Functional Consequences of the Human Cardiac Troponin I Hypertrophic Cardiomyopathy Mutation R145G in Transgenic Mice
| Autor: | W. Glenn L. Kerrick, James D. Potter, Yuhui Wen, Yuanyuan Xu, Aldrin V. Gomes, Ying Wang, Jose R. Pinto, Yingcai Wang |
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| Rok vydání: | 2008 |
| Předmět: |
Genetically modified mouse
medicine.medical_specialty ATPase Cardiomyopathy Mice Transgenic Arginine Biochemistry Cardiac Troponin complex Mice Internal medicine medicine Animals Humans Molecular Biology Adenosine Triphosphatases Calcium metabolism biology Body Weight Troponin I Wild type Hypertrophic cardiomyopathy Organ Size Cell Biology Cardiomyopathy Hypertrophic medicine.disease Endocrinology Gene Expression Regulation Mutation Protein Structure and Folding biology.protein Calcium Intracellular |
| Zdroj: | Journal of Biological Chemistry. 283:20484-20494 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m801661200 |
| Popis: | In this study, we addressed the functional consequences of the human cardiac troponin I (hcTnI) hypertrophic cardiomyopathy R145G mutation in transgenic mice. Simultaneous measurements of ATPase activity and force in skinned papillary fibers from hcTnI R145G transgenic mice (Tg-R145G) versus hcTnI wild type transgenic mice (Tg-WT) showed a significant decrease in the maximal Ca2+-activated force without changes in the maximal ATPase activity and an increase in the Ca2+ sensitivity of both ATPase and force development. No difference in the cross-bridge turnover rate was observed at the same level of cross-bridge attachment (activation state), showing that changes in Ca2+ sensitivity were not due to changes in cross-bridge kinetics. Energy cost calculations demonstrated higher energy consumption in Tg-R145G fibers compared with Tg-WT fibers. The addition of 3 mm 2,3-butanedione monoxime at pCa 9.0 showed that there was ∼2-4% of force generating cross-bridges attached in Tg-R145G fibers compared with less than 1.0% in Tg-WT fibers, suggesting that the mutation impairs the ability of the cardiac troponin complex to fully inhibit cross-bridge attachment under relaxing conditions. Prolonged force and intracellular [Ca2+] transients in electrically stimulated intact papillary muscles were observed in Tg-R145G compared with Tg-WT. These results suggest that the phenotype of hypertrophic cardiomyopathy is most likely caused by the compensatory mechanisms in the cardiovascular system that are activated by 1) higher energy cost in the heart resulting from a significant decrease in average force per cross-bridge, 2) slowed relaxation (diastolic dysfunction) caused by prolonged [Ca2+] and force transients, and 3) an inability of the cardiac TnI to completely inhibit activation in the absence of Ca2+ in Tg-R145G mice. |
| Databáze: | OpenAIRE |
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