Reduced Expression of MTSS1 Increases Sarcomere Number and Improves Contractility in Select Forms of Monogenic DCM DOI Open Access

Hannah M. Kleppe,

Anastasia Budan,

Luke Zhang

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 20, 2024

ABSTRACT Background The I-bar protein MTSS1 is a known modifier of heart failure and contractile phenotypes but its role in modulating dysfunction genetic forms Mendelian dilated cardiomyopathy (DCM) not known. Methods potential cardiac TTN DCM was explored using time-to-event models longitudinal human datasets. Using induced siRNA mutant pluripotent stem cell cardiomyocytes (iPSC-CMs) the impact knockdown MTSS upon sarcomere Cardiomyocyte biology assessed via quantitative high-content microscopy, mechanism contractility engineered tissues (EHTs). Results Amongst individuals affected with DCM, variant conferring lower levels associated significantly improved event-free survival from cardiovascular death or transplant (HR 0.29, p=0.0016). Knockdown by appearance iPSC-CM (p=2.9e-06), CSRP3 (p=3.1e-14), RBM20 (p=4.4e-04) as microscopy. Correspondingly, increased EHT (p=0.003), (p=0.008), (p<2e-16). Across all backgrounds, observed to increase number sarcomeres (p<0.0001), co-immunoprecipitation experiments physically interacts MYO18A key determinant early formation. resulted transcription MYH7 (0.29 log 2 FC, p=2.9e-06) along other genes. Conclusions In iPSC-CMs twitch force select vitro models, may suggest plays previously unrecognized production. Human observational experimental data supports hypothesis that reduced expression be beneficial caused TTN, RBM20, CSRP3.

Язык: Английский

Reduced Expression of MTSS1 Increases Sarcomere Number and Improves Contractility in Select Forms of Monogenic DCM DOI Open Access

Hannah M. Kleppe,

Anastasia Budan,

Luke Zhang

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 20, 2024

ABSTRACT Background The I-bar protein MTSS1 is a known modifier of heart failure and contractile phenotypes but its role in modulating dysfunction genetic forms Mendelian dilated cardiomyopathy (DCM) not known. Methods potential cardiac TTN DCM was explored using time-to-event models longitudinal human datasets. Using induced siRNA mutant pluripotent stem cell cardiomyocytes (iPSC-CMs) the impact knockdown MTSS upon sarcomere Cardiomyocyte biology assessed via quantitative high-content microscopy, mechanism contractility engineered tissues (EHTs). Results Amongst individuals affected with DCM, variant conferring lower levels associated significantly improved event-free survival from cardiovascular death or transplant (HR 0.29, p=0.0016). Knockdown by appearance iPSC-CM (p=2.9e-06), CSRP3 (p=3.1e-14), RBM20 (p=4.4e-04) as microscopy. Correspondingly, increased EHT (p=0.003), (p=0.008), (p<2e-16). Across all backgrounds, observed to increase number sarcomeres (p<0.0001), co-immunoprecipitation experiments physically interacts MYO18A key determinant early formation. resulted transcription MYH7 (0.29 log 2 FC, p=2.9e-06) along other genes. Conclusions In iPSC-CMs twitch force select vitro models, may suggest plays previously unrecognized production. Human observational experimental data supports hypothesis that reduced expression be beneficial caused TTN, RBM20, CSRP3.

Язык: Английский

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