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

Abstract

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 Ca(2+) 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 alpha-myosin heavy chain (MyHC) with the beta-MyHC isoform. While beta-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 Ca(2+) 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 Ca(2+) kinetics. These data reveal a previously unrecognized role for MyHC isoforms with respect to Ca(2+) 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.

• Authors: Ron Rice, Pia Guinto, Candice Dowell-Martino, Huamei He, Kirsten Hoyer, Maike Krenz, Jeffrey Robbins, Joanne S Ingwall, Jil C Tardiff
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 48 Issue 5 Pg. 979-88 (May 2010) ISSN: 1095-8584 [Electronic] England
• PMID: 20004663 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Chemical References

• Protein Isoforms
• Troponin T
• Myosin Heavy Chains
• Calcium

Topics

• Animals
• Blotting, Western
• Calcium (metabolism)
• Cardiomyopathy, Hypertrophic, Familial (metabolism)
• Heart Ventricles (cytology)
• Humans
• In Vitro Techniques
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myofibrils (metabolism)
• Myosin Heavy Chains (genetics, metabolism)
• Phosphorylation
• Protein Isoforms (metabolism)
• Sarcomeres (metabolism)
• Troponin T (genetics, metabolism)