Abstract
The major goal of this study was to elucidate how troponin T (TnT) dilated cardiomyopathy (DCM) mutations in fetal TnT and fetal troponin affect the functional properties of the fetal heart that lead to infantile cardiomyopathy. The DCM mutations R141W and ΔK210 were created in the TnT1 isoform, the primary isoform of cardiac TnT in the embryonic heart. In addition to a different TnT isoform, a different troponin I (TnI) isoform, slow skeletal TnI (ssTnI), is the dominant isoform in the embryonic heart. In skinned fiber studies, TnT1-wild-type (WT)-treated fibers reconstituted with cardiac TnI-troponin C (TnC) or ssTnI-TnC significantly increased Ca2+ sensitivity of force development when compared with TnT3-WT-treated fibers at both pH 7.0 and pH 6.5. Porcine cardiac fibers treated with TnT1 that contained the DCM mutations (R141W and ΔK210), when reconstituted with either cardiac TnI-TnC or SsTnI·TnC, significantly decreased Ca2+ sensitivity of force development compared with TnT1-WT at both pH values. The R141W mutation, which showed no significant change in the Ca2+ sensitivity of force development in the TnT3 isoform, caused a significant decrease in the TnT1 isoform. The ΔK210 mutation caused a greater decrease in Ca2+ sensitivity and maximal isometric force development compared with the R141W mutation in both the fetal and adult TnT isoforms. When complexed with cardiac TnI·TnC or ssTnI-TnC, both TnT1 DCM mutations strongly decreased maximal actomyosin ATPase activity as compared with TnT1-WT. Our results suggest that a decrease in maximal actomyosin ATPase activity in conjunction with decreased Ca2+ sensitivity of force development may cause a severe DCM phenotype in infants with the mutations.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 17584-17592 |
| Number of pages | 9 |
| Journal | Journal of Biological Chemistry |
| Volume | 280 |
| Issue number | 18 |
| DOIs | |
| State | Published - May 6 2005 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform. / Venkatraman, Gayathri; Gomes, Aldrin V; Kerrick, W. Glenn L; Potter, James D.
In: Journal of Biological Chemistry, Vol. 280, No. 18, 06.05.2005, p. 17584-17592.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform
AU - Venkatraman, Gayathri
AU - Gomes, Aldrin V
AU - Kerrick, W. Glenn L
AU - Potter, James D.
PY - 2005/5/6
Y1 - 2005/5/6
N2 - The major goal of this study was to elucidate how troponin T (TnT) dilated cardiomyopathy (DCM) mutations in fetal TnT and fetal troponin affect the functional properties of the fetal heart that lead to infantile cardiomyopathy. The DCM mutations R141W and ΔK210 were created in the TnT1 isoform, the primary isoform of cardiac TnT in the embryonic heart. In addition to a different TnT isoform, a different troponin I (TnI) isoform, slow skeletal TnI (ssTnI), is the dominant isoform in the embryonic heart. In skinned fiber studies, TnT1-wild-type (WT)-treated fibers reconstituted with cardiac TnI-troponin C (TnC) or ssTnI-TnC significantly increased Ca2+ sensitivity of force development when compared with TnT3-WT-treated fibers at both pH 7.0 and pH 6.5. Porcine cardiac fibers treated with TnT1 that contained the DCM mutations (R141W and ΔK210), when reconstituted with either cardiac TnI-TnC or SsTnI·TnC, significantly decreased Ca2+ sensitivity of force development compared with TnT1-WT at both pH values. The R141W mutation, which showed no significant change in the Ca2+ sensitivity of force development in the TnT3 isoform, caused a significant decrease in the TnT1 isoform. The ΔK210 mutation caused a greater decrease in Ca2+ sensitivity and maximal isometric force development compared with the R141W mutation in both the fetal and adult TnT isoforms. When complexed with cardiac TnI·TnC or ssTnI-TnC, both TnT1 DCM mutations strongly decreased maximal actomyosin ATPase activity as compared with TnT1-WT. Our results suggest that a decrease in maximal actomyosin ATPase activity in conjunction with decreased Ca2+ sensitivity of force development may cause a severe DCM phenotype in infants with the mutations.
AB - The major goal of this study was to elucidate how troponin T (TnT) dilated cardiomyopathy (DCM) mutations in fetal TnT and fetal troponin affect the functional properties of the fetal heart that lead to infantile cardiomyopathy. The DCM mutations R141W and ΔK210 were created in the TnT1 isoform, the primary isoform of cardiac TnT in the embryonic heart. In addition to a different TnT isoform, a different troponin I (TnI) isoform, slow skeletal TnI (ssTnI), is the dominant isoform in the embryonic heart. In skinned fiber studies, TnT1-wild-type (WT)-treated fibers reconstituted with cardiac TnI-troponin C (TnC) or ssTnI-TnC significantly increased Ca2+ sensitivity of force development when compared with TnT3-WT-treated fibers at both pH 7.0 and pH 6.5. Porcine cardiac fibers treated with TnT1 that contained the DCM mutations (R141W and ΔK210), when reconstituted with either cardiac TnI-TnC or SsTnI·TnC, significantly decreased Ca2+ sensitivity of force development compared with TnT1-WT at both pH values. The R141W mutation, which showed no significant change in the Ca2+ sensitivity of force development in the TnT3 isoform, caused a significant decrease in the TnT1 isoform. The ΔK210 mutation caused a greater decrease in Ca2+ sensitivity and maximal isometric force development compared with the R141W mutation in both the fetal and adult TnT isoforms. When complexed with cardiac TnI·TnC or ssTnI-TnC, both TnT1 DCM mutations strongly decreased maximal actomyosin ATPase activity as compared with TnT1-WT. Our results suggest that a decrease in maximal actomyosin ATPase activity in conjunction with decreased Ca2+ sensitivity of force development may cause a severe DCM phenotype in infants with the mutations.
UR - http://www.scopus.com/inward/record.url?scp=23344435710&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=23344435710&partnerID=8YFLogxK
U2 - 10.1074/jbc.M409337200
DO - 10.1074/jbc.M409337200
M3 - Article
C2 - 15623536
AN - SCOPUS:23344435710
VL - 280
SP - 17584
EP - 17592
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 18
ER -