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ISBN:978-0-12-803991-5 ISSN:1877-1173 ForinformationonallAcademicPresspublications visitourwebsiteatstore.elsevier.com CONTRIBUTORS NadiaAgha DepartmentofHealthandHumanPerformance,LaboratoryofIntegratedPhysiology, UniversityofHouston,Houston,Texas,USA JacobAllen DepartmentofKinesiologyandCommunityHealth,UniversityofIllinoisatUrbana- Champaign,Urbana,Illinois,USA PhilipJ.Atherton MRC-ARUKCentreofExcellenceforMusculoskeletalAgeingResearch,Clinical, MetabolicandMolecularPhysiology,UniversityofNottingham,RoyalDerbyHospital Centre,Derby,UnitedKingdom FrankW.Booth DepartmentofBiomedicalSciences;DepartmentofNutritionandExercisePhysiology; DepartmentofMedicalPharmacologyandPhysiology,andDaltonCardiovascularResearch Center,UniversityofMissouri,Columbia,Missouri,USA MarniD.Boppart DepartmentofKinesiologyandCommunityHealth,andBeckmanInstituteforAdvanced ScienceandTechnology,UniversityofIllinois,Urbana,Illinois,USA ClaudeBouchard HumanGenomicsLaboratory,PenningtonBiomedicalResearchCenter,BatonRouge, Louisiana,USA HeatherCarter MuscleHealthResearchCentre,SchoolofKinesiologyandHealthScience,York University,Toronto,Ontario,Canada ChrisChen MuscleHealthResearchCentre,SchoolofKinesiologyandHealthScience,York University,Toronto,Ontario,Canada MatthewJ.Crilly MuscleHealthResearchCentre,SchoolofKinesiologyandHealthScience,York University,Toronto,Ontario,Canada MichaelDeLisio DepartmentofKinesiologyandCommunityHealth,UniversityofIllinois,Urbana,Illinois, USA ChristianA.Drevon DepartmentofNutrition,InstituteofBasicMedicalSciences,FacultyofMedicine, UniversityofOslo,Oslo,Norway KristinEckardt DepartmentofNutrition,InstituteofBasicMedicalSciences,FacultyofMedicine, UniversityofOslo,Oslo,Norway xiii xiv Contributors Ju¨rgenEckel Paul-Langerhans-GroupforIntegrativePhysiology,GermanDiabetesCenter(DDZ), Auf‘mHennekamp,andGermanCenterforDiabetesResearch(DZDe.V.),Du¨sseldorf, Germany BrianS.Ferguson DepartmentofBiomedicalSciences,UniversityofMissouri,Columbia,Missouri,USA NuriaGaratachea FacultyofHealthandSportScience,UniversityofZaragoza,Huesca,Spain LaurieJ.Goodyear SectiononIntegrativePhysiologyandMetabolism,JoslinDiabetesCenter,andDepartment ofMedicine,Brigham,andWomen’sHospital,HarvardMedicalSchool,Boston, Massachusetts,USA RachelGraff DepartmentofHealthandHumanPerformance,LaboratoryofIntegratedPhysiology, UniversityofHouston,Houston,Texas,USA SvenW.Go€rgens Paul-Langerhans-GroupforIntegrativePhysiology,GermanDiabetesCenter(DDZ),Auf‘m Hennekamp,Du¨sseldorf,Germany AnthonyC.Hackney DepartmentofExerciseandSportScience;DepartmentofNutrition,GillingsSchoolof PublicHealth,andCurriculuminHumanMovementScience,DepartmentofAlliedHealth Sciences,UniversityofNorthCarolina,ChapelHill,NorthCarolina,USA GilianF.Hamilton DepartmentofPsychology,TheBeckmanInstitute,UniversityofIllinoisatUrbana- Champaign,Urbana,Illinois,USA MarkHargreaves DepartmentofPhysiology,TheUniversityofMelbourne,Melbourne,Australia KatjaHeinemeier InstituteofBiomedicalSciences,FacultyofHealthandMedicalSciencesandInstituteof SportsMedicine,BispebjergHospital,Copenhagen,Denmark MichaelF.Hirshman SectiononIntegrativePhysiologyandMetabolism,JoslinDiabetesCenter,HarvardMedical School,Boston,Massachusetts,USA DavidA.Hood MuscleHealthResearchCentre,SchoolofKinesiologyandHealthScience,York University,Toronto,Ontario,Canada JørgenJensen DepartmentofPhysicalPerformance,NorwegianSchoolofSportSciences,Oslo,Norway NiklasRyeJørgensen DepartmentofClinicalChemistry,GlostrupHospitalandUniversityofSouthernDenmark, Glostrup,Denmark Contributors xv MichaelKjaer InstituteofSportsMedicine,DepartmentofOrthopedicSurgery,BispebjergHospitaland