The microtubule signature in cardiac disease: etiology, disease stage, and age dependency

Sıla Algül*, Larissa M. Dorsch, Oana Sorop, Aryan Vink, Michelle Michels, Cristobal G. dos Remedios, Michiel Dalinghaus, Daphne Merkus, Dirk J. Duncker, Diederik W.D. Kuster, Jolanda van der Velden

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Employing animal models to study heart failure (HF) has become indispensable to discover and test novel therapies, but their translatability remains challenging. Although cytoskeletal alterations are linked to HF, the tubulin signature of common experimental models has been incompletely defined. Here, we assessed the tubulin signature in a large set of human cardiac samples and myocardium of animal models with cardiac remodeling caused by pressure overload, myocardial infarction or a gene defect. We studied levels of total, acetylated, and detyrosinated α-tubulin and desmin in cardiac tissue from hypertrophic (HCM) and dilated cardiomyopathy (DCM) patients with an idiopathic (n = 7), ischemic (n = 7) or genetic origin (n = 59), and in a pressure-overload concentric hypertrophic pig model (n = 32), pigs with a myocardial infarction (n = 28), mature pigs (n = 6), and mice (n = 15) carrying the HCM-associated MYBPC3 2373insG mutation. In the human samples, detyrosinated α-tubulin was increased 4-fold in end-stage HCM and 14-fold in pediatric DCM patients. Acetylated α-tubulin was increased twofold in ischemic patients. Across different animal models, the tubulin signature remained mostly unaltered. Only mature pigs were characterized by a 0.5-fold decrease in levels of total, acetylated, and detyrosinated α-tubulin. Moreover, we showed increased desmin levels in biopsies from NYHA class II HCM patients (2.5-fold) and the pressure-overload pig model (0.2–0.3-fold). Together, our data suggest that desmin levels increase early on in concentric hypertrophy and that animal models only partially recapitulate the proliferated and modified tubulin signature observed clinically. Our data warrant careful consideration when studying maladaptive responses to changes in the tubulin content in animal models. Graphical Abstract: [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)581-595
Number of pages15
JournalJournal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology
Volume193
Issue number5
Early online date29 Aug 2023
DOIs
Publication statusPublished - Oct 2023

Bibliographical note

Funding Information:
The Sydney Heart Bank cryofacility was funded by Medical Advances Without Animals (MAWA). We also acknowledge support from the Dutch CardioVascular Alliance initiatives of the Dutch Heart Foundation (2020B005 Dutch Cardiovascular Alliance [DVCA]-DOUBLE-DOSE, 2014-40 CVON-DOSIS) and the Dutch Heart Foundation grants 2017B018 ARENA-PRIME and 2020B008 RECONNEXT. In addition, this work was supported by a Leducq Fondation award TNE ID#: 673168 and NWO (NWO-ZonMW; 91818602 VICI) grant to JV.

Publisher Copyright:
© 2023, The Author(s).

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