Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice

Chen Ching Yuan, Katarzyna Kazmierczak, Jingsheng Liang, Zhiqun Zhou, Sunil Yadav, Aldrin V. Gomes, Thomas C. Irving, Danuta Szczesna-Cordary

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Dilated cardiomyopathy (DCM) is a devastating heart disease that affects about 1 million people in the United States, but the underlying mechanisms remain poorly understood. In this study, we aimed to determine the biomechanical and structural causes of DCM in transgenic mice carrying a novel mutation in the MYL2 gene, encoding the cardiac myosin regulatory light chain. Transgenic D94A (aspartic acid-to-alanine) mice were created and investigated by echocardiography and invasive hemodynamic and molecular structural and functional assessments. Consistent with the DCM phenotype, a significant reduction of the ejection fraction (EF) was observed in ∼5- and ∼12-mo-old male and female D94A lines compared with respective WT controls. Younger male D94A mice showed a more pronounced left ventricular (LV) chamber dilation compared with female counterparts, but both sexes of D94A lines developed DCM by 12 mo of age. The hypocontractile activity of D94A myosin motors resulted in the rightward shift of the force–pCa dependence and decreased actin-activated myosin ATPase activity. Consistent with a decreased Ca2+ sensitivity of contractile force, a small-angle X-ray diffraction study, performed in D94A fibers at submaximal Ca2+ concentrations, revealed repositioning of the D94A cross-bridge mass toward the thick-filament backbone supporting the hypocontractile state of D94A myosin motors. Our data suggest that structural perturbations at the level of sarcomeres result in aberrant cardiomyocyte cytoarchitecture and lead to LV chamber dilation and decreased EF, manifesting in systolic dysfunction of D94A hearts. The D94A-induced development of DCM in mice closely follows the clinical phenotype and suggests that MYL2 may serve as a new therapeutic target for dilated cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)E2338-E2347
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number10
DOIs
StatePublished - Mar 6 2018

Fingerprint

Dilated Cardiomyopathy
Myosins
Dilatation
Cardiac Myosins
Phenotype
Myosin Light Chains
Sarcomeres
Cardiac Myocytes
Aspartic Acid
X-Ray Diffraction
Alanine
Transgenic Mice
Echocardiography
Heart Diseases
Hemodynamics
Mutation
Genes

Keywords

  • DCM
  • Invasive hemodynamics
  • MYL2
  • Myosin RLC
  • Transgenic D94A mice

ASJC Scopus subject areas

  • General

Cite this

Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice. / Yuan, Chen Ching; Kazmierczak, Katarzyna; Liang, Jingsheng; Zhou, Zhiqun; Yadav, Sunil; Gomes, Aldrin V.; Irving, Thomas C.; Szczesna-Cordary, Danuta.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 10, 06.03.2018, p. E2338-E2347.

Research output: Contribution to journalArticle

Yuan, Chen Ching ; Kazmierczak, Katarzyna ; Liang, Jingsheng ; Zhou, Zhiqun ; Yadav, Sunil ; Gomes, Aldrin V. ; Irving, Thomas C. ; Szczesna-Cordary, Danuta. / Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 10. pp. E2338-E2347.
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abstract = "Dilated cardiomyopathy (DCM) is a devastating heart disease that affects about 1 million people in the United States, but the underlying mechanisms remain poorly understood. In this study, we aimed to determine the biomechanical and structural causes of DCM in transgenic mice carrying a novel mutation in the MYL2 gene, encoding the cardiac myosin regulatory light chain. Transgenic D94A (aspartic acid-to-alanine) mice were created and investigated by echocardiography and invasive hemodynamic and molecular structural and functional assessments. Consistent with the DCM phenotype, a significant reduction of the ejection fraction (EF) was observed in ∼5- and ∼12-mo-old male and female D94A lines compared with respective WT controls. Younger male D94A mice showed a more pronounced left ventricular (LV) chamber dilation compared with female counterparts, but both sexes of D94A lines developed DCM by 12 mo of age. The hypocontractile activity of D94A myosin motors resulted in the rightward shift of the force–pCa dependence and decreased actin-activated myosin ATPase activity. Consistent with a decreased Ca2+ sensitivity of contractile force, a small-angle X-ray diffraction study, performed in D94A fibers at submaximal Ca2+ concentrations, revealed repositioning of the D94A cross-bridge mass toward the thick-filament backbone supporting the hypocontractile state of D94A myosin motors. Our data suggest that structural perturbations at the level of sarcomeres result in aberrant cardiomyocyte cytoarchitecture and lead to LV chamber dilation and decreased EF, manifesting in systolic dysfunction of D94A hearts. The D94A-induced development of DCM in mice closely follows the clinical phenotype and suggests that MYL2 may serve as a new therapeutic target for dilated cardiomyopathy.",
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AU - Liang, Jingsheng

AU - Zhou, Zhiqun

AU - Yadav, Sunil

AU - Gomes, Aldrin V.

AU - Irving, Thomas C.

AU - Szczesna-Cordary, Danuta

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AB - Dilated cardiomyopathy (DCM) is a devastating heart disease that affects about 1 million people in the United States, but the underlying mechanisms remain poorly understood. In this study, we aimed to determine the biomechanical and structural causes of DCM in transgenic mice carrying a novel mutation in the MYL2 gene, encoding the cardiac myosin regulatory light chain. Transgenic D94A (aspartic acid-to-alanine) mice were created and investigated by echocardiography and invasive hemodynamic and molecular structural and functional assessments. Consistent with the DCM phenotype, a significant reduction of the ejection fraction (EF) was observed in ∼5- and ∼12-mo-old male and female D94A lines compared with respective WT controls. Younger male D94A mice showed a more pronounced left ventricular (LV) chamber dilation compared with female counterparts, but both sexes of D94A lines developed DCM by 12 mo of age. The hypocontractile activity of D94A myosin motors resulted in the rightward shift of the force–pCa dependence and decreased actin-activated myosin ATPase activity. Consistent with a decreased Ca2+ sensitivity of contractile force, a small-angle X-ray diffraction study, performed in D94A fibers at submaximal Ca2+ concentrations, revealed repositioning of the D94A cross-bridge mass toward the thick-filament backbone supporting the hypocontractile state of D94A myosin motors. Our data suggest that structural perturbations at the level of sarcomeres result in aberrant cardiomyocyte cytoarchitecture and lead to LV chamber dilation and decreased EF, manifesting in systolic dysfunction of D94A hearts. The D94A-induced development of DCM in mice closely follows the clinical phenotype and suggests that MYL2 may serve as a new therapeutic target for dilated cardiomyopathy.

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KW - Invasive hemodynamics

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