Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T

Javadpour, Maryam M.; Tardiff, Jil C.; Pinz, Ilka; Ingwall, Joanne S.

doi:10.1172/jci15967

Cited by 115 publications

(78 citation statements)

References 28 publications

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“…The maximal ATPase level in Tn containing the TnI L144Q mutation was significantly decreased when compared with wild-type Tn, consistent with the lower level of force seen in the reconstituted fibers. However, the lower level of force seen with Tn containing the TnI R145W mutation was not accompanied by a decrease in the maximal ATPase level suggesting that this R145W mutation would cause impaired energetics (lower force for the same ATPase activity as wild-type Tn) similar to what is seen in animal models of HCM (26,27). The R145G mutation caused a 25% decrease in the inhibitory ATPase activity of cTnI (14), whereas the R145W mutation caused an 80% decrease in the inhibitory activity of cTnI.…”

Section: Discussionmentioning

confidence: 66%

Mutations in Human Cardiac Troponin I That Are Associated with Restrictive Cardiomyopathy Affect Basal ATPase Activity and the Calcium Sensitivity of Force Development

Gomes

Liang

Potter

2005

Journal of Biological Chemistry

113

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Human cardiac Troponin I (cTnI) is the first sarcomeric protein for which mutations have been associated with restrictive cardiomyopathy. To determine whether five mutations in cTnI (L144Q, R145W, A171T, K178E, and R192H) associated with restrictive cardiomyopathy were distinguishable from hypertrophic cardiomyopathy-causing mutations in cTnI, actomyosin ATPase activity and skinned fiber studies were carried out. All five mutations investigated showed an increase in the Ca 2؉ sensitivity of force development compared with wildtype cTnI. The two mutations with the worst clinical phenotype (K178E and R192H) both showed large increases in Ca 2؉ sensitivity (⌬pCa 50 ‫؍‬ 0.47 and 0.36, respectively). Although at least one of these mutations is not in the known inhibitory regions of cTnI, all of the mutations investigated caused a decrease in the ability of cTnI to inhibit actomyosin ATPase activity. Mixtures of wild-type and mutant cTnI showed that cTnI mutants could be classified into three different groups: dominant (L144Q, A171T and R192H), equivalent (K178E), or weaker (R145W) than wild-type cTnI in actomyosin ATPase assays in the absence of Ca 2؉ . Although most of the mutants were able to activate actomyosin ATPase similarly to wild-type cTnI, L144Q had significantly lower maximal ATPase activities than any of the other mutants or wild-type cTnI. Three mutants (L144Q, R145W, and K178E) were unable to fully relax contraction in the absence of Ca 2؉ . The inability of the five cTnI mutations investigated to fully inhibit ATPase activity/ force development and the generally larger increases in Ca 2؉ sensitivity than observed for most hypertrophic cardiomyopathy mutations would likely lead to severe diastolic dysfunction and may be the major physiological factors responsible for causing the restrictive cardiomyopathy phenotype in some of the genetically affected individuals.

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Section: Discussionmentioning

confidence: 66%

Mutations in Human Cardiac Troponin I That Are Associated with Restrictive Cardiomyopathy Affect Basal ATPase Activity and the Calcium Sensitivity of Force Development

Gomes

Liang

Potter

2005

Journal of Biological Chemistry

113

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“…In experimental studies with transgenic rats (207) and mice (208), the mutation of cTnT has been reported to result in a high incidence of ventricular tachycardia and early sudden death in the absence of overt ventricular hypertrophy. A significant change in cardiac energetics linked to mutation within the TM-binding domain of cTnT was also reported in transgenic mice (208).…”

Section: Hypertrophic Cardiomyopathymentioning

confidence: 99%

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

Macháčková¹,

Barta²,

Dhalla³

2006

Canadian Journal of Cardiology

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“…The energetic cost for muscle contraction mainly depends on two components, the ATP used by the cross-bridges and the ATP used by the Ca 2ϩ pumps. A higher energetic cost is seen in most hypertrophic cardiomyopathy mutations, and in skinned fiber and actomyosin studies no clear relationship between maximal force and ATPase activity is observed (15,35,40). cTnC plays a critical role in regulating muscle contraction and has one low affinity Ca 2ϩ -binding site (site II) and two high affinity Ca 2ϩ /Mg 2ϩ sites (sites III and IV).…”

Section: ϫ015) Than Intact Fibers Similar To What Has Been Reported mentioning

confidence: 99%

Cardiac Troponin T Isoforms Affect the Ca2+ Sensitivity of Force Development in the Presence of Slow Skeletal Troponin I

Gomes¹,

Venkatraman

Davis

et al. 2004

Journal of Biological Chemistry

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In this study we investigated the physiological role of the cardiac troponin T (cTnT) isoforms in the presence of human slow skeletal troponin I (ssTnI). ssTnI is the main troponin I isoform in the fetal human heart. In reconstituted fibers containing the cTnT isoforms in the presence of ssTnI, cTnT1-containing fibers showed increased Ca 2؉ sensitivity of force development compared with cTnT3-and cTnT4-containing fibers. The maximal force in reconstituted skinned fibers was significantly greater for the cTnT1 (predominant fetal cTnT isoform) when compared with cTnT3 (adult TnT isoform) in the presence of ssTnI. Troponin (Tn) complexes containing ssTnI and reconstituted with cTnT isoforms all yielded different maximal actomyosin ATPase activities. Tn complexes containing cTnT1 and cTnT4 (both fetal isoforms) had a reduced ability to inhibit actomyosin ATPase activity when compared with cTnT3 (adult isoform) in the presence of ssTnI. The rate at which Ca 2؉ was released from site II of cTnC in the cTnI⅐cTnC complex (122/s) was 12.5-fold faster than for the ssTnI⅐cTnC complex (9.8/s). Addition of cTnT3 to the cTnI⅐cTnC complex resulted in a 3.6-fold decrease in the Ca 2؉ dissociation rate from site II of cTnC. Addition of cTnT3 to the ssTnI⅐cTnC complex resulted in a 1.9-fold increase in the Ca 2؉ dissociation rate from site II of cTnC. The rate at which Ca 2؉ dissociated from site II of cTnC in Tn complexes also depended on the cTnT isoform present. However, the TnI isoforms had greater effects on the Ca 2؉ dissociation rate of site II than the cTnT isoforms. These results suggest that the different N-terminal TnT isoforms would produce distinct functional properties in the presence of ssTnI when compared with cTnI and that each isoform would have a specific physiological role in cardiac muscle.

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Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T

Cited by 115 publications

References 28 publications

Mutations in Human Cardiac Troponin I That Are Associated with Restrictive Cardiomyopathy Affect Basal ATPase Activity and the Calcium Sensitivity of Force Development

Mutations in Human Cardiac Troponin I That Are Associated with Restrictive Cardiomyopathy Affect Basal ATPase Activity and the Calcium Sensitivity of Force Development

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

Cardiac Troponin T Isoforms Affect the Ca2+ Sensitivity of Force Development in the Presence of Slow Skeletal Troponin I

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