Cardiac troponin T mutations: Correlation between the type of mutation and the nature of myofilament dysfunction in transgenic mice

David E. Montgomery, Jil C. Tardiff, Murali Chandra

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

1. The heterogenic nature of familial hypertrophic cardiomyopathy (FHC) in humans suggests a link between the type of mutation and the nature of patho-physiological alterations in cardiac myocytes. Exactly how FHC-associated mutations in cardiac troponin T (cTnT) lead to impaired cardiac function is unclear. 2. We measured steady-state isometric force and ATPase activity in detergent-skinned cardiac fibre bundles from three transgenic (TG) mouse hearts in which 50, 92 and 6% of the native cTnT was replaced by the wild type (WT) cTnT, R92Q mutant cTnT (R92Q) and the C-terminal deletion mutant of cTnT (cTnTDEL), respectively. 3. Normalized pCa-tension relationships of R92Q and cTnTDEL fibres demonstrated a significant increase in sensitivity to Ca2+ at short (2.0 μm) and long (2.3 μm) sarcomere lengths (SL). At short SL, the pCa50 values, representing the midpoint of the pCa-tension relationship, were 5.69 ± 0.01, 5.96 ± 0.01 and 5.81 ± 0.01 for WT, R92Q and cTnTDEL fibres, respectively. At long SL, the pCa50 values were 5.81 ± 0.01, 6.08 ± 0.01 and 5.95 ± 0.01 for WT, R92Q and cTnTDEL fibres, respectively. 4. The difference in pCa required for half-maximal activation (ΔpCa50) at short and long SL was 0.12 ± 0.01 for the R92Q (92%) TG fibres, which is significantly less than the previously reported ΔpCa50 value of 0.29 ± 0.02 for R92Q (67%) TG fibres. 5. At short SL, Ca2+-activated maximal tension in both R92Q and cTnTDEL fibres decreased significantly (24 and 21%, respectively; P < 0.005), with no corresponding decrease in Ca2+-activated maximal ATPase activity. Therefore, at short SL, the tension cost in R92Q and cTnTDEL fibres increased by 35 and 29%, respectively (P < 0.001). 6. The fibre bundles reconstituted with the recombinant mutant cTnTDEL protein developed only 37% of the Ca2+-activated maximal force developed by recombinant WT cTnT reconstituted fibre bundles, with no apparent changes in Ca2+ sensitivity. 7. Our data indicate that an important mutation-linked effect on cardiac function is the result of an inefficient use of ATP at the myofilament level. Furthermore, the extent of the mutation-induced dysfunction depends not only on the nature of the mutation, but also on the concentration of the mutant protein in the sarcomere.

Original languageEnglish (US)
Pages (from-to)583-592
Number of pages10
JournalJournal of Physiology
Volume536
Issue number2
DOIs
StatePublished - Oct 15 2001
Externally publishedYes

ASJC Scopus subject areas

  • Physiology

Fingerprint Dive into the research topics of 'Cardiac troponin T mutations: Correlation between the type of mutation and the nature of myofilament dysfunction in transgenic mice'. Together they form a unique fingerprint.

Cite this