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The microtubule cytoskeleton in cardiac mechanics and heart failure

Abstract

The microtubule network of cardiac muscle cells has unique architectural and biophysical features to accommodate the demands of the working heart. Advances in live-cell imaging and in deciphering the ‘tubulin code’ have shone new light on this cytoskeletal network and its role in heart failure. Microtubule-based transport orchestrates the growth and maintenance of the contractile apparatus through spatiotemporal control of translation, while also organizing the specialized membrane systems required for excitation–contraction coupling. To withstand the high mechanical loads of the working heart, microtubules are post-translationally modified and physically reinforced. In response to stress to the myocardium, the microtubule network remodels, typically through densification, post-translational modification and stabilization. Under these conditions, physically reinforced microtubules resist the motion of the cardiomyocyte and increase myocardial stiffness. Accordingly, modified microtubules have emerged as a therapeutic target for reducing stiffness in heart failure. In this Review, we discuss the latest evidence on the contribution of microtubules to cardiac mechanics, the drivers of microtubule network remodelling in cardiac pathologies and the therapeutic potential of targeting cardiac microtubules in acquired heart diseases.

Key points

  • Microtubule-based transport establishes, maintains and remodels important subcellular compartments in cardiomyocytes, including the intercalated disc, transverse tubule and sarcoplasmic reticulum membrane systems.

  • Microtubules distribute mRNA and the translational machinery throughout cardiomyocytes to control local protein synthesis and cardiomyocyte hypertrophy.

  • The microtubule network remodels in terms of its density, post-translational modifications, tubulin isoform composition, stability and crosslinking in various cardiac pathologies.

  • A modified, dense and crosslinked microtubule network increases the viscoelastic resistance to cardiomyocyte motion in heart failure, which can contribute to elevated myocardial stiffness.

  • Although gross microtubule disruption improves cardiac outcomes in certain large-animal and small-animal models of heart failure, more targeted therapeutic approaches are needed for clinical application.

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Fig. 1: The tubulin code in the heart.
Fig. 2: Microtubules organize subcellular domains in cardiomyocytes.
Fig. 3: The mechanical properties of the microtubule cytoskeleton.
Fig. 4: Microtubule remodelling in heart failure.

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Acknowledgements

The authors are supported by NIH R01s HL133080 and HL149891 and by Foundation Leducq Research grant no. 20CVD01 to B.L.P. and American Heart Association Career Development Award 856504 to M.A.C.

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Correspondence to Benjamin L. Prosser.

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B.L.P. is an inventor on a pending patent application that is relevant to this Review: US Patent Application no. 15/959,181 for “Compositions and Methods for Improving Heart Function and Treating Heart Failure”. M.A.C. declares no competing interests.

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Caporizzo, M.A., Prosser, B.L. The microtubule cytoskeleton in cardiac mechanics and heart failure. Nat Rev Cardiol 19, 364–378 (2022). https://doi.org/10.1038/s41569-022-00692-y

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