Characterization of Troponin T Dilated Cardiomyopathy Mutations in the Fetal Troponin Isoform

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. 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. Troponin T (TnT) 1The abbreviations used are: TnT, troponin T; TnI, troponin I; cTnI, cardiac TnI; ssTnI, slow skeletal TnI; TnC, troponin C; Tn, troponin; DCM, dilated cardiomyopathy; WT, wild-type; Tm, α-tropomyosin; MOPS, 4-morpholinepropanesulfonic acid. 1The abbreviations used are: TnT, troponin T; TnI, troponin I; cTnI, cardiac TnI; ssTnI, slow skeletal TnI; TnC, troponin C; Tn, troponin; DCM, dilated cardiomyopathy; WT, wild-type; Tm, α-tropomyosin; MOPS, 4-morpholinepropanesulfonic acid. isoforms are encoded by distinct genes in different muscle types: fast skeletal, slow skeletal, and cardiac muscle (1Cooper T.A. Ordahl C.P. Science. 1984; 226: 979-982Crossref PubMed Scopus (80) Google Scholar). Multiple isoforms of TnT have been identified in skeletal and cardiac muscle. The expression of more than one cardiac TnT isoform was first identified in chicken. Subsequently, multiple cardiac TnT isoforms were found in different species including the rabbit, rat, mouse, bovine, and human heart, and the number of isoforms expressed varies among different species. In the human heart, alternative splicing of exons 4 and 5 generates up to four different isoforms (TnT1–TnT4) with varying electrophoretic mobility. The four isoforms differ by the presence or absence of exons 4 and 5. Cardiac TnT1 has both exons 4 and 5, in cardiac TnT2 exon 4 is missing, in cardiac TnT3 exon 5 is missing, and in cardiac TnT4 both exons 4 and 5 are missing (2Gomes A.V. Guzman G. Zhao J. Potter J.D. J. Biol. Chem. 2002; 277: 35341-35349Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). The multiple cardiac TnT isoforms are expressed in a developmentally regulated manner. Anderson et al. (3Anderson P.A. Greig A. Mark T.M. Malouf N.N. Oakeley A.E. Ungerleider R.M. Allen P.D. Kay B.K. Circ. Res. 1995; 76: 681-686Crossref PubMed Scopus (199) Google Scholar) showed that TnT3 is the dominant TnT isoform in the adult human heart, and TnT1 and TnT2 are the two isoforms present in the fetal heart, with TnT2 being present at low levels (4Anderson P.A. Malouf N.N. Oakeley A.E. Pagani E.D. Allen P.D. Circ. Res. 1991; 69: 1226-1233Crossref PubMed Scopus (309) Google Scholar). The switch in the expression of these different isoforms is believed to be at least partially responsible for the different Ca2+ sensitivity seen between the neonatal and adult cardiac muscle (5Nassar R. Malouf N.N. Kelly M.B. Oakeley A.E. Anderson P.A. Circ. Res. 1991; 69: 1470-1475Crossref PubMed Scopus (97) Google Scholar). Dilated cardiomyopathy (DCM) characterized by increased left ventricular cavity dimensions and systolic dysfunction is caused by mutations in sarcomeric proteins including cardiac TnT, troponin I (TnI), troponin C (TnC), actin, β-myosin heavy chain, and α-tropomyosin (Tm) (6Fatkin R.M. 2002; PubMed Scopus Google J. A. Full Text Full Text PDF PubMed Scopus Google Scholar). et al. E.D. J. PubMed Scopus Google Scholar) the first TnT mutation as the cause of DCM in two mutation to a of the at in exon of the with DCM ventricular a of cardiomyopathy. In the mutation caused ventricular caused a of cardiac in both infants and and a of infantile cardiomyopathy. et al. A. R. R. Anderson R. PubMed Scopus Google Scholar) TnT mutation, in a of of the DCM, in the of the of and in this of of this was to is how of these were the functional properties of TnT DCM mutations in the adult isoform of TnT G. A.V. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a different TnT isoform is present in the embryonic heart and both these DCM mutations cause infantile created mutations in the TnT1 isoform to elucidate the of the mutations in the fetal TnT isoform. In addition to a different TnT isoform, a different TnI isoform is expressed in the embryonic heart. slow skeletal TnI and cardiac TnI are expressed in the heart development J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar). In is present the of Oakeley A.E. Allen P.D. Anderson P.A. PubMed Scopus Google Scholar). In the human heart, and and are both expressed in the and is expressed in the adult heart. expression in the human the first of J. Circ. Res. 1991; 69: PubMed Scopus Google 1991; PubMed Scopus Google Scholar). and the in the of muscle by the actomyosin ATPase to Ca2+ and are different J. J. Full Text PDF PubMed Scopus Google Scholar). In to the of DCM in fetal the mutations in fetal TnT and of in the isoforms used in the the troponin isoforms in the fetal heart, these were to how DCM mutations affect the functional properties of troponin in the fetal heart. The for human adult cardiac troponin T was in by a of human and for the and of the R. Zhao J. Guzman G. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The TnT1 isoform, which is the primary TnT isoform in the embryonic heart, was as the R141W and were in TnT1 by the of the R. in and were the of the expression that contained the were to the presence of the TnT isoform to as and were expressed in were for of Potter J.D. J. Biol. Chem. Full Text PDF PubMed Google Potter J.D. J. Biol. Chem. Full Text PDF PubMed Google Scholar). expressed TnT was and with a of The TnT were a fast and with a The of the was The proteins were a that The of the proteins was The for human and were in by a of human and for the and of the R. A.V. Zhao J. Potter J.D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). were with or The proteins were and the of and was by or were a and with a of and and and The of the proteins was was used to the isometric force and the Ca2+ sensitivity of force development at both pH and pH The was of the and with either or TnT1 DCM and with the human or human ssTnI·TnC is in (2Gomes A.V. Guzman G. Zhao J. Potter J.D. J. Biol. Chem. 2002; 277: 35341-35349Abstract Full Text Full Text PDF PubMed Scopus (107) Google R. Zhao J. Guzman G. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google R. A.V. Zhao J. Potter J.D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Cardiac the were to the in 4 and 5 pH Cardiac muscle was the left and skinned by with and in the The of the was 5 pH and at 4 for partially skinned was at in the and in TnI·TnC cardiac was with either or in a of and in a MOPS, pH and the TnI·TnC was in MOPS, pH and and and The TnI that the was by The TnI·TnC was to at of the Ca2+ of muscle fiber of to fibers a of were a force and treated with the for and of the fibers for the were and The of was 5 pH and the muscle and to to the Subsequently, the fibers were to and for the force The of the is the as that of the that the Ca2+ was the Ca2+ sensitivity of force the fibers were to the of Ca2+ to the the fibers were in a MOPS, pH 5 5 and TnT isoform, or TnT DCM for at a the fibers were in TnT for was to the of troponin the fibers were with the the at and for the force that to the absence of the and The Ca2+ of force was with a human The with the TnI·TnC was in the for at for the force to a fibers were in and treated with the the The Ca2+ sensitivity of force development was human as by the fiber to Ca2+ to The were the in The is as force Ca2+ of the in which of force is and is the The proteins used are skeletal actin, cardiac and cardiac skeletal was as by et al. J. PubMed Scopus Google Scholar). Porcine cardiac was as by et al. J. PubMed Scopus Google Scholar). Porcine cardiac was to Potter J.D. PubMed Scopus Google Scholar). TnT, TnI, and were used to functional troponin The ATPase were with skeletal muscle cardiac and as (2Gomes A.V. Guzman G. Zhao J. Potter J.D. J. Biol. Chem. 2002; 277: 35341-35349Abstract Full Text Full Text PDF PubMed Scopus (107) Google R. Zhao J. Guzman G. