title: L71F mutation in rat cardiac troponin T augments crossbridge recruitment and detachment dynamics against α-myosin heavy chain, but not against β-myosin heavy chain.
abstract: The N-terminal extension of human cardiac troponin T (TnT), which modulates myofilament Ca2+sensitivity, contains several hypertrophic cardiomyopathy (HCM)-causing mutations including S69F. However, the functional consequence of S69F mutation is unknown. The human analog of S69F in rat TnT is L71F (TnTL71F). Because the functional consequences due to structural changes in the N-terminal extension are influenced by the type of myosin heavy chain (MHC) isoform, we hypothesized that the TnTL71F-mediated effect would be differently modulated by α- and β-MHC isoforms. TnTL71Fand wild-type rat TnT were reconstituted into de-membranated muscle fibers from normal (α-MHC) and propylthiouracil-treated rat hearts (β-MHC) to measure steady-state and dynamic contractile parameters. The magnitude of the TnTL71F-mediated attenuation of Ca2+-activated maximal tension was greater in α- than in β-MHC fibers. For example, TnTL71Fattenuated maximal tension by 31% in α-MHC fibers but only by 10% in β-MHC fibers. Furthermore, TnTL71Freduced myofilament Ca2+sensitivity by 0.11 pCa units in α-MHC fibers but only by 0.05 pCa units in β-MHC fibers. TnTL71Faugmented rate constants of crossbridge recruitment and crossbridge detachment dynamics in α-MHC fibers but not in β-MHC fibers. Collectively, our data demonstrate that TnTL71Finduces greater contractile deficits against α-MHC than against β-MHC background.
authors.affiliation: Department of Integrative Physiology and Neuroscience (IPN), Washington State University, PO Box 647620, 251 Veterinary and Biomedical Research Building, Pullman, WA, 99164, USA.
authors.forename: Sherif M
authors.initials: SM
authors.lastname: Reda
authors.affiliation: Department of Integrative Physiology and Neuroscience (IPN), Washington State University, PO Box 647620, 251 Veterinary and Biomedical Research Building, Pullman, WA, 99164, USA.
authors.forename: Sampath K
authors.initials: SK
authors.lastname: Gollapudi
authors.affiliation: Department of Integrative Physiology and Neuroscience (IPN), Washington State University, PO Box 647620, 251 Veterinary and Biomedical Research Building, Pullman, WA, 99164, USA. murali@vetmed.wsu.edu.
authors.forename: Murali
authors.initials: M
authors.lastname: Chandra
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D009200:Myocardial Contraction / Q000235:genetics; D009210:Myofibrils / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020107:Troponin T / Q000235:genetics*; D024723:Ventricular Myosins / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D020107:Troponin T; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains; D002118:Calcium
keywords: Contractile dynamics; Dilated cardiomyopathy; Hypertrophic cardiomyopathy; Myosin heavy chain; Troponin T