Modifications of Sarcoplasmic Reticulum Function Prevent Progression of Sarcomere-Linked Hypertrophic Cardiomyopathy Despite a Persistent Increase in Myofilament Calcium Response
Author
Chowdhury, Shamim A KWarren, Chad M
Simon, Jillian N
Ryba, David M
Batra, Ashley
Varga, Peter
Kranias, Evangelia G
Tardiff, Jil C
Solaro, R John
Wolska, Beata M
Affiliation
Univ Arizona, Dept Med, Div CardiolIssue Date
2020-03-10Keywords
Ca2+/calmodulin-dependent protein kinase II (CaMKII)Hypertrophic cardiomyopathy
myofilament Ca2+ sensitivity
phospholamban
speckle strain
treatment
troponin T (TnT)
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FRONTIERS MEDIA SACitation
Chowdhury SAK, Warren CM, Simon JN, Ryba DM, Batra A, Varga P, Kranias EG, Tardiff JC, Solaro RJ and Wolska BM (2020) Modifications of Sarcoplasmic Reticulum Function Prevent Progression of Sarcomere-Linked Hypertrophic Cardiomyopathy Despite a Persistent Increase in Myofilament Calcium Response. Front. Physiol. 11:107. doi: 10.3389/fphys.2020.00107Journal
FRONTIERS IN PHYSIOLOGYRights
Copyright © 2020 Chowdhury, Warren, Simon, Ryba, Batra, Varga, Kranias, Tardiff, Solaro and Wolska. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in different genes mainly encoding myofilament proteins and therefore called a "disease of the sarcomere." Despite the discovery of sarcomere protein mutations linked to HCM almost 30 years ago, the cellular mechanisms responsible for the development of this disease are not completely understood and likely vary among different mutations. Moreover, despite many efforts to develop effective treatments for HCM, these have largely been unsuccessful, and more studies are needed to better understand the cellular mechanisms of the disease. In experiments reported here, we investigated a mouse model expressing the mutant cTnT-R92Q, which is linked to HCM and induces an increase in myofilament Ca2+ sensitivity and diastolic dysfunction. We found that early correction of the diastolic dysfunction by phospholamban knockout (PLNKO) was able to prevent the development of the HCM phenotype in troponin T (TnT)-R92Q transgenic (TG) mice. Four groups of mice in FVB/N background were generated and used for the experiments: (1) non-transgenic (NTG)/PLN mice, which express wild-type TnT and normal level of PLN; (2) NTG/PLNKO mice, which express wild-type TnT and no PLN; (3) TG/PLN mice, which express TnT-R92Q and normal level of PLN; (4) TG/PLNKO mice, which express TnT-R92Q and no PLN. Cardiac function was determined using both standard echocardiographic parameters and speckle tracking strain measurements. We found that both atrial morphology and diastolic function were altered in TG/PLN mice but normal in TG/PLNKO mice. Histological analysis showed a disarray of myocytes and increased collagen deposition only in TG/PLN hearts. We also observed increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation only in TG/PLN hearts but not in TG/PLNKO hearts. The rescue of the HCM phenotype was not associated with differences in myofilament Ca2+ sensitivity between TG/PLN and TG/PLNKO mice. Moreover, compared to standard systolic echo parameters, such as ejection fraction (EF), speckle strain measurements provided a more sensitive approach to detect early systolic dysfunction in TG/PLN mice. In summary, our results indicate that targeting diastolic dysfunction through altering Ca2+ fluxes with no change in myofilament response to Ca2+ was able to prevent the development of the HCM phenotype and should be considered as a potential additional treatment for HCM patients.Note
Open access journalISSN
1664-042XPubMed ID
32210830Version
Final published versionae974a485f413a2113503eed53cd6c53
10.3389/fphys.2020.00107
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Except where otherwise noted, this item's license is described as Copyright © 2020 Chowdhury, Warren, Simon, Ryba, Batra, Varga, Kranias, Tardiff, Solaro and Wolska. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).
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