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of cardiac was ATPase were in the presence or absence of The ATPase MOPS, and 4 pH were with a at the was with acid. The that was was to the of and J. Biol. Chem. Full Text PDF Google Scholar). of the between was by are as in the Ca2+ of by TnT1 DCM at pH to study the functional between TnT3 and the troponin was with either or TnT1-WT and reconstituted with human and the Ca2+ sensitivity of was at pH 7.0 and the troponin the Ca2+ of force development was and was no significant in either or between the different fibers used in fibers treated with TnT1-WT increased Ca2+ sensitivity of force development compared with TnT3-WT-treated of is with results (2Gomes A.V. Guzman G. Zhao J. Potter J.D. J. Biol. Chem. 2002; 277: 35341-35349Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar) for the the of the significantly increased in TnT1 When cardiac fibers were with and both of the DCM mutations decreased the Ca2+ sensitivity of force development compared with TnT1-WT. The Ca2+ force by fibers treated with TnT isoforms and is in the ΔK210 a Ca2+ force than this was G. A.V. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) showed that in the TnT3 isoform, the decreased Ca2+ sensitivity of force development when compared with the in the TnT1 isoform, both mutations decreased the Ca2+ sensitivity of force and the of the in Ca2+ sensitivity was increased compared with was in the TnT3 isoform. was no significant in the between TnT1-WT and TnT1 DCM of in fibers reconstituted with either cardiac TnI·TnC or ssTnI·TnC at pH Ca2+ are compared are compared are compared are compared are compared are compared are compared are compared are compared are compared are compared are compared in a In the of cardiac fibers were treated with either or TnT1 DCM and reconstituted with ssTnI·TnC of in that the of TnT3-WT-treated fibers reconstituted with ssTnI·TnC is when was used to TnT3-WT-treated the was The in Ca2+ sensitivity ssTnI·TnC is to the of to the for Ca2+ of force development Circ. Res. PubMed Scopus Google A. PubMed Scopus (97) Google J. Scopus Google Scholar). The in fibers with TnT1-WT and reconstituted with ssTnI·TnC is in The Ca2+ sensitivity of force development significantly increased in fibers compared with TnT3-WT-treated fibers reconstituted with results that TnT1 isoform is more to Ca2+ than TnT3 with Our results that both the TnT1 isoform and to the in Ca2+ sensitivity of force development in cardiac the of the DCM mutations in the TnT1 isoform reconstituted with ssTnI·TnC in fiber The for fibers treated with and and reconstituted with ssTnI·TnC was and significant decrease in Ca2+ sensitivity was for both the TnT1 DCM compared with TnT1-WT. the of TnT1-WT and in Ca2+ sensitivity of force development is in the presence of TnT DCM mutations. Ca2+ of with at pH fiber studies, the isometric force The maximal force by fibers treated with and reconstituted with was The of the fibers treated with for the as the fiber was Our results showed that the maximal force by fibers with TnT1-WT and reconstituted with was significantly than fibers with The fibers maximal of Ca2+ maximal force in the fetal adult TnT isoform that the R141W mutation to the in both the fetal and adult isoform. the the ΔK210 mutation decreased Ca2+ maximal force in both the fetal and adult TnT isoforms the Ca2+ maximal force in fibers treated with and TnT1 DCM and reconstituted with The maximal force for fibers treated with was When the TnT3-WT-treated fibers were reconstituted with the maximal force was results that is to the of maximal force in addition to the Ca2+ sensitivity of force The maximal isometric force for fibers reconstituted with ssTnI·TnC was is a significant compared with force when fibers were reconstituted with Our results that the maximal force is the when is in with TnT1-WT than fibers significant in maximal force compared with TnT1-WT in the presence of in the ΔK210 a significant decrease in the maximal force for TnT1-WT for when reconstituted with ATPase TnT1 DCM is that TnI by ATPase activity and that the addition of this When TnT is is of actomyosin ATPase activity that is J.D. Zhao J. