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

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. Her...

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Autores principales: Algül, Sıla, Dorsch, Larissa M., Sorop, Oana, Vink, Aryan, Michels, Michelle, dos Remedios, Cristobal G., Dalinghaus, Michiel, Merkus, Daphne, Duncker, Dirk J., Kuster, Diederik W. D., van der Velden, Jolanda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533615/
https://www.ncbi.nlm.nih.gov/pubmed/37644284
http://dx.doi.org/10.1007/s00360-023-01509-1
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author Algül, Sıla
Dorsch, Larissa M.
Sorop, Oana
Vink, Aryan
Michels, Michelle
dos Remedios, Cristobal G.
Dalinghaus, Michiel
Merkus, Daphne
Duncker, Dirk J.
Kuster, Diederik W. D.
van der Velden, Jolanda
author_facet Algül, Sıla
Dorsch, Larissa M.
Sorop, Oana
Vink, Aryan
Michels, Michelle
dos Remedios, Cristobal G.
Dalinghaus, Michiel
Merkus, Daphne
Duncker, Dirk J.
Kuster, Diederik W. D.
van der Velden, Jolanda
author_sort Algül, Sıla
collection PubMed
description 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: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00360-023-01509-1.
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spelling pubmed-105336152023-09-29 The microtubule signature in cardiac disease: etiology, disease stage, and age dependency Algül, Sıla Dorsch, Larissa M. Sorop, Oana Vink, Aryan Michels, Michelle dos Remedios, Cristobal G. Dalinghaus, Michiel Merkus, Daphne Duncker, Dirk J. Kuster, Diederik W. D. van der Velden, Jolanda J Comp Physiol B Original Paper 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: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00360-023-01509-1. Springer Berlin Heidelberg 2023-08-29 2023 /pmc/articles/PMC10533615/ /pubmed/37644284 http://dx.doi.org/10.1007/s00360-023-01509-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Paper
Algül, Sıla
Dorsch, Larissa M.
Sorop, Oana
Vink, Aryan
Michels, Michelle
dos Remedios, Cristobal G.
Dalinghaus, Michiel
Merkus, Daphne
Duncker, Dirk J.
Kuster, Diederik W. D.
van der Velden, Jolanda
The microtubule signature in cardiac disease: etiology, disease stage, and age dependency
title The microtubule signature in cardiac disease: etiology, disease stage, and age dependency
title_full The microtubule signature in cardiac disease: etiology, disease stage, and age dependency
title_fullStr The microtubule signature in cardiac disease: etiology, disease stage, and age dependency
title_full_unstemmed The microtubule signature in cardiac disease: etiology, disease stage, and age dependency
title_short The microtubule signature in cardiac disease: etiology, disease stage, and age dependency
title_sort microtubule signature in cardiac disease: etiology, disease stage, and age dependency
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533615/
https://www.ncbi.nlm.nih.gov/pubmed/37644284
http://dx.doi.org/10.1007/s00360-023-01509-1
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