Ourpreviousstudiesidentifiedthecircadianclockcomponentcryptochromes(CRY1andCRY2) asnutrientresponsivetranscriptionalregulatorsbyvirtueoftheirsusceptibilityto phosphorylationbyAMP-activatedproteinkinase(AMPK).Wehavealsodescribedafunctionof CRY1andCRY2asdiurnallyactiverepressorsoftheglucocorticoidreceptor,aprototypical memberofalargefamilyoftranscriptionalregulatorsknownasnuclearhormonereceptors (NRs).NRsarebroadlyimportantinmodulatingmetabolicphysiologyandonememberofthis family,theso-calledperoxisomeproliferatoractivatedreceptordelta(PPAR?)hasbeen establishedasacriticaldriverofexercisecapacity.Wedescribeinourpreliminarydatahere thatCRY1andCRY2canrepressPPAR?andgeneticdeletionofCry1andCry2ubiquitously andthroughoutdevelopmentresultsinenhancedsprintexercisecapacity.Inthecourseofour studies,wehavegenerateduniquetoolsandexpertisethatenableustousebiochemical, genetic,molecularandphysiologicalapproachestofurtherelucidatetherolesofCRY1and CRY2intheregulationofPPAR?andofexercisephysiologyinthefollowingspecificaims:1) DoesskeletalmuscledriveenhancedexercisecapacityinCry1/2-deficientmice?2)Howdoes AMPK-mediatedCRY1phosphorylationimpactexercise?and3)WhatistheimpactofCry1/2 deletionormutationonskeletalmusclecellularmetabolism?Advancingourfunctional understandingoftheseinteractionsmayhighlightnewtherapeuticandregulatorystrategiesfor preventingand/ortreatingdisease.
Physicalexercisereducestheriskofnumerouspathologiesincludingobesity,diabetes,cancer, mentalhealthproblems,andindeedagingitself.Thisprojectinvolvesthestudyofanovel regulatorofexercisecapacitythatisinvolvedinchangingthewaythatmusclesstoreandutilize differentfuelsources.Thus,thisprojectwillcontributetotheknowledgebaseneededforthe developmentoroptimizationoftherapeuticstrategiesoroccupationalhealthandsafety practicestoenablebetterphysicalfitnessandoverallmetabolichealth.
