Article Impact Level: HIGH Data Quality: STRONG Summary of Circulation Research, 135(5), 554–574. https://doi.org/10.1161/CIRCRESAHA.124.324588 Dr. Nora Josefine Paulke et al.
Points
- This study explores the role of dysferlin, a protein crucial for membrane repair, in supporting the transverse-axial tubule (TAT) network in heart cells during cardiac hypertrophy.
- Dysferlin was found near the junctions of the TAT network and sarcoplasmic reticulum. It is essential for calcium release, a critical process in heart muscle contraction.
- Dysferlin-knockout mice displayed early signs of dilated cardiomyopathy, with proteomic changes before systolic heart failure, indicating dysferlin’s protective role.
- Increased dysferlin expression was observed in hypertrophied wild-type hearts under pressure overload, enabling tubule reorganization, while knockout mice showed less hypertrophy.
- Dysferlin is identified as a potential therapeutic target for heart conditions linked to hypertrophy and heart failure due to its role in maintaining TAT network integrity and function.
Summary
This research paper investigates the role of dysferlin, a membrane fusion and repair protein, in maintaining the integrity of the transverse-axial tubule (TAT) network within cardiomyocytes during pressure overload-induced cardiac hypertrophy. Cardiac hypertrophy serves as a compensatory mechanism to address increased biomechanical stress on the heart, but it can lead to heart failure if not adequately managed. The study utilized stimulated emission depletion microscopy and electron microscopy to localize dysferlin in mouse and human cardiomyocytes and data-independent acquisition mass spectrometry to analyze the cardiac dysferlin interactome and identify proteomic alterations in dysferlin-knockout mice.
The findings revealed that dysferlin is localized within a vesicular compartment near the junctional complexes of the TAT network and the sarcoplasmic reticulum, which are critical for calcium-induced calcium release. Notably, dysferlin-knockout mice exhibited a mild progressive phenotype of dilated cardiomyopathy, with global proteomic analyses indicating changes prior to systolic failure. After transverse aortic constriction, there was a significant increase in dysferlin protein expression in hypertrophied wild-type myocardium, while dysferlin-knockout mice showed markedly reduced left ventricular hypertrophy (p < 0.05). Live-cell membrane imaging demonstrated substantial reorganization of the TAT network in wild-type left-ventricular myocytes post-constriction, characterized by a robust proliferation of axial tubules, which was critically dependent on the enhanced expression of dysferlin in newly forming tubule components.
In conclusion, dysferlin emerges as a novel molecular target in cardiac disease, crucial for maintaining the integrity of tubule-sarcoplasmic reticulum junctional complexes that facilitate regulated excitation-contraction coupling. This study highlights dysferlin’s essential role in TAT network reorganization and tubular membrane proliferation during cardiomyocyte hypertrophy induced by pressure overload, suggesting potential therapeutic implications for cardiac pathologies associated with hypertrophy and heart failure.
Link to the article: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.124.324588
References Paulke, N. J., Fleischhacker, C., Wegener, J. B., Riedemann, G. C., Cretu, C., Mushtaq, M., Zaremba, N., Möbius, W., Zühlke, Y., Wedemeyer, J., Liebmann, L., Gorshkova, A. A., Kownatzki-Danger, D., Wagner, E., Kohl, T., Wichmann, C., Jahn, O., Urlaub, H., Toischer, K., … Brandenburg, S. (2024). Dysferlin enables tubular membrane proliferation in cardiac hypertrophy. Circulation Research, 135(5), 554–574. https://doi.org/10.1161/CIRCRESAHA.124.324588
