Dataset Information

Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice.

ABSTRACT:

Background

Dilated cardiomoypathies (DCM) are a heterogeneous group of inherited and acquired diseases characterized by decreased contractility and enlargement of cardiac chambers and a major cause of morbidity and mortality. Mice with Glu54Lys mutation in ?-tropomyosin (Tm54) demonstrate typical DCM phenotype with reduced myofilament Ca2+ sensitivity. We tested the hypothesis that early sensitization of the myofilaments to Ca2+ in DCM can prevent the DCM phenotype.

Methods and results

To sensitize Tm54 myofilaments, we used a genetic approach and crossbred Tm54 mice with mice expressing slow skeletal troponin I (ssTnI) that sensitizes myofilaments to Ca2+. Four groups of mice were used: non-transgenic (NTG), Tm54, ssTnI and Tm54/ssTnI (DTG). Systolic function was significantly reduced in the Tm54 mice compared to NTG, but restored in DTG mice. Tm54 mice also showed increased diastolic LV dimensions and HW/BW ratios, when compared to NTG, which were improved in the DTG group. ?-myosin heavy chain expression was increased in the Tm54 animals compared to NTG and was partially restored in DTG group. Analysis by 2D-DIGE indicated a significant decrease in two phosphorylated spots of cardiac troponin I (cTnI) in the DTG animals compared to NTG and Tm54. Analysis by 2D-DIGE also indicated no significant changes in troponin T, regulatory light chain, myosin binding protein C and tropomyosin phosphorylation.

Conclusion

Our data indicate that decreased myofilament Ca2+ sensitivity is an essential element in the pathophysiology of thin filament linked DCM. Sensitization of myofilaments to Ca2+ in the early stage of DCM may be a useful therapeutic strategy in thin filament linked DCM.

SUBMITTER: Alves ML

PROVIDER: S-EPMC5852625 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice.

Alves Marco L ML Warren Chad M CM Simon Jillian N JN Gaffin Robert D RD Montminy Eric M EM Wieczorek David F DF Solaro R John RJ Wolska Beata M BM

Cardiovascular research 20170701 8

<h4>Background</h4>Dilated cardiomoypathies (DCM) are a heterogeneous group of inherited and acquired diseases characterized by decreased contractility and enlargement of cardiac chambers and a major cause of morbidity and mortality. Mice with Glu54Lys mutation in α-tropomyosin (Tm54) demonstrate typical DCM phenotype with reduced myofilament Ca2+ sensitivity. We tested the hypothesis that early sensitization of the myofilaments to Ca2+ in DCM can prevent the DCM phenotype.<h4>Methods and result ...[more]

PMID: 28379313

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Project description:Background: Hypertrophic cardiomyopathy (HCM) patients often present with diastolic dysfunction and a normal to supranormal systolic function. To counteract this hypercontractility, guideline therapies advocate treatment with beta-adrenoceptor and Ca2+ channel blockers. One well established pathomechanism for the hypercontractile phenotype frequently observed in HCM patients and several HCM mouse models is an increased myofilament Ca2+ sensitivity. Nebivolol, a commonly used beta-adrenoceptor antagonist, has been reported to lower maximal force development and myofilament Ca2+ sensitivity in rabbit and human heart tissues. The aim of this study was to evaluate the effect of nebivolol in cardiac muscle strips of an established HCM Mybpc3 mouse model. Furthermore, we investigated actions of nebivolol and epigallocatechin-gallate, which has been shown to desensitize myofilaments for Ca2+ in mouse and human HCM models, in cardiac strips of HCM patients with a mutation in the most frequently mutated HCM gene MYBPC3. Methods and Results: Nebivolol effects were tested on contractile parameters and force-Ca2+ relationship of skinned ventricular muscle strips isolated from Mybpc3-targeted knock-in (KI), wild-type (WT) mice and cardiac strips of three HCM patients with MYBPC3 mutations. At baseline, KI strips showed no difference in maximal force development compared to WT mouse heart strips. Neither 1 nor 10 μM nebivolol had an effect on maximal force development in both genotypes. 10 μM nebivolol induced myofilament Ca2+ desensitization in WT strips and to a greater extent in KI strips. Neither 1 nor 10 μM nebivolol had an effect on Ca2+ sensitivity in cardiac muscle strips of three HCM patients with MYBPC3 mutations, whereas epigallocatechin-gallate induced a right shift in the force-Ca2+ curve. Conclusion: Nebivolol induced a myofilament Ca2+ desensitization in both WT and KI strips, which was more pronounced in KI muscle strips. In human cardiac muscle strips of three HCM patients nebivolol had no effect on myofilament Ca2+ sensitivity.

Dataset Information

Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice.

Background

Methods and results

Conclusion

Publications

Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice.

Similar Datasets

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