Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization
| Autor: | Stephen H Smith, Samir Saba, Guy Salama, David W. Wang, Ferhaan Ahmad, Xueyin N Huang, Sanjeev G. Shroff, Mohun Ramratnam, Ravi K. Sharma, Bethann Gabris, Michele L. Pruce, Lindsey M Gifford, Sanjay K. Banerjee |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male TNNT2 Cardiomyopathy lcsh:Medicine 030204 cardiovascular system & hematology Biochemistry Mice 0302 clinical medicine Myofibrils Heart Rate Animal Cells Medicine and Health Sciences Gene Knock-In Techniques Post-Translational Modification Phosphorylation lcsh:Science Multidisciplinary Chemistry Messenger RNA Dilated cardiomyopathy Heart Animal Models Phospholamban Nucleic acids Phenotypes Gene Targeting Cardiology Female Anatomy Cellular Types Research Article Cardiomyopathy Dilated Sarcomeres medicine.medical_specialty Transgene Muscle Tissue Mice Transgenic Mouse Models Research and Analysis Methods Contractility 03 medical and health sciences Model Organisms Troponin T Internal medicine medicine Genetics Animals Humans Point Mutation Calcium metabolism Muscle Cells lcsh:R Wild type Biology and Life Sciences Proteins Cell Biology medicine.disease Myocardial Contraction 030104 developmental biology Endocrinology Biological Tissue Mutation Cardiovascular Anatomy RNA lcsh:Q Calcium |
| Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 12, p e0167681 (2016) |
| ISSN: | 1932-6203 |
| Popis: | Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM) have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2R141W/+) recapitulated the human phenotype, developing left ventricular dilation and reduced contractility. There was a gene dosage effect, so that the phenotype in Tnnt2R141W/+mice was attenuated by transgenic overexpression of wildtype Tnnt2 mRNA transcript. Male mice exhibited poorer survival than females. Biomechanical studies on skinned fibers from Tnnt2R141W/+ hearts showed a significant decrease in pCa50 (-log[Ca2+] required for generation of 50% of maximal force) relative to wildtype hearts, indicating Ca2+ desensitization. Optical mapping studies of Langendorff-perfused Tnnt2R141W/+ hearts showed marked increases in diastolic and peak systolic intracellular Ca2+ ([Ca2+]i), and prolonged systolic rise and diastolic fall of [Ca2+]i. Perfused Tnnt2R141W/+ hearts had slower intrinsic rates in sinus rhythm and reduced peak heart rates in response to isoproterenol. Tnnt2R141W/+ hearts exhibited a reduction in phosphorylated phospholamban relative to wildtype mice. However, crossing Tnnt2R141W/+ mice with phospholamban knockout (Pln-/-) mice, which exhibit increased Ca2+ transients and contractility, had no effect on the DCM phenotype. We conclude that the Tnnt2 R141W mutation causes a Ca2+ desensitization and mice adapt by increasing Ca2+-transient amplitudes, which impairs Ca2+ handling dynamics, metabolism and responses to β-adrenergic activation. |
| Databáze: | OpenAIRE |
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