A Spatially Explicit 3-D Model of the Muscle Sarcomere一个直观的三维模型肌小节

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Cell&Molecular Biomechanics:Dynamics of Ca,2+,Regulation and Muscle Performance,P.Bryant Chase,Florida State University,Dept.of Biological Science and Program in Molecular Biophysics,OSU MBI Workshop 4,Signal Transduction II:Muscle and Synapse,March 11,2004,Gagn,and Sykes,in:,Berchtold et al.,2000,“Blocked,-Ca2+,“Open,+Ca2+,+S1,Time(ms),1A.Ca,2+,modulates isometric force,and,rate of tension(re)development(,k,TR,),Chase,Martyn&Hannon(1994)Biophys.J.67:1994,Skinned muscle fiber,1B.At sub-saturating Ca,2+,k,TR,reflects:(i)properties of TnC,and(ii)dynamics of individual regulatory units,Time(ms),Chase,Martyn&Hannon(1994)Biophys.J.67:1994,Constitutively activated TnC(aTnC),ActoMyosin kinetics predominate,Ca,2+,-regulatory dynamics predominate,Regnier,Martyn&Chase(1996)Biophys J 71:2786,Regnier,Martyn&Chase(1998)Biophys J 74:2005,Regnier et al.(1999)Biophys J 76:2664,Moreno-Gonzalez et al.,in preparation,1C.A simple,dynamic view ofcalcium regulation of tension development,State 1,:,Ca-free,no force,State 3,:,Ca-bound,force,State 2,:,Ca-bound,no force,State 4,:,Ca-free,force,Cross-bridge kinetics,Landesberg&Sideman,1994,Hancock,Huntsman&Gordon,1997,Regnier,Rivera,Chase,Smillie&Sorenson,1999,Ca,2+,/regulatory unit dynamics,2A.Ca,2+,control and cardiovascular disease:Regulated in vitro motility assays,pCa 9(1 nM Ca,2+,),pCa 5(10,m,M Ca,2+,),Mutations in,cTnI,(,a,-Tm,cTnT,)increase Ca,2+,sensitivity,cause hypertrophic cardiomyopathy,Khler et al.(2003)Physiological Genomics 14:117,Wang et al.,in preparation,C-terminal mutations in,cTnI,enhance,filament sliding,To,20,200,2000,20000,2,4,6,8,Thin filament,spring constant,(pN/nm),Cross-bridge,spring constant,(pN/nm),Daniel,Trimble and Chase(1998)Biophys.J.74:1611,3A.Mechanical Tuning Emerged from a 2-D,Two Filament Model with Filament Compliance,UPDATING OUR MODEL OF THE MUSCLE HALF-SARCOMERE WITH FILAMENT COMPLIANCE,OLD(2D,2 filament):,Finite element matrix,Monte Carlo,stochastics,3-state cross-bridge cycle,3 thick filaments(300 heads),13 thin filaments(1,200 sites),mirroring,Ca2+regulation“activation probability,No cooperativity between Ca2+regulatory units,Model output fromChase,Macpherson&Daniel,submittedQuestion:Is there any experimental evidence that myofilament compliance affects muscle function?,Myofilament compliance can explain activation-dependent crossbridge kinetics(rapid tension transients)in muscle fibers,Martyn,Chase,Regnier&Gordon(2002)Biophysical Journal 83:In press,Ca,2+,-activation dependence of rapid tension transient kinetics:model predicts 69%of sarcomere compliance is in the myofilaments,Prediction agrees with structural estimates of filament compliance,Additional experiments show that force,not Ca,2+,is major variable:,AlF,4,-,(,pCa,4)60%,aTnC,(,pCa,9)76%,CONCLUSIONS,Kinetics of muscle tension(re)development reflect dynamics of individual thin filament regulatory units at sub-saturating Ca,2+,Increased contractile Ca,2+,sensitivity is associated with,hypertrophic cardiomyopathy,Myofilament,compliance could modulate isometric and near-isometric force at sub-saturating Ca,2+,and force development kinetics at high Ca,2+,activation,Acknowledgements,University of Washington,Michael Regnier,Don Martyn,Al Gordon,Tony Rivera,Mike Macpherson(Stanford),Alan Trimble,Tom Daniel,