Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure
Abstract
:1. Titin Is an Essential Molecule within the Sarcomere Where It Contributes to Cardiac Function
1.1. Titin Contains Four Structural Domains That Impart Important Molecular Properties to the Sarcomere during Cardiac Function
1.2. Titin’s Structure Is Essential to Normal Cardiac Function, Passive Tension, and Length Dependent Activation
1.3. Abnormalities in Titin Contribute to Systolic and Diastolic Heart Failure
2. Truncation Mutations in TTN Cause Dilated Cardiomyopathy (DCM)
2.1. TTN Truncation Variations in Highly Constitutively Expressed Exons Cause DCM
2.2. TTNtv Cause DCM through Haploinsufficiency, Increased Metabolic Stress, and Activation of the mTOR Signalling Cascade
2.3. TTNtv Are Associated with Late Presentation Of DCM, Are More Pathogenic in European Ancestry, and Are Associated with Early Atrial Arrhythmias
2.4. TTNtv Are Associated with Worse Outcomes When Combined with Additional Cardiac Risk Factors
2.5. Inhibition of the mTOR Pathway and Antisense Oligo Nucleotide Mediated Exon Skipping Are Potential Therapies for TTNtv Related DCM
3. Titin Transcriptional Modifications Are Associated with Development of Cardiomyopathy and Represent a Therapeutic Target for Inherited and Acquired Heart Failure
3.1. Transcriptional Changes of Titin Isosforms Alter Passive Tension and Myocardial Stiffness in Heart Failure
3.2. RBM20 Is a Key Regulator of Titin Isoform Preference
3.3. Modifications of Titin Isoforms Represent a Therapeutic Target for Treatment of Heart Failure
4. Post-Translational Modifications of Titin Affect Myocardial Physiology and Can Be Modified to Treat Heart Failure
4.1. Phosphorylation of the PEVK Element of Titin Increases Cardiomyocyte Passive Tension
4.2. Phosphorylation of the N2B Unique Sequence (N2Bus) Element of Titin Decreases Cardiomyocyte Passive Tension
4.3. Diabetes Contributes to Diastolic Dysfunction via Abnormal Phosphorylation of Titin, Which Can Be Reversed by Treatment with Metformin, and Neuregulin-1 (NRG-1)
4.4. Activation of Cyclic Guanosine Monophosphate (cGMP) and PKG Decreases Titin Passive Tension and Represents a Viable Therapy for Treatment of Heart Failure
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Proposed Titin Modifying Therapy | Mechanism of Action | Effect on Cardiac Function |
---|---|---|
mTOR inhibitor: rapamycin | Decrease mTOR complex signaling that is activated Titin truncation variations (TTNtv) mediated mRNA decay | Improve DCM phenotype for patients with TTNtv |
Antisense oligonucleotide mediated exon skipping | Bind mRNA during transcription to skip exon containing missense mutation and prevent early termination | Improve DCM phenotype for patients with TTNtv |
T3 hormone, insulin | Increase RBM20 expression to transcriptionally select shorter, stiffer N2B TTN isoform | Increase passive tension to treat DCM |
Cardenolides: digoxin and digitoxin | Decrease RBM20 expression to transcriptionally select longer, softer N2BA TTN isoform | Decrease passive tension to treat diastolic dysfunction |
Metformin, insulin | Increase ERK2 mediated phosphorylation of N2Bus element | Decrease passive tension to treat diastolic dysfunction |
Neuregulin-1 (NRG-1) | Increase ERK2 mediated phosphorylation of N2Bus element, inhibit PKC⍺ phosphorylation of PEVK element | Decrease passive tension to treat diastolic dysfunction |
cGMP agonists: sildenafil, vericiguat | Increases cGMP activity to increase PKG mediated phosphorylation of N2Bus element | Decrease passive tension to treat diastolic dysfunction |
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Tharp, C.; Mestroni, L.; Taylor, M. Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure. J. Clin. Med. 2020, 9, 2770. https://doi.org/10.3390/jcm9092770
Tharp C, Mestroni L, Taylor M. Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure. Journal of Clinical Medicine. 2020; 9(9):2770. https://doi.org/10.3390/jcm9092770
Chicago/Turabian StyleTharp, Charles, Luisa Mestroni, and Matthew Taylor. 2020. "Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure" Journal of Clinical Medicine 9, no. 9: 2770. https://doi.org/10.3390/jcm9092770
APA StyleTharp, C., Mestroni, L., & Taylor, M. (2020). Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure. Journal of Clinical Medicine, 9(9), 2770. https://doi.org/10.3390/jcm9092770