title: The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by α- and β-myosin heavy chain isoforms.
abstract: Given the differential impact of α- and β-myosin heavy chain (MHC) isoforms on how troponin T (TnT) modulates contractile dynamics, we hypothesized that the effects of dilated cardiomyopathy (DCM) mutations in TnT would be altered differently by α- and β-MHC. We characterized dynamic contractile features of normal (α-MHC) and transgenic (β-MHC) mouse cardiac muscle fibers reconstituted with a mouse TnT analog (TnTR144W) of the human DCM R141W mutation. TnTR144W did not alter maximal tension but attenuated myofilament Ca(2+) sensitivity (pCa50) to a similar extent in α- and β-MHC fibers. TnTR144W attenuated the speed of cross-bridge (XB) distortion dynamics (c) by 24% and the speed of XB recruitment dynamics (b) by 17% in α-MHC fibers; however, both b and c remained unaltered in β-MHC fibers. Likewise, TnTR144W attenuated the rates of XB detachment (g) and tension redevelopment (ktr) only in α-MHC fibers. TnTR144W also decreased the impact of strained XBs on the recruitment of new XBs (γ) by 30% only in α-MHC fibers. Because c, b, g, ktr, and γ are strongly influenced by thin filament-based cooperative mechanisms, we conclude that the TnTR144W- and β-MHC-mediated changes in the thin filament interact to produce a less severe functional phenotype, compared with that brought about by TnTR144W and α-MHC. These observations provide a basis for lower mortality rates of humans (β-MHC) harboring the TnTR141W mutant compared with transgenic mouse studies. Our findings strongly suggest that some caution is necessary when extrapolating data from transgenic mouse studies to human hearts.
authors: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington; and.
authors: Sampath K
authors: SK
authors: Gollapudi
authors: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona.
authors: Jil C
authors: JC
authors: Tardiff
authors: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington; and murali@vetmed.wsu.edu.
authors: Murali
authors: M
authors: Chandra
mesh_terms: D000818:Animals; D024722:Cardiac Myosins / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D018995:Myosin Heavy Chains / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D020107:Troponin T; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains
keywords: contractile dynamics; dilated cardiomyopathy mutation in cardiac troponin T; myosin heavy chain; thin filament cooperativity