Cardiac myosin heavy chain isoform exchange alters the phenotype of cTnT-related cardiomyopathies in mouse hearts

Ron Rice, Pia Guinto, Candice Dowell-Martino, Huamei He, Kirsten Hoyer, Maike Krenz, Jeffrey Robbins, Joanne S. Ingwall, Jil C. Tardiff

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Familial hypertrophic cardiomyopathy, FHC, is a clinically heterogeneous, autosomal-dominant disease of the cardiac sarcomere leading to extensive remodeling at both the whole heart and molecular levels. The remodeling patterns are mutation-specific, a finding that extends to the level of single amino acid substitutions at the same peptide residue. Here we utilize two well-characterized transgenic FHC mouse models carrying independent amino acid substitutions in the TM-binding region of cardiac troponin T (cTnT) at residue 92. R92Q and R92L cTnT domains have mutation-specific average peptide conformation and dynamics sufficient to alter thin filament flexibility and cross-bridge formation and R92 mutant myocytes demonstrate mutation-specific temporal molecular remodeling of Ca2+ kinetics and impaired cardiac contractility and relaxation. To determine if a greater economy of contraction at the crossbridge level would rescue the mechanical defects caused by the R92 cTnT mutations, we replaced the endogenous murine α-myosin heavy chain (MyHC) with the β-MyHC isoform. While β-MyHC replacement rescued the systolic dysfunction in R92Q mice, it failed to rescue the defects in diastolic function common to FHC-associated R92 mutations. Surprisingly, a significant component of the whole heart and molecular contractile improvement in the R92Q mice was due to improvements in Ca2+ homeostasis including SR uptake, [Ca2+]i amplitude and phospholamban phosphorylation. Our data demonstrate that while genetically altering the myosin composition of the heart bearing a thin filament FHC mutation is sufficient to improve contractility, diastolic performance is refractory despite improved Ca2+ kinetics. These data reveal a previously unrecognized role for MyHC isoforms with respect to Ca2+ homeostasis in the setting of cardiomyopathic remodeling and demonstrate the overall dominance of the thin filament mutation in determining the degree of diastolic impairment at the myofilament level.

Original languageEnglish (US)
Pages (from-to)979-988
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Issue number5
StatePublished - May 2010


  • Ca kinetics
  • Cardiac Troponin T
  • Cardiac relaxation
  • Contractile performance
  • Familial Hypertrophic Cardiomyopathy
  • Myosin heavy chain Isoforms

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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