusingtissue-specificgenetargetingandthediscoveryofmusclemass(4).However,consistentwithotherstudies,thenewTGF-pathwaymediatorsmayfurtherelucidatetherolesPointhemyostatin-nullstatewasreducedcomparedwiththatofTGF-inskeletalmuscle.
oftheirwild-typelittermates.Aswell,thePowasslightlyhigherintheEDLmuscleoftheMstnϪ/ϪmicecomparedwithMYOSTATINSIGNALINGINSKELETALMUSCLE
thewild-typemice.FurthercomparisonofthecontractileWhiletherelevanceofTGF-propertiesoftheEDLmusclefromMstnϪ/Ϫandwild-type1invivohasjustbeguntobeunderstood,theinvivoimportanceofmyostatinwasobviousmiceexhibiteddifferencesϪinsingletwitchcharacteristics.fromtheearlyphaseofitsdiscovery.However,characteriza-EDLmusclefromMstnϪ/micecontractedandrelaxedfastertionoftheintracellularsignalingpathwayformyostatinisstillduringasingletwitch(4).
initsinfancy.MuchofwhatisknownhasbeeninferredbyAgreaterproportionoftypeIIbfibersintheMstnϪ/ϪmiceknowledgeoftheTGF-signalingpathwaybuttheremaystillcanexplaintheshortercontractionandrelaxationtimesre-besomesurprisestounfoldsincestudiesarenowidentifyingported.AssessedϪ/byϪmyosinheavychain(MHC)isoformdifferencesinTGF-expression,MstnmicehadlessIIaandIIxfibersinEDL,1andmyostatinsignaling(31).
Myostatin:aroleinvivo.Myostatinnullmice(MstnϪ/Ϫ)buthadmoreIIbfibersthanthewild-typemice(4,21).Inthehaveprovedtobeanexcellentmodelforunderstandingthesoleusmuscle,MstnϪ/ϪmicehadlessIIamRNA,butmoreIIxgeneticroleofmyostatinduringbothmuscledevelopmentandandIIbmRNAthanthewildtype,althoughthischangeatthepostnatalmusclephysiology(52).InadditiontoalterationsinmRNAlevelneedstobeconfirmedattheproteinlevel.musclemass,changesinfibercontractileproperties,fibertype,However,functionalassessmentusingATPasestainingandandfiberrecoveryhavenowbeenreportedinthisgeneticsuccinatedehydrogenase(SDH)activitydidconfirmashiftmodel(4,55,79).
towardmorefastfibersandglycolyticfibers,respectively(21).InadditiontotheincreasedmusclemassanddecreasedfatinTheanalysisofoxidativeenzymesintheEDLmusclereportedtheMstnϪ/Ϫmicetherearealsocorrespondingincreasesinadecreaseinmitochondrialenzymes,SDH,cytochromeoxi-strengthandchangesinfibertypedistributionwithashiftdase(COX),andNADHreductase,intheMstnϪ/ϪmicetowardthetypeconsistentwiththeshifttofastglycolyticIIbfibers.Further-Ϫ/ϪIIbfibers.Furthermore,thecontractileprop-ertiesofMstnmicedifferedfromheterozygous(Mstnϩ/Ϫ)more,thenumberofmitochondriaperunitareawasreduced.andwild-typemice(55).InphysiologicalstudiesofskeletalTakentogetherthesedatasuggestthatmodificationofmusclederivedfromthemice,theextensordigitorumlongusmyostatinlevelsdoesalteradultmusclecontractileproperties.(EDL)muscleandthesoleusmuscleareoftenusedasindica-Reducedmyostatinlevelshavebeenshowntobepotentiallytorsoffasttwitchandslowtwitchmusclefibers,respectively.beneficialinagingmuscle.ComparingolderMstnϪ/ϪϪmice/Ϫ(24Invitrocontractilemo)toolderwild-typemiceitwasshownthatMstnmice/ϪanalysisofEDLandsoleusmusclesfromwild-type,Mstnϩ,andMstnϪ/Ϫmicerevealedthatthemax-hadlessIIbfibersandsizelossescomparedwithwild-typemice(70).Geneticremovalofmyostatinfromconceptionimumtetanicforce(Po)intheEDLmuscleandsoleusmuscleexhibitsprofoundeffectsonmusclemassandfibertype,butwasgreaterintheMstnϪ/Ϫthaninthewild-typeanimals(55).anotherextantquestionconcernswhetherpostnatalmyostatinAdditionally,thespecificmaximumtetanicforce(sPo;cor-repressioncanalsohavethesameeffects.ReducingmyostatinrectedϪ/forϪcrosssectionalarea,N/mm2)wasreducedintheinmicepostweaningthroughtheuseofmyostatinneutralizingMstncomparedwiththewild-typeEDLmuscle.However,antibodies,orbypostnatalconditionalgenetictargeting,alsointhe/Ϫsoleus,nodifferencewasfoundinthesPooftheleadstoincreasedmusclemass(77–79).DependingontheMstnϪcomparedwithmicewiththewild-typegenotype.Inlengthoftreatmentandtheageofthemicethereisa10–30%thecaseoftheEDLmuscle,thephenomenonofdecreasedsPoincreaseinmusclemasswithneutralizingantibodies(77).withincreasedPooccursbecauseasthewholemusclecrossWhittemoreandcolleagues(79)reportedthatmicetreatedwithsectionalareaincreasestheangleofpennationbymusclefibers
neutralizingantibodieshadincreasedskeletalmusclemassand
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increasedgripstrength.Critically,thiswasthefirststudyinmyostatinasanegativeregulatoroffibersize.However,thepostnatalanimalstoshowthatrepressingmyostatinsignalingdecreaseinmyostatinmRNAduringrunningismoredifficultnotonlyincreasesmusclemassbutalsoenhancesfunctionaltoreconcileasonewouldexpectmyostatinlevelstoincreasemusclestrength.Recently,postnatalconditionalgenetictarget-withthisperturbation.
ingofmyostatinalsoshowedincreasemusclemass(78).OlderApossiblemechanismforexercisemodulationofmyostatinmicethathaveceasednormalmusclegrowthalsorespondtomRNAmaybethroughcalcium-dependentsignalingviacal-myostatinrepressionwithincreasedmusclemassbuttoalessercineurin.Calcineurinisacalcium-dependentphosphatasethatdegree.Additionally,short-terminhibitionofmyostatininhasbeenshowntoplayakeyroleinthecontrolofmusclegeneagedmice(14–16mo)enhancedmuscleregenerationandexpressionbyitsregulationofthenuclearfactorofactivatedactivatedsatellitecellactivation(71).Sinceoldermiceretaintranscription(NFAT)transcriptionalregulator(10).Myostatinthecapabilitytorespondtomyostatinrepressionwithin-creasedmusclemassitistantalizingtoconsiderthepossibilitymRNAwasreducedinmouseplantarismusclethatwasover-oftreatingsarcopenia,age-relatedlossofmusclemassandloaded.However,whencalcineurinisinhibitedthroughtheusestrength,byinhibitingmyostatin.ThesefindingsindicatethatofcyclosporinA,myostatinmRNAwasmaintainedatnormalrepressionofmyostatincouldprofferatreatmentforsarcope-levels,suggestingthatcalcineurinmayplayapotentiallyim-nia.Furthermore,inhibitingthemyostatinpathwayusingtheportantroleintheregulationofmyostatinlevelsduringiSmadscouldbeanotherpotentiallytherapeuticstrategyformuscleremodeling(56,57).Furthermore,expressionofmaintainingmusclemassinageinganimals.
constitutivelyactivatedcalcineurinintransgenicmicere-Inconcertwiththefunctionalconsequenceoflossofmyo-sultsinhigherlevelsofmyostatinmRNAlevels(56).Instatinsignaling,whenmyostatinsignalingisincreased,miceaddition,anumberofexperimentalmanipulationsthatresultundergoapredictedseveremuscleloss.Inexperimentsininreducedlevelsofcalcineurinactivity,suchascalmodu-whichmiceweresystemicallyadministeredmyostatin,pro-lin-bindingprotein(CaMBP)-overexpressingmice,parvalbu-nouncedskeletalmusclelosswasobserved(83).Thesemicemin-overexpressingmice,andNFATc2nullmicealsoexhib-exhibitedsymptomssimilartothoseofcachexia,whichoccursitedreducedmyostatinmRNAlevels(56).Collectively,theseinmanydiseasestatessuchascancer,heartfailure,AIDS,anddataclearlyindicateaconnectionbetweencalcineurinactivitysepsis.ThusitisnowbecomingclearthatmyostatinhastheandmyostatinmRNAlevels.