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). the ATPase in the absence of Ca2+ in The actomyosin ATPase activity in the absence of human cardiac troponin was to be the In the absence of ATPase was at were to of the were to as as for TnT1-WT for in was found to be significant by DCM mutations R141W and ΔK210 in the TnT1 isoform ATPase activity to TnT1-WT at the In to how the DCM mutations affect ATPase in the fetal heart at the of ssTnI·TnC to troponin and TnT1 DCM In the absence of when of are the activity to was to of the ATPase When was complexed with at the was was to of the ATPase When complexed with TnT1-WT was to of the ATPase activity TnT1 DCM complexed with ssTnI·TnC ATPase activity to a as TnT1-WT for both proteins Our results that ssTnI·TnC are to as as at and this was found to be significant by ATPase in the presence of Ca2+ at at which the maximal activity was and the results are as a The ATPase activity in the absence of was to be the activity and The ATPase activity of TnT1-WT was to maximal ATPase the fetal isoform of TnT, to which is the adult TnT isoform. The ATPase activity of was and the ATPase activity of was The maximal ATPase activity of both DCM in the TnT1 isoform was significantly decreased compared with the TnT1-WT. is to was when the mutations were present in the adult cardiac TnT isoform G. A.V. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ATPase activity in the presence of Ca2+ for and TnT1 DCM complexed with ssTnI·TnC at The ATPase activity of was TnT1-WT The in ATPase activity for TnT1-WT was found to be significant The maximal ATPase activity of was and the maximal ATPase activity of was The maximal activity for the TnT1 DCM was significantly compared with TnT1-WT when complexed with Our results suggest that both ATPase and in Ca2+ of and to TnT1 DCM at pH the of pH TnT1-WT and TnT1 DCM in the presence of be in pH caused a decrease of of at pH compared with of at pH is that the to the pH at pH a significant decrease in the was at pH in When and mutations were used in the fiber studies, with both the TnT1 DCM mutations caused a significant decrease in Ca2+ sensitivity of force development when compared with fibers at pH 6.5. The of decrease in Ca2+ sensitivity of force development increased as the pH was 7.0 to for both mutations for and for The isometric force with maximal was at pH for TnT1-WT as as for TnT1 DCM fibers of maximal force at pH compared with of maximal force at pH The fibers of the maximal and the fibers of the of Ca2+ maximal force at pH in the fetal adult TnT isoform that the R141W mutation the maximal force in both the fetal and adult TnT isoform the ΔK210 mutation significantly decreased the maximal force in both the fetal and adult TnT isoforms of TnT DCM Ca2+ maximal force at pH 6.5. The Ca2+ maximal force of TnT3 and TnT1 DCM are compared with by are expressed as force when fibers were reconstituted with force when fibers were reconstituted with of in fibers reconstituted with either or ssTnI·TnC at pH are compared are compared are compared TnT1-WT. are compared TnT1-WT. are compared TnT1-WT. are compared TnT1-WT. are compared TnT1-WT. are compared TnT1-WT. are compared are compared TnT1-WT. in a the pH in fibers treated with and TnT1 DCM and reconstituted with pH a of was for TnT3-WT-treated fibers pH TnT3-WT-treated fibers reconstituted with ssTnI·TnC a of The which is the between the at pH 7.0 and pH was to in in TnT3-WT-treated fibers with ssTnI·TnC was significantly than was is to the of ssTnI, which in pH than in that at pH the of fibers reconstituted with ssTnI·TnC is in for TnT1-WT compared with was When and mutations were used in the fiber studies, both the TnT1 DCM mutations caused a significant decrease in Ca2+ sensitivity of force development when compared with fibers at pH significant in were between different fiber and the maximal force at pH for of fibers reconstituted with The in maximal force by pH was significantly decreased ssTnI·TnC in fiber in cardiac TnT have been to cause both cardiomyopathy and The functional properties of TnT mutations cardiomyopathy and DCM have been characterized by G. A.V. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google R. Zhao J. Guzman G. