Microtubule detyrosination alters nuclear mechanotransduction and leads to pro-hypertrophic signaling in hypertrophic cardiomyopathy

Duursma, I.; Nollet, E. E.; Jansen, V. J.; Malone, J. A.; Bloem, J. S.; Bedi, K.; Margulies, K. B.; Schoonvelde, S. A. C.; Michels, M.; van der Wel, N. N.; van der Velden, J.; Kirby, T. J.; Kuster, D. W. D.

doi:10.1101/2025.03.28.646061

bioRxiv · 10.1101/2025.03.28.646061

Microtubule detyrosination alters nuclear mechanotransduction and leads to pro-hypertrophic signaling in hypertrophic cardiomyopathy

Duursma, I.·Nollet, E. E.·Jansen, V. J.·Malone, J. A.·Bloem, J. S.·Bedi, K.·Margulies, K. B.·Schoonvelde, S. A. C.·Michels, M.·van der Wel, N. N.·van der Velden, J.·Kirby, T. J.·Kuster, D. W. D.

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Abstract

BackgroundHypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and diastolic dysfunction and is accompanied by extensive cytoskeletal remodeling, including increased protein levels of desmin, tubulin and detyrosinated tubulin. We have previously demonstrated that tubulin detyrosination contributes to diastolic dysfunction. Microtubules are connected to the nucleus by the LINC complex, yet the role of cytoskeleton-nucleus interactions in HCM remain poorly understood. ObjectivesWe investigated whether cytoskeletal remodeling in HCM alters nuclear morphology and mechanics, and modulates hypertrophy-associated signaling pathways. MethodsNuclear morphology was assessed by electron microscopy and immunofluorescence in cardiac septal tissue from obstructive HCM patients (N=19) and non-failing donors (NF, N=8), as well as in Wild-Type (WT, N=18) and homozygous HCM-associated Mybpc3 c.2373InsG mice (Mybpc3c.2373InsG, N=19). A novel live-cell imaging approach was used to study nuclear deformation during cardiomyocyte contraction. YAP1 nuclear translocation was measured to evaluate downstream mechanosensitive signaling and detyrosination inhibitor epoY was used to test causality. ResultsNuclei were highly invaginated and enlarged in HCM in both patients and mice. Nuclear deformation during contraction was restricted in HCM cardiomyocytes, indicating altered mechanotransduction. These changes were associated with increased YAP1 nuclear localization and induction of YAP1 target and hypertrophic genes. Inhibition of microtubule detyrosination reduced nuclear invaginations, restored nuclear deformation and decreased YAP1 nuclear translocation. ConclusionCytoskeletal remodeling in HCM is associated with altered nuclear morphology and mechanotransduction, accompanied by YAP1 translocation which may contribute to hypertrophic remodeling. Targeting microtubule detyrosination rescues this phenotype, identifying nuclear mechanotransduction as a potential therapeutic target for HCM. Unstructured abstractHypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and diastolic dysfunction and is accompanied by extensive cytoskeletal remodeling, including increased desmin, tubulin, and detyrosinated tubulin levels, which we previously showed contribute to impaired relaxation. Since microtubules connect to the nucleus via the LINC complex, we investigated whether cytoskeletal remodeling alters nuclear morphology, mechanics, and hypertrophy-associated signaling. Using electron microscopy and immunofluorescence in cardiac septal tissue from obstructive HCM patients and non-failing donors, and immunofluorescence and live-cell imaging in septal tissue from Wild-Type and homozygous HCM-associated Mybpc3 c.2373InsG mice, we found that nuclei were enlarged and highly invaginated, with restricted nuclear deformation during contraction, indicating altered mechanotransduction. These changes were associated with increased YAP1 nuclear localization and increased expression of YAP1 target and hypertrophic genes. Inhibiting microtubule detyrosination reduced nuclear abnormalities, restored nuclear deformation, and decreased YAP1 nuclear translocation, identifying nuclear mechanotransduction as a potential therapeutic target in HCM. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/646061v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@7f915forg.highwire.dtl.DTLVardef@12131c6org.highwire.dtl.DTLVardef@4aff5eorg.highwire.dtl.DTLVardef@1c3a3a8_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICytoskeletal remodeling contributes to nuclear abnormalities and impaired mechanotransduction in hypertrophic cardiomyopathy. C_LIO_LIMicrotubule detyrosination promotes nuclear invaginations and increased YAP1 signaling in hypertrophic cardiomyopathy. C_LIO_LIPharmacological reduction of detyrosinated tubulin normalizes nuclear structure and mechanosignaling. C_LIO_LITargeting nuclear-cytoskeletal coupling may provide new therapeutic strategies for hypertrophic cardiomyopathy. C_LI

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Duursma, I., Nollet, E. E., Jansen, V. J., Malone, J. A., Bloem, J. S., Bedi, K., Margulies, K. B., Schoonvelde, S. A. C., Michels, M., van der Wel, N. N., van der Velden, J., Kirby, T. J., Kuster, D. W. D.. 2025-04-02. Microtubule detyrosination alters nuclear mechanotransduction and leads to pro-hypertrophic signaling in hypertrophic cardiomyopathy. https://doi.org/10.1101/2025.03.28.646061

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