capacitytoactasaspecificandpotentnegativeregulatorofThenextand,probably,mostimportantquestiontoaddressskeletalmusclemassduringdevelopment,whichisalsopar-iswhetherthealterationinmyostatinlevelsisfundamentaltoalleledinpostnatalskeletalmuscle.
theadaptationofthemuscleinthesecontexts.ThequestionasRecently,severalstudieshaveimplicatedmodulationoftowhethermyostatinlevelsarefunctionallylinkedtomusclemyostatinmRNAlevelsinresponsetoalteredfunctionalde-performanceisindeedintriguing.Arecentstudysuggeststhatmandimposedbyexercisetraining.Itisclearthatresistanceitmaybe,basedontheobservationthatinaparticularbreedoftrainingrepressesmyostatinmRNA.Long-termresistanceracingdogs(whippets),performancecharacteristicswerecor-trainingreducesmyostatinlevelsinrodentsandhumans(20,relatedwithamutationinthemyostatingeneinthatthedogs67).Anacuteboutofresistanceexercisealsoinhibitsmyosta-withthemutationarefasterthanthosewiththewild-typealleletinmRNAexpressioninrodentsandhumans(25,29).Further-(58).Thisisthefirstreportofmyostatingenemutationleadingmore,resistancetrainingmitigatesatrophyandincreasesintoenhancedathleticperformance.Althoughincreasedmusclemyostatincausedbyskeletalmuscleunloadinginrodents(1).massandstrengthinmyostatinnullanimalsisfirmlyestab-Interestingly,hypertrophiccapabilityofanindividualhadnolished,therehasbeenlittleevidencetodatethatitnecessarilyimpactonthelevelofmyostatinreductioncausedbyresistancetranslatestoincreasedathleticperformance.Withregardtothisexercise(30).Thusbothlong-termandacuteresistancetrain-issue,whippetsheterozygousforamutantcopyofmyostatininginhibitmyostatinmRNAexpression.However,individuals(mh/ϩ)aremoremuscularthannormalwhippets,ϳ20%morewithgreaterhypertrophyinresponsetotrainingdidnotmass/heightcomparedwithnormals,andareamongthefastest,concomitantlyhavethelowestlevelsofmyostatin.
asdeterminedbytheirracinggrade.Interestingly,whippetsTheeffectofsubmaximalintensityrunningexerciseonhomozygousforthemutantcopyofmyostatin(mh/mh)aremyostatinmRNAlevelshasalsobeenreported(41).Acuteconsiderablymoremuscular(60%moremass/height)com-boutsofbothresistanceexercise(3setsof10paredwithnormalwhippets,butwerenotasfastasthe70%1RM)andsubmaximalrunning(75%V
˙repetitionsat
heterozygousdogs.ThusitisimportanttoconsiderthattheO2maxfor30min)reducedmyostatinmRNAlevelsinyounguntrainedpartici-balancebetweenmusclemassandmuscularperformancemaypants.Postexercisetimepointscomparingthetwomodesofbemoreoptimalintheheterozygousratherthanthehomozy-acuteexerciseshowedthatresistanceexercisehasamoregousnullstate.
pronouncedandlongersuppressionofmyostatin.Resistanceexercisereducedmyostatinoversixfoldfor23h(1–24hFUTUREPERSPECTIVES
postexercise)whilesubmaximalrunningdecreasedmyostatinRepressingTGF-andmyostatinsignalinginmusclecouldoverthreefoldfor3h(8–12hpostexercise).Myostatinexpres-havepotentialtherapeuticapplicationssincebothTGF-andsionissuppressedbybothresistanceexerciseandrunning,butmyostatinactivityareelevatedinavarietyofclinicalcondi-withtheformerbeingamuchmorerobustsuppressor.Thustionsassociatedwithmuscleloss.IncreasedTGF-signalingthesedataimplicateaninversecorrelationbetweenexerciseinmicedeficientinfibrillin-1haveimpairedskeletalmuscletrainingandmyostatinmRNAlevelsinavarietyofexerciseregeneration(11).Acorrelationbetweenenhancedmyostatinregimens.DecreasesinmyostatinmRNAlevelsinresponsetolevelsandmuscleatrophyhasalsobeenobservedinAIDSresistanceexerciseareconsistentwiththeknownroleof
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