title: 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.
abstract: 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 Ca(2+) 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 Ca(2+) 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 (Ca(2+)-sensitivity, cooperativity, k2) are similarly modified by these two FHC associated mutations.
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA. li-wang-1@uiowa.edu
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Priya
authors.initials: P
authors.lastname: Muthu
authors.forename: Danuta
authors.initials: D
authors.lastname: Szczesna-Cordary
authors.forename: Masataka
authors.initials: M
authors.lastname: Kawai
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008962:Models, Theoretical; D009154:Mutation; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism*; D010210:Papillary Muscles / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D018994:Myosin Light Chains; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: Cardiac contractility; Cardiomyopathy; Elementary steps; Myosin regulatory light chain; Sinusoidal analysis