CentreforHealthyAging,FacultyofHealthandMedicalSciences,Universityof Copenhagen,Copenhagen,Denmark KarstenKru¨ger DepartmentofSportsMedicine,UniversityofGiessen,Giessen,Germany HawleyKunz DepartmentofHealthandHumanPerformance,LaboratoryofIntegratedPhysiology, UniversityofHouston,Houston,Texas,USA Se´verineLamon CentreforPhysicalActivityandNutrition(C-PAN)Research,SchoolofExerciseand NutritionSciences,DeakinUniversity,Burwood,Victoria,Australia AmyR.Lane CurriculuminHumanMovementScience,DepartmentofAlliedHealthSciences, UniversityofNorthCarolina,ChapelHill,NorthCarolina,USA M.HaroldLaughlin DepartmentofBiomedicalSciences;DepartmentofMedicalPharmacologyandPhysiology, andDaltonCardiovascularResearchCenter,UniversityofMissouri,Columbia, Missouri,USA AlejandroLucia EuropeanUniversityandResearchInstituteofHospital12deOctubre(“i+12”),Madrid, Spain S.PeterMagnusson MusculoskeletalRehabilitationResearchUnit,DepartmentofPhysiotherapyandInstituteof SportsMedicine,BispebjergHospital,FacultyofHealthandMedicalSciences,Universityof Copenhagen,Copenhagen,Denmark ChrisMcGlory DepartmentofKinesiology,McMasterUniversity,Hamilton,Ontario,Canada JonathanMemme MuscleHealthResearchCentre,SchoolofKinesiologyandHealthScience,York University,Toronto,Ontario,Canada FrankC.Mooren DepartmentofSportsMedicine,UniversityofGiessen,Giessen,Germany JoramD.Mul SectiononIntegrativePhysiologyandMetabolism,JoslinDiabetesCenter,HarvardMedical School,Boston,Massachusetts,USA RobertC.Noland PenningtonBiomedicalResearchCenter,LouisianaStateUniversity,BatonRouge, Louisiana,USA T.DylanOlver DepartmentofBiomedicalSciences,UniversityofMissouri,Columbia,Missouri,USA xvi Contributors HeliosPareja-Galeano EuropeanUniversityandResearchInstituteofHospital12deOctubre(“i+12”),Madrid, Spain MarionPauly MuscleHealthResearchCentre,SchoolofKinesiologyandHealthScience,York University,Toronto,Ontario,Canada BethanE.Phillips MRC-ARUKCentreofExcellenceforMusculoskeletalAgeingResearch,Clinical, MetabolicandMolecularPhysiology,UniversityofNottingham,RoyalDerbyHospital Centre,Derby,UnitedKingdom StuartM.Phillips DepartmentofKinesiology,McMasterUniversity,Hamilton,Ontario,Canada JustinS.Rhodes DepartmentofPsychology,TheBeckmanInstitute,UniversityofIllinoisatUrbana- Champaign,Urbana,Illinois,USA GregoryN.Ruegsegger DepartmentofBiomedicalSciences,UniversityofMissouri,Columbia,Missouri,USA AaronP.Russell CentreforPhysicalActivityandNutrition(C-PAN)Research,SchoolofExerciseand NutritionSciences,DeakinUniversity,Burwood,Victoria,Australia RichardJ.Simpson DepartmentofHealthandHumanPerformance,LaboratoryofIntegratedPhysiology, UniversityofHouston,Houston,Texas,USA KristinI.Stanford SectiononIntegrativePhysiologyandMetabolism,JoslinDiabetesCenter,HarvardMedical School,Boston,Massachusetts,USA YiSun DepartmentofKinesiologyandCommunityHealth,UniversityofIllinoisatUrbana- Champaign,Urbana,Illinois,USA RyanG.Toedebusch DepartmentofBiomedicalSciences,UniversityofMissouri,Columbia,Missouri,USA ElijahTrefts DepartmentofMolecularPhysiologyandBiophysics,VanderbiltUniversitySchoolof Medicine,Nashville,Tennessee,USA LiamD.Tryon MuscleHealthResearchCentre,SchoolofKinesiologyandHealthScience,York University,Toronto,Ontario,Canada ThomasTsiloulis BiologyofLipidMetabolismLaboratory,DepartmentofPhysiology,MonashUniversity, Clayton,Victoria,Australia Contributors xvii AnnaVainshtein MuscleHealthResearchCentre,SchoolofKinesiologyandHealthScience,York University,Toronto,Ontario,Canada DavidH.Wasserman DepartmentofMolecularPhysiologyandBiophysics,VanderbiltUniversitySchoolof Medicine,Nashville,Tennessee,USA MatthewJ.Watt BiologyofLipidMetabolismLaboratory,DepartmentofPhysiology,MonashUniversity, Clayton,Victoria,Australia DanielJ.Wilkinson