title: The effect of cardiomyopathy mutation (R97L) in mouse cardiac troponin T on the muscle length-mediated recruitment of crossbridges is modified divergently by α- and β-myosin heavy chain.
abstract: Hypertrophic cardiomyopathy mutations in cardiac troponin T (TnT) lead to sudden cardiac death. Augmented myofilament Ca(2+) sensitivity is a common feature in TnT mutants, but such observations fail to provide a rational explanation for severe cardiac phenotypes. To better understand the mutation-induced effect on the cardiac phenotype, it is imperative to determine the effects on dynamic contractile features such as the muscle length (ML)-mediated activation against α- and β-myosin heavy chain (MHC) isoforms. α- and β-MHC are not only differentially expressed in rodent and human hearts, but they also modify ML-mediated activation differently. Mouse analog of human TnTR94L (TnTR97L) or wild-type TnT was reconstituted into de-membranated muscle fibers from normal (α-MHC) and transgenic (β-MHC) mouse hearts. TnTR97L augmented myofilament Ca(2+) sensitivity by a similar amount in α- and β-MHC fibers. However, TnTR97L augmented the negative impact of strained crossbridges on other crossbridges (γ) by 22% in α-MHC fibers, but attenuated γ by 21% in β-MHC fibers. TnTR97L decreased the magnitude of ML-mediated recruitment of crossbridges (ER) by 37% in α-MHC fibers, but increased ER by 35% in β-MHC fibers. We provide a mechanistic basis for the TnTR97L-induced effects in α- and β-MHC fibers and discuss the relevance to human hearts.
authors.affiliation: Department of Integrative Physiology and Neuroscience (IPN), Washington State University, Pullman, WA, USA.
authors.forename: Sampath K
authors.initials: SK
authors.lastname: Gollapudi
authors.affiliation: Department of Integrative Physiology and Neuroscience (IPN), Washington State University, Pullman, WA, USA. Electronic address: murali@vetmed.wsu.edu.
authors.forename: Murali
authors.initials: M
authors.lastname: Chandra
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009200:Myocardial Contraction; D009210:Myofibrils / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013314:Stress, Mechanical; D020107:Troponin T / Q000235:genetics*; D024723:Ventricular Myosins / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D020107:Troponin T; D000251:Adenosine Triphosphatases; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains
keywords: Cardiac troponin T; Hypertrophic cardiomyopathy mutation; Length-mediated activation; Myosin heavy chain; Sudden cardiac death; Thin filament cooperativity