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

Familial hypertrophic cardiomyopathy, FHC, is a clinically heterogeneous, autosomal-dominant disease the cardiac sarcomere leading to extensive remodeling at both the whole heart and molecular levels. remodeling patterns are mutation-specific, a finding that extends to the level of single amino substitutions at the same peptide residue. Here we utilize two well-characterized transgenic FHC models carrying independent amino acid substitutions in the TM-binding region of cardiac troponin T at residue 92. R92Q and R92L cTnT domains have mutation-specific average peptide conformation dynamics sufficient to alter thin filament flexibility and cross-bridge formation and R92 mutant demonstrate mutation-specific temporal molecular remodeling of Ca2+ kinetics and impaired contractility and relaxation. To determine if a greater economy of contraction at the crossbridge level rescue the mechanical defects caused by the R92 cTnT mutations, we replaced the endogenous murine myosin heavy chain (MyHC) with the beta-MyHC isoform. While beta-MyHC replacement rescued the dysfunction in R92Q mice, it failed to rescue the defects in diastolic function common to FHC-associated mutations. Surprisingly, a significant component of the whole heart and molecular contractile in the R92Q mice was due to improvements in Ca2+ homeostasis including SR uptake, [Ca2+](i), amplitude phospholamban phosphorylation. Our data demonstrate that while genetically altering the composition of the heart bearing a thin filament FHC mutation is sufficient to improve diastolic performance is refractory despite improved Ca2+ kinetics. These data reveal a unrecognized role for MyHC isoforms with respect to Ca2+ homeostasis in the setting of remodeling and demonstrate the overall dominance of the thin filament mutation in determining the of diastolic impairment at the myofilament level. (C) 2009 Elsevier Ltd. All rights reserved.