MRC-ARUKCentreofExcellenceforMusculoskeletalAgeingResearch,Clinical, MetabolicandMolecularPhysiology,UniversityofNottingham,RoyalDerbyHospital Centre,Derby,UnitedKingdom AshleyS.Williams DepartmentofMolecularPhysiologyandBiophysics,VanderbiltUniversitySchoolof Medicine,Nashville,Tennessee,USA SarahWitkowski DepartmentofKinesiology,SchoolofPublicHealthandHealthSciences,Universityof Massachusetts,Amherst,Massachusetts,USA JeffreyA.Woods DepartmentofKinesiologyandCommunityHealth,UniversityofIllinoisatUrbana- Champaign,Urbana,Illinois,USA ZhenYan DepartmentofMedicine;DepartmentofPharmacology;DepartmentofMolecular PhysiologyandBiologicalPhysics,andCenterforSkeletalMuscleResearch,Universityof Virginia,Charlottesville,Virginia,USA PREFACE ThisvolumeintheseriesProgressinMolecularBiologyandTranslationalScience isdevotedtothemechanismsregulatingmolecularandcellularadaptationto acuteandchronicexerciseinavarietyofsettings.ProgressinMolecularBiology and Translational Science providesa forumfor discussionof new discoveries, approaches, and ideas in molecular biology which is what we aimed for in thedevelopmentofthevolume.Webelievethatitisatimelycontribution toourunderstandingofexercisebiology.Wehavebeenfortunateinbeing able to secure contributions from leading scientists and most major labora- toriesthatareactivelyengagedinthestudyofthemolecularmechanismsat playwhenpeopleandotherlivingorganismsarephysicallyactive.Thepub- licationisparticularlytimelyasitoccursjustafewmonthsaftertheleader- shipoftheNationalInstitutesofHealthannouncedthattheCommonFund of NIH will support a 6-year plan to uncover the molecular transducers of adaptation to physical activity in various tissues and organs. Astheeditorofthevolume,Iamextremelypleasedbythedistinguished panel of authors that was assembled for the publication. Sixty-one authors and coauthors from seven countries have contributed to the volume. I am very grateful for their willingness to participate in this effort. Iwouldliketoexpressmygratitudetothemnotonlyfortheiroutstanding science but also for the timely delivery of their contributions. They have been a delight to work with. Unfortunately, some topics had to be left outduetothepagenumberlimitationbutthevastmajorityoftherelevant topic found a home in the volume. TheleadershipofthePMBTSpublicationseriesandthestaffatElsevier havebeenadelighttoworkwith.IwouldliketoexpressmythankstoDr. Michael Conn, Editor of the PMBTS serial, from Texas Tech University HealthSciencesCenterwhosupportedtheconceptofhavingafullvolume dedicatedtothemolecularbiologyofadaptationtoexercise.Ialsobenefited greatlyfromthesupportofMaryAnnZimmerman,AcquisitionEditor,and HeleneKabes,SeniorEditorialProjectManager,allattheElsevierpublish- inghouse.IalsowanttorecognizethediligentworkofRoshmiJoy,Project Manager in the Book Publishing Division at Elsevier. They were all very supportive at various stages of the development of the publication, and I would like to express my most sincere thanks to them. xix xx Preface Finally, I would not have been able to undertake the task of serving as editorsforthisvolumewithouttheoutstandingandcompetentsupportini- tially of Allison Templet and then later of Robin Post of the Pennington Biomedical Research Center. They worked diligently with each author inordertoensurethattheinstructionswerewellunderstoodbythecontrib- utingauthorsandthattheirmanuscriptsmetalltherequirementsofthepub- lisher.Duringthelastphaseoftheproductionofthevolume,Robinworked diligentlyoncomplexscientificmaterialwithadedicationtoexcellencethat made a difference in our ability to deliver a high-quality volume. I feel greatly indebted to both of them. However, if errors are later discovered