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

Content Provider	PubMed Central
Author	Montgomery, David E. Tardiff, Jil C. Chandra, Murali
Copyright Year	2001
Abstract	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. 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. 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. 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. 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). 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. 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.
Related Links	http://dx.doi.org/10.1111/j.1469-7793.2001.0583c.xd
Ending Page	592
Page Count	10
Starting Page	583
File Format	PDF
ISSN	00223751
e-ISSN	14697793
Journal	The Journal of Physiology
Issue Number	Pt 2
Volume Number	536
Language	English
Publisher	Blackwell Science Inc
Publisher Date	2001-10-01
Access Restriction	Open
Rights Holder	Blackwell Science Inc
Subject Keyword	Physiology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology Sports Science

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