Effects of R92 mutations in mouse cardiac troponin T are influenced by changes in myosin heavy chain isoform

Steven J. Ford, Ranganath Mamidi, Jesus Jimenez, Jil C. Tardiff, Murali Chandra

Research output: Contribution to journalArticle

36 Scopus citations

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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)542-551
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume53
Issue number4
DOIs
StatePublished - Oct 1 2012

Keywords

  • Cardiac troponin T
  • Hypertrophic cardiomyopathy
  • Mutations
  • Myosin heavy chain
  • Transgenic mice

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Effects of R92 mutations in mouse cardiac troponin T are influenced by changes in myosin heavy chain isoform'. Together they form a unique fingerprint.

  • Cite this