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google R. A. 2002; PubMed Scopus Google 2002; Google Res. PubMed Scopus Google Potter J.D. J. PubMed Scopus Google Scholar). In these studies, the mutations were created in the adult cardiac TnT isoform that DCM caused to TnT mutations infants as as E.D. J. PubMed Scopus Google A. R. R. Anderson R. PubMed Scopus Google Scholar). Multiple cardiac TnT isoforms are expressed in the heart in a developmentally regulated manner. is that TnT1 is the primary TnT isoform found in the fetal and neonatal heart (3Anderson P.A. Greig A. Mark T.M. Malouf N.N. Oakeley A.E. Ungerleider R.M. Allen P.D. Kay B.K. Circ. Res. 1995; 76: 681-686Crossref PubMed Scopus (199) Google J. 1995; Full Text PDF PubMed Scopus Google Scholar). expression of the TnT1 isoform and TnT3 expression and the dominant TnT isoform. In to elucidate the functional properties of DCM at the of fetal TnT, created the TnT DCM mutations R141W and ΔK210 in the primary fetal isoform of TnT and skinned fiber and reconstituted actomyosin ATPase In addition to a different TnT isoform, a different TnI isoform is present in the fetal heart. The dominant TnI isoform in the fetal and neonatal heart is In to how the TnT DCM mutations the functional properties of the troponin in the fetal heart, of in the Ca2+ sensitivity of force development that fibers reconstituted with caused a significant in Ca2+ sensitivity and of force development compared with TnT3-WT-treated fibers is with that TnT1 is more to Ca2+ than TnT3 and that the in the of cardiac TnT to the Ca2+ sensitivity of force development in the cardiac muscle (2Gomes A.V. Guzman G. Zhao J. Potter J.D. J. Biol. Chem. 2002; 277: 35341-35349Abstract Full Text Full Text PDF PubMed Scopus (107) Google R. Malouf N.N. Kelly M.B. Oakeley A.E. Anderson P.A. Circ. Res. 1991; 69: 1470-1475Crossref PubMed Scopus (97) Google J. Res. 1991; PubMed Scopus Google Scholar). The R141W mutation showed a significant decrease in the Ca2+ sensitivity of force development in the TnT3 isoform G. A.V. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in fetal troponin T the R141W mutation significantly decreased the Ca2+ sensitivity of force development compared with TnT1-WT. The R141W mutation is in a of TnT that with by et al. J. Full Text Full Text PDF PubMed Scopus Google Scholar) a showed that the R141W mutation increased the of cardiac TnT for The that the change in of TnT for the of the more Ca2+ to to the TnI The decrease in Ca2+ sensitivity that the may the of with the mutation a of cardiac in infants of E.D. J. PubMed Scopus Google Scholar). In fiber studies, showed a significant decrease in Ca2+ sensitivity of force development as as maximal When ssTnI·TnC was used to TnT3-WT-treated fibers of the Ca2+ sensitivity of force development increased with results that showed a to Ca2+ in compared with et al. A. PubMed Scopus (97) Google Scholar) that expression of in adult cardiac the for Ca2+ The Ca2+ sensitivity of force development increased in fibers treated with TnT1-WT and reconstituted with ssTnI·TnC, to was by et al. A.V. G. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in Ca2+ sensitivity is to the of both TnT1 and and fibers reconstituted with ssTnI·TnC decreased the Ca2+ sensitivity compared with is the TnT1 the of TnT in the between cardiac and compared with the for Ca2+ force is that the of with is in the presence of the TnT DCM to Ca2+ of the the Ca2+ maximal force increased significantly in fibers treated with TnT1-WT and reconstituted with ssTnI·TnC compared with TnT3-WT-treated fibers reconstituted with in to cardiac fibers showed a significant decrease in maximal and the fibers compared with fibers reconstituted with ssTnI·TnC showed no change in maximal the of TnT1-WT and TnT1 DCM to and actomyosin ATPase In the absence of found that TnT1-WT were to ATPase activity as as is with was by et al. (2Gomes A.V. Guzman G. Zhao J. Potter J.D. J. Biol. Chem. 2002; 277: 35341-35349Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). the and ΔK210 mutations were to to that the DCM mutations in the fetal TnT are the of is the a with or TnI and When ssTnI·TnC were in ATPase that ssTnI·TnC were to actomyosin ATPase activity as as at The of to significantly ATPase activity that the of to the and this in to was in in the presence of ssTnI·TnC, both mutations were to as as TnT1-WT. in maximal ATPase was between and TnT1-WT complexed with is with was by et al. (2Gomes A.V. Guzman G. Zhao J. Potter J.D. J. Biol. Chem. 2002; 277: 35341-35349Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). both DCM mutations in the TnT1 isoform caused a significant decrease in maximal ATPase activity The of the in the of actomyosin ATPase has been by et al. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the in TnT of skeletal in a significant in the maximal ATPase J. Full Text PDF PubMed Scopus Google Scholar). maximal ATPase activity to a major in the ATPase activity in the presence of The maximal ATPase activity of complexed with ssTnI·TnC was to the activity with the maximal ATPase activity significantly increased for TnT1-WT and DCM when complexed with ssTnI·TnC of compared with the maximal activity for the TnT1 DCM was significantly the Ca2+ sensitivity of force development and maximal force at pH for the TnT DCM mutations in the fetal isoform of TnT and fetal which the pH varies to When the pH was to TnT3-WT-treated fibers showed a decrease in of in was in was no significant in the Ca2+ sensitivity of force development between and TnT1-WT at pH pH in the TnT1 isoform, both the mutations significantly decreased the Ca2+ sensitivity of force development to that the mutations are in is the R141W mutation is the of in that are responsible for the of Ca2+ of cardiac muscle Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). has been by that the change in and the force caused by pH in neonatal heart are than is in the adult heart A. PubMed Scopus (97) Google Circ. Res. PubMed Scopus Google Res. PubMed Scopus Google Scholar). The to pH is of this be one of the for embryonic or neonatal heart the in fibers treated with and TnT1 DCM and reconstituted with The in with ssTnI·TnC at pH was significantly than was for four is to the of ssTnI, which in pH than has been that the at is responsible for the of to pH R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). both the TnT1 DCM mutations caused a significant decrease in Ca2+ sensitivity of force development when compared with fibers at pH the maximal force at pH for of fibers reconstituted with The in maximal force by pH was significantly decreased ssTnI·TnC in fiber was by et al. R.M. R. J. Scopus Google Scholar) in in the heart. that the of the TnI isoform a major in the of force development pH fibers showed no change in maximal force compared with fibers reconstituted with ssTnI·TnC, the treated fibers showed a significant decrease in maximal In this study the functional of DCM mutations in the fetal cardiac TnT isoform and fetal cardiac Our results that both DCM mutations R141W and ΔK210 decrease the Ca2+ sensitivity of force development in both the TnT1 isoform and fetal mutations have in a decrease in the Ca2+ ATPase with the decrease being more in ΔK210 than in R141W in adult TnT G. A.V. Potter J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google fetal TnT, and fetal The in results suggest that both the R141W and ΔK210 mutations cause a severe DCM phenotype in the fetal and neonatal for the the ΔK210 mutation decreased Ca2+ sensitivity of force maximal force and maximal ATPase of the mutation was present in the adult TnT, fetal TnT, or fetal The R141W mutation decreased Ca2+ sensitivity of force development in the fetal TnT and fetal In the adult isoform of TnT, the R141W mutation caused no change in Ca2+ sensitivity of force development compared with The TnT DCM mutations in the fetal isoform showed significantly greater in the Ca2+ sensitivity of force development with to the when these mutations were present in the adult TnT3 isoform. greater decrease in change in Ca2+ sensitivity in with a decrease in maximal actomyosin ATPase activity in fetal TnT1 may to a more severe phenotype in with these with E.D. J. PubMed Scopus Google Scholar). In addition to TnT and TnI, and and heavy have different isoforms cardiac affect the of TnT and TnI to Ca2+ sensitivity and ATPase activity to be