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Myosin‐driven rescue of contractile reserve and energetics in mouse hearts bearing familial hypertrophic cardiomyopathy‐associated mutant troponin T is mutation‐specific
Author(s) -
He Huamei,
Hoyer Kirsten,
Tao Hai,
Rice Ronald,
Jimenez Jesus,
Tardiff Jil C.,
Ingwall Joanne S.
Publication year - 2012
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2012.234252
Subject(s) - missense mutation , troponin complex , sarcomere , troponin t , cardiomyopathy , mutant , biology , myosin , medicine , troponin , mutation , hypertrophic cardiomyopathy , endocrinology , genetics , heart failure , myocyte , microbiology and biotechnology , gene , myocardial infarction
Key points• Familial hypertrophic cardiomyopathy (FHC)‐associated missense mutations in the tail portion of cardiac troponin T (cTnT) lead to a phenotype characterized by an increased cost of cardiac contraction, contractile dysfunction and impaired energetics. • Arginine 92 (R92) in cTnT is a ‘hotspot’ with many FHC‐associated missense mutations; each mutation leads to a clinically distinct cardiomyopathy. Both R92Q and R92L cTnT mutant mouse hearts exhibit the FHC phenotype. • Here we found that genetically remodelling the sarcomere by substituting αα‐myosin heavy chain (αα‐MyHC) with ββ‐MyHC normalizes the increased cost of cardiac contraction, rescuing both contractile dysfunction and energetic abnormalities, in R92Q cTnT mutant hearts, while wild‐type R92 and R92L cTnT mutant hearts were unaffected. • Our results demonstrate that the conformation of the tropomyosin‐binding domain of cTnT induced by each unique amino acid substitution at R92 is a major determinant of sarcomere function.Abstract The thin filament protein troponin T (TnT) is a regulator of sarcomere function. Whole heart energetics and contractile reserve are compromised in transgenic mice bearing missense mutations at R92 within the tropomyosin‐binding domain of cTnT, despite being distal to the ATP hydrolysis domain of myosin. These mutations are associated with familial hypertrophic cardiomyopathy (FHC). Here we test the hypothesis that genetically replacing murine αα‐MyHC with murine ββ‐MyHC in hearts bearing the R92Q cTnT mutation, a particularly lethal FHC‐associated mutation, leads to sufficiently large perturbations in sarcomere function to rescue whole heart energetics and decrease the cost of contraction. By comparing R92Q cTnT and R92L cTnT mutant hearts, we also test whether any rescue is mutation‐specific. We defined the energetic state of the isolated perfused heart using 31 P‐NMR spectroscopy while simultaneously measuring contractile performance at four work states. We found that the cost of increasing contraction in intact mouse hearts with R92Q cTnT depends on the type of myosin present in the thick filament. We also found that the salutary effect of this manoeuvre is mutation‐specific, demonstrating the major regulatory role of cTnT on sarcomere function at the whole heart level.