TY - JOUR
T1 - Diversity and similarity of motor function and cross-bridge kinetics in papillary muscles of transgenic mice carrying myosin regulatory light chain mutations D166V and R58Q
AU - Wang, Li
AU - Muthu, Priya
AU - Szczesna-Cordary, Danuta
AU - Kawai, Masataka
N1 - Funding Information:
We thank Ana I. Rojas and Jingsheng Liang (University of Miami) for their excellent technical assistance with transgenic mice and cardiac muscle. This work was supported in part by grants from the National Institutes of Health HL070041 (M.K.); HL108343 , HL071778 and HL090786 (D.S-C.); and the American Heart Association 10POST3420009 (P.M.). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the funding organizations.
PY - 2013/9
Y1 - 2013/9
N2 - Mechanical properties of skinned papillary muscle fibers from transgenic mice expressing familial hypertrophic cardiomyopathy associated mutations D166V and R58Q in myosin regulatory light chain were investigated. Elementary steps and the apparent rate constants of the cross-bridge cycle were characterized from the tension transients induced by sinusoidal length changes during maximal Ca2+ activation, together with ATP, ADP, and Pi studies. The tension-pCa relation was also tested in two sets of solutions with differing Pi and ionic strength. Our results showed that in both mutants the fast apparent rate constant 2πc and the rate constants of the cross-bridge detachment step (k2) were smaller than those of wild type (WT), demonstrating the slower cross-bridge kinetics. D166V showed significantly smaller ATP (K1) and ADP (K0) association constants than WT, displaying weaker ATP binding and easier ADP release, whereas those of R58Q were not significantly different from WT. In tension-pCa study, both D166V and R58Q mutations exhibited increased Ca2+ sensitivity and less cooperativity. We conclude that, while the two FHC mutations have similar clinical manifestations and prognosis, some of the mechanical parameters of cross-bridges (K0, K1) are differently modified, whereas some others (Ca2+-sensitivity, cooperativity, k2) are similarly modified by these two FHC associated mutations.
AB - Mechanical properties of skinned papillary muscle fibers from transgenic mice expressing familial hypertrophic cardiomyopathy associated mutations D166V and R58Q in myosin regulatory light chain were investigated. Elementary steps and the apparent rate constants of the cross-bridge cycle were characterized from the tension transients induced by sinusoidal length changes during maximal Ca2+ activation, together with ATP, ADP, and Pi studies. The tension-pCa relation was also tested in two sets of solutions with differing Pi and ionic strength. Our results showed that in both mutants the fast apparent rate constant 2πc and the rate constants of the cross-bridge detachment step (k2) were smaller than those of wild type (WT), demonstrating the slower cross-bridge kinetics. D166V showed significantly smaller ATP (K1) and ADP (K0) association constants than WT, displaying weaker ATP binding and easier ADP release, whereas those of R58Q were not significantly different from WT. In tension-pCa study, both D166V and R58Q mutations exhibited increased Ca2+ sensitivity and less cooperativity. We conclude that, while the two FHC mutations have similar clinical manifestations and prognosis, some of the mechanical parameters of cross-bridges (K0, K1) are differently modified, whereas some others (Ca2+-sensitivity, cooperativity, k2) are similarly modified by these two FHC associated mutations.
KW - Cardiac contractility
KW - Cardiomyopathy
KW - Elementary steps
KW - Myosin regulatory light chain
KW - Sinusoidal analysis
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U2 - 10.1016/j.yjmcc.2013.05.012
DO - 10.1016/j.yjmcc.2013.05.012
M3 - Article
C2 - 23727233
AN - SCOPUS:84879474456
VL - 62
SP - 153
EP - 163
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
ER -