in the volume, they are entirely my responsibility. CLAUDE BOUCHARD July 2015 CHAPTER ONE Adaptation to Acute and Regular Exercise: From Reductionist Approaches to Integrative Biology Claude Bouchard1 HumanGenomicsLaboratory,PenningtonBiomedicalResearchCenter,BatonRouge,Louisiana,USA 1Correspondingauthor:e-mailaddress:[email protected] Contents 1. Introduction 2 2. SedentaryTime,PhysicalActivity,andFitness 4 3. Reductionism,SystemsBiology,andIntegrativePhysiology 8 4. GenomicandENCODEFacts:AGoldMineforExerciseBiology 10 5. AbouttheContentoftheVolume 12 6. SummaryandConclusions 13 References 13 Abstract Thischapterservesasanintroductiontothevolumefocusedonthemolecularandcel- lularregulationofadaptationtoacuteandchronicexerciseexposure.Itbeginswitha definition of the overall content of the “sedens–physical activity–exercise training– fitness”domain.Oneconclusionfromthisbriefoverviewisthatpastandcurrentstudies haveprimarilydealtwithverylimitedsubsetsofthetraitsandparametersofinterestto exercisebiologists.Molecularandcellularstudieshavefocusedmoreonadaptationto exerciseandlessonvariablelevelsofcardiorespiratoryfitnesseventhoughthelatterisa powerful indicator of current and future health status and longevity. In this regard, molecular profiling of intrinsic versus acquired cardiorespiratory fitness would seem tobeanareaofresearchdeservingmoreattention.Althoughmolecularandcellular studiesareclearlyreductionistbynature,theyconstitutetheprimarymaterialallowing systemsbiologytodrawinferencesaboutpathways,networks,andsystems.Integrative physiologycanbesubstantiallyenrichedbytakingadvantageofthefindingsandles- sonsfrommolecularstudiesandsystemsbiologyapproaches.DNAsequencevariation withinandbetweenpopulationsaswellasrecentadvancesinthedefinitionofthefunc- tionalelementsinthehumanandothergenomesofferuniqueopportunitiestopursue newandmorepowerfulmolecularstudies,andtoreconcilereductionistandintegrative approaches. ProgressinMolecularBiologyandTranslationalScience,Volume135 #2015ElsevierInc. 1 ISSN1877-1173 Allrightsreserved. http://dx.doi.org/10.1016/bs.pmbts.2015.07.009 2 ClaudeBouchard 1. INTRODUCTION Alltissuesandorgansofthehumanbodyareaffectedbyexercisepar- ticularlywhenitisenergeticallydemandingandsustained.Thereisanabun- dant literature on the metabolic and physiological changes taking place in response to acute endurance, high intensity, and resistance exercise even thoughmuchremainstobelearned.Similarly,thereisagrowingbodyofdata regarding adaptation of tissues, organs, and systems to regular exercise and exercisetraining,particularlywithrespecttoenduranceandresistancetrain- ing.Althoughimpressiveadvanceshavebeenmadeonthegeneraltopicof adaptationtoexercise,therearestillbiggapsinknowledgethatdeserveour attention.Onecriticalgapinthefoundationalbodyofknowledgeofexercise biologyisthelimitedunderstandingoftheuniverseofmoleculartransducers involved in the regulation of adaptation to all forms of acute and chronic exercise and of the molecular pathways and networks associated with the health benefits of being physically active. There are many other gaps in knowledgeandafewareofparticularinterest andarehighlightedhere. Oneblatantweaknessisthatexercisebiologystudiesbyandlargecover only a fraction of the sedens–physical activity–exercise–fitness domain. Figure 1 provides a schematic overview of the multiple dimensions of this domain. Included in the diagram are the sedens–physical activity–exercise training continuum, the fitness traits, the exercise exposure dimensions, Figure1 Schematicdescriptionofthesedentarybehavior,physicalactivitylevel,exer- cise training, and fitness domain with its multiple dimensions and some of its implications.