title: Effects of R92 mutations in mouse cardiac troponin T are influenced by changes in myosin heavy chain isoform.
abstract: One limitation in understanding how different familial hypertrophic cardiomyopathy (FHC)-related mutations lead to divergent cardiac phenotypes is that such mutations are often studied in transgenic (TG) mouse hearts which contain a fast cycling myosin heavy chain isoform (α-MHC). However, the human heart contains a slow cycling MHC isoform (β-MHC). Given the physiological significance of MHC-troponin interplay effects on cardiac contractile function, we hypothesized that cardiac troponin T (cTnT) mutation-mediated effects on contractile function depend on the type of MHC isoform present in the sarcomere. We tested our hypothesis using two variants of cTnT containing mutations at FHC hotspot R92 (R92L or R92Q), expressed against either an α-MHC or β-MHC background in TG mouse hearts. One finding from our study was that R92L attenuated the length-dependent increase in tension and abolished the length-dependent increase in myofilament Ca(2+) sensitivity only when β-MHC was present. In addition, α- and β-MHC isoforms differentially affected how R92 mutations altered crossbridge (XB) recruitment dynamics. For example, the rate of XB recruitment was faster in R92L or R92Q fibers when β-MHC was present, but was unaffected when α-MHC was present. The R92Q mutation sped XB detachment in the presence of β-MHC, but not in the presence of α-MHC. R92Q affected the XB strain-dependent influence on XB recruitment dynamics, an effect not observed for R92L. Our findings have major implications for understanding not only the divergent effects of R92 mutations on cardiac phenotype, but also the distinct effects of MHC isoforms in determining the outcome of mutations in cTnT.
authors.affiliation: Department of Veterinary and Comparative Anatomy, Washington State University, Pullman, WA 99164, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ford
authors.forename: Ranganath
authors.initials: R
authors.lastname: Mamidi
authors.forename: Jesus
authors.initials: J
authors.lastname: Jimenez
authors.forename: Jil C
authors.initials: JC
authors.lastname: Tardiff
authors.forename: Murali
authors.initials: M
authors.lastname: Chandra
mesh_terms: D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009132:Muscles / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020107:Troponin T / Q000235:genetics*
chemical_list: D020107:Troponin T; D018995:Myosin Heavy Chains