Orai1 Mediates Exacerbated Ca2+ Entry in Dystrophic Skeletal Muscle 英文参考文献.docVIP

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Orai1 Mediates Exacerbated Ca2+ Entry in Dystrophic Skeletal Muscle 英文参考文献.doc

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Orai1MediatesExacerbatedCa2EntryinDystrophicSkeletalMuscle英文参考文献

Orai1MediatesExacerbatedCa2+EntryinDystrophic SkeletalMuscle XiaoliZhao1,2*,JosephG.Moloughney1,SaiZhang1,ShinjiKomazaki3,NoahWeisleder1,4* 1DepartmentofPhysiologyandBiophysics,RobertWoodJohnsonMedicalSchool,Piscataway,NewJersey,UnitedStatesofAmerica,2DivisionofPharmacology,College ofPharmacy,DavisHeartandLungResearchInstitute,TheOhioStateUniversity,Columbus,Ohio,UnitedStatesofAmerica,3DepartmentofAnatomy,SaitamaMedical University,Saitama,Japan,4DepartmentofPhysiologyCellBiology,DavisHeartandLungResearchInstitute,TheOhioStateUniversity,Columbus,Ohio,UnitedStates ofAmerica Abstract ThereissubstantialevidenceindicatingthatdisruptionofCa2+homeostasisandactivationofcytosolicproteasesplayakey roleinthepathogenesisandprogressionofDuchenneMuscularDystrophy(DMD).However,theexactnatureoftheCa 2+ 2+ deregulationandtheCa signalingpathwaysthatarealteredindystrophicmuscleshavenotyetbeenresolved.Herewe examinedthecontributionofthestore-operatedCa entry(SOCE)forthepathogenesisofDMD.RT-PCRandWesternblot 2+ foundthattheexpressionlevelofOrai1,thepore-formingunitofSOCE,wassignificantlyelevatedinthedystrophicmuscles, whileparallelincreasesinSOCEactivityandSRCa2+storageweredetectedinadultmdxmusclesusingFura-2fluorescence measurements. High-efficient shRNA probes against Orai1 were delivered into the flexor digitorum brevis muscle in live miceandknockdownofOrai1eliminatedthedifferencesinSOCEactivityandSRCa2+storagebetweenthemdxandwild type muscle fibers. SOCE activity was repressed by intraperitoneal injection of BTP-2, an Orai1 inhibitor, and cytosolic calpain1activityinsinglemusclefiberswasmeasuredbyamembrane-permeablecalpainsubstrate.WefoundthatBTP-2 injectionfor2weekssignificantlyreducedthecytosoliccalpain1activityinmdxmusclefibers.Additionally,ultrastructural changes were observed by EM as an increase in the number of triad junctions was identified in dystrophic muscles. Compensatory changes in protein levels of SERCA1, TRP and NCX3 appeared in the mdx muscles, suggesting tha