Skeletal muscle regeneration requiresactivationand proliferationofa resident populationof stemcells known assatellitecells.Satellitecellsarenotonlyrequiredformuscleregenerationafterinjurybutarealsothoughtto contributetoongoingmaintenanceofmusclemass.Unfortunately,thenumberandactivityoftheseprogenitors declines with aging and muscular dystrophy. Therefore, pharmacologic strategies to promote expansion of myogenicsatellitecellscouldpotentiallybeusedtoimprovemuscleregenerationandpreservemusclefunction in individuals with muscle disease or individuals of advanced age. Signaling through the cAMP pathway stimulates myogenic progenitor cell proliferation during embryonic development and is sufficient to stimulate proliferationofthesecellsinvitro.Thispathwayisalsoactivatedduringregenerationinadultmice.However,it is unknown whether cAMP signaling in myogenicprogenitor cells in responseto injury is sufficientto enhance proliferation in vivo. We previously showed that the cAMP-responsive transcription factor CREB isactivated in areasofproliferation after acute muscle injury inmice and that mice expressing an activated mutant of CREB haveenhancedmyoblastproliferationafterinjury.Thisprojectemploysbiochemicalandchemical-genetictools todeterminewhetherchemical-geneticelevationandgeneticregulationofcAMPsignalingspecificallyinsatellite cells alters proliferation and muscle regeneration in vivo through regulation of CREB/CRTC transcriptional complexes. We will interrogate the regulationand function ofcAMP-regulated CREB co-activators (CRTCs) in satellitecellproliferationanduseunbiasedtranscriptomicapproachestoidentifyCREB/CRTCtargetgenesthat contribute to the cAMP-driven proliferative response. We will undertake mechanistic studies to characterize molecular regulation of CRTCs and the mechanism of CRTC recruitment to cAMP-regulated genes in proliferating satellite cells. Results of this project will yield insights into fundamental mechanisms that drive satellitecellproliferationandexpansion.Thelong-termgoalistoidentifynewpharmacologictargetstoimprove muscleregenerationandfunctioninpatientswithmusclediseaseandage-relatedsarcopenia.
The proposed studies will investigate cellular signaling pathways that regulate skeletal muscle stem cell proliferation. Loss of skeletal muscle stem cell capacity is associated with aging and degenerative muscle disease. Identification of the signaling pathways and genes that stimulate muscle stem cell proliferation could revealnewwaystohelpmaintainmusclehealthandfunctionduringaging.
