The ryanodine receptor stabilizer S107 ameliorates contractility of adult Rbm20 knockout rat cardiomyocytes
Year: 2021
Type: article
Abstract: RNA binding motif 20 (RBM20) cardiomyopathy has been detected in approximately 3% of populations afflicted with dilated cardiomyopathy (DCM). It is well conceived that RBM20 cardiomyopathy is provoked by titin isoform switching in combination with resting Ca2+ leaking. In this study, we characterized the cardiac function in Rbm20 knockout (KO) rats at 3-, 6-, 9-, and 12-months of age and examined the effect of the ryanodine receptor stabilizer S107 on resting intracellular levels and cardiomyocyte contractile properties. Our results revealed that even though Rbm20 depletion promoted expression of larger titin isoform and reduced myocardial stiffness in young rats (3 months of age), the established DCM phenotype required more time to embellish. S107 restored elevated intracellular Ca2+ to normal levels and ameliorated cardiomyocyte contractile properties in isolated cardiomyocytes from 6-month-old Rbm20 KO rats. However, S107 failed to preserve cardiac homeostasis in Rbm20 KO rats at 12 months of age, unexpectedly, likely due to the existence of multiple pathogenic mechanisms. Taken together, our data suggest the therapeutic promises of S107 in the management of RBM20 cardiomyopathy.
Source: Physiological Reports
DOI: 10.14814/phy2.15011
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,700
Funders: American Heart Association, Wisconsin Alumni Research Foundation, University of Wisconsin Foundation, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: The role of posttranslational modification of RBM20 in regulating titin isoform transition, G1542379004, G186705966, Cytoplasmic trafficking of titin mRNA binding protein 20 in heart failure progression, G2113021930, G2451848122, G2635073672, G3627945491, G3630554311, Posttranscriptional Regulation of RNA Binding Proteins in Heart Failure, G4130880593, G455263890, G4846153411, G5172151881, Epigenetic Readers as Downstream Effectors of Beta1-Adrenergic Receptor Signaling in HFrEF, Wyoming IDeA Networks for Biomedical Research Excellence Phase 4, Targeting titin for the treatment of Heart Failure with Preserved Ejection Fraction (HFpEF), G7323737860, Sex-specific regulation of myofibrillar function in the aging heart, G7683404682, Mechanism of the myofibril relaxation abnormalities in heart failure with preserved ejection fraction, Bioenergetic and Cardiometabolic Consequences of the Loss of Gonadal Function, G9000018328
OpenAlex ID: W3201596099