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

Proceedings of the National Academy of Sciences of the United States of America
Chen-Ching YuanDanuta Szczesna-Cordary

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+ concentratio...Continue Reading

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Citations

Oct 27, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Katarzyna KazmierczakDanuta Szczesna-Cordary
May 19, 2019·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Sunil YadavDanuta Szczesna-Cordary
Jun 27, 2018·International Journal of Molecular Sciences·Alf MånssonDilson E Rassier
Jan 8, 2020·International Journal of Molecular Sciences·Osamu Tsukamoto
Sep 25, 2020·Proceedings of the National Academy of Sciences of the United States of America·Trisha TucholskiYing Ge
Nov 22, 2020·International Journal of Molecular Sciences·Camden RichterDanuta Szczesna-Cordary
May 1, 2021·International Journal of Molecular Sciences·Kasturi MarkandranChristine Cheung
May 11, 2021·Frontiers in Cell and Developmental Biology·Yifeng WangZhibin Hu
May 21, 2021·The Journal of General Physiology·Yoel H SitbonDanuta Szczesna-Cordary
Nov 20, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Marie-Louise BangJu Chen

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Methods Mentioned

BETA
exome sequencing
transgenic
transmission electron microscopy
X-Ray
electron microscopy

Software Mentioned

! Tandem
IonOptix

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