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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 * and Murali Chandra

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 (cTnT_DEL), respectively.
3. Normalized pCa-tension relationships of R92Q and cTnT_DEL 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 cTnT_DEL 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 cTnT_DEL fibres, respectively.
4. The difference in pCa required for half-maximal activation (pCa₅₀) at short and long SL was 0.12 ± 0.01 for the R92Q (92 %) TG fibres, which is significantly less than the previously reported pCa₅₀ value of 0.29 ± 0.02 for R92Q (67 %) TG fibres.
5. At short SL, Ca²⁺-activated maximal tension in both R92Q and cTnT_DEL 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 cTnT_DEL fibres increased by 35 and 29 %, respectively (P < 0.001).
6. The fibre bundles reconstituted with the recombinant mutant cTnT_DEL 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.

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