Key result
Knockout of the long noncoding RNA Trdn-as in mice downregulates cardiac triadin, impairs Ca2+ handling, and causes premature death, with fewer than 20% of knockout mice surviving beyond 24 months compared to over 60% of wild-type mice.
Why the study?
Decreased levels of the cardiac-predominant triadin isoform Trisk32 cause cardiac dysfunction and arrhythmias, but the mechanisms that maintain triadin isoform composition in the heart remain elusive.
Does the long noncoding RNA Trdn-as regulate alternative splicing of the triadin gene and maintain cardiac function?
Does the long noncoding RNA Trdn-as regulate alternative splicing of the triadin gene and maintain cardiac function?
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We reported a novel role for a poorly characterized cardiac long noncoding RNA, Trdn-as, in regulating alternative splicing of the calcium handling protein Triadin. Using mouse models, hiPSC-CMs, as well as explants from healthy and failing human heart tissue, we found that loss of Trdn-as expression results in aberrant catecholamine response, and dysfunctional calcium handling in isolated cardiomyocytes. More strikingly, Trdn-as1 knockout mice displayed loss of triadin expression, cardiac functional abnormalities, arrhythmia, and premature death, possibly due to said arrhythmias.”
“In this issue of Circulation, Zhao et al uncover the function of the cardiomyocyte-specific lncRNA triadin-antisense (Trdn-as). Trdn-as is encoded within the triadin (Trdn) gene. Triadin is a well-known molecular component of the calcium release unit of the cardiomyocyte. It interacts with the ryanodine receptor and with calsequestrin to enhance the sarcoplasmic reticulum Ca2+ release that couples cell excitation with contraction.”
Trdn-as is a cardiomyocyte-specific long noncoding RNA that regulates alternative splicing of the triadin gene, presenting a potential therapeutic target for heart failure and arrhythmias.
Background: Abnormalities in Ca 2+ homeostasis are associated with cardiac arrhythmias and heart failure. Triadin plays an important role in Ca 2+ homeostasis in cardiomyocytes. Alternative splicing of a single triadin gene produces multiple triadin isoforms. The cardiac-predominant isoform, mouse MT-1 or human Trisk32, is encoded by triadin exons 1 to 8. In humans, mutations in the triadin gene that lead to a reduction in Trisk32 levels in the heart can cause cardiac dysfunction and arrhythmias. Decreased levels of Trisk32 in the heart are also common in patients with heart failure. However, mechanisms that maintain triadin isoform composition in the heart remain elusive. Methods: We analyzed triadin expression in heart explants from patients with heart failure and cardiac arrhythmias and in hearts from mice carrying a knockout allele for Trdn-as , a cardiomyocyte-specific long noncoding RNA encoded by the antisense strand of the triadin gene, between exons 9 and 11. Catecholamine challenge with isoproterenol was performed on Trdn-as knockout mice to assess the role of Trdn-as in cardiac arrhythmogenesis, as assessed by ECG. Ca 2+ transients in adult mouse cardiomyocytes were measured with the IonOptix platform or the GCaMP system. Biochemistry assays, single-molecule fluorescence in situ hybridization, subcellular localization imaging, RNA sequencing, and molecular rescue assays were used to investigate the mechanisms by which Trdn-as regulates cardiac function and triadin levels in the heart. Results: We report that Trdn-as maintains cardiac function, at least in part, by regulating alternative splicing of the triadin gene. Knockout of Trdn-as in mice downregulates cardiac triadin, impairs Ca 2+ handling, and causes premature death. Trdn-as knockout mice are susceptible to cardiac arrhythmias in response to catecholamine challenge. Normalization of cardiac triadin levels in Trdn-as knockout cardiomyocytes is sufficient to restore Ca 2+ handling. Last, Trdn-as colocalizes and interacts with serine/arginine splicing factors in cardiomyocyte nuclei and is essential for efficient recruitment of splicing factors to triadin precursor mRNA. Conclusions: These findings reveal regulation of alternative splicing as a novel mechanism by which a long noncoding RNA controls cardiac function. This study indicates potential therapeutics for heart disease by targeting the long noncoding RNA or pathways regulating alternative splicing.
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Zhao et al. (2022) studied Heart failure and cardiac arrhythmias (preclinical models). Trdn-as knockout and overexpression vs. Wild-type or control was evaluated on Cardiac triadin expression, Ca2+ handling, and survival. Knockout of the long noncoding RNA Trdn-as in mice downregulates cardiac triadin, impairs Ca2+ handling, and causes premature death, with fewer than 20% of knockout mice surviving beyond 24 months compared to over 60% of wild-type mice.
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