New insights into the mechanisms of heart failure suggest that detyrosination, a microtubule post-translational modification that increases the mechanical resistance of the cytoskeleton, is a potential therapeutic target. “Suppressing detyrosination … reduced the stiffness of myocytes isolated from patients with heart failure, and improved the magnitude and kinetics of both myocyte contraction and relaxation,” says lead study investigator Benjamin Prosser.
Prosser and colleagues used mass spectrometry, super-resolution imaging, and single-cell mechanical assays to assess cardiomyocytes isolated from left ventricular samples from patients with heart failure of various aetiologies and severity and from individuals with non-failing hearts. Failing cardiomyocytes had upregulation and stabilization of the cytoskeleton, specifically microtubules, intermediate filaments, and associated proteins, compared with non-failing cardiomyocytes. The microtubule network in failing cardiomyocytes was dense and heavily detyrosinated, which led to increased cardiomyocyte stiffness and impaired contractility, and these features were independent of disease origin.
Suppression of microtubule detyrosination … reduced the stiffness of failing cardiomyocytes and restored … contractile function
Suppression of microtubule detyrosination with pharmacological or genetic approaches reduced the stiffness of failing cardiomyocytes and restored 40–50% of the lost contractile function. “We saw marked improvements in relaxation kinetics particularly in cardiomyocytes from patients with diastolic dysfunction, raising the possibility that a microtubule-based intervention could one day be used for treating patients with heart failure with preserved ejection fraction, a burgeoning patient population that lacks any viable therapeutic interventions,” remarks Prosser. Compounds for manipulating detyrosination have been approved by the FDA, but Prosser cautions that the long-term safety and efficacy of this approach must be examined. “Preclinical studies in small and large animal models are next on the docket,” says Prosser, “but we must be careful to select the appropriate animal models that accurately reflect the cytoskeletal phenotypes of patient populations to avoid repeating the mistakes of the past.”
References
Original article
Chen, C. Y. et al. Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure. Nat. Med. https://doi.org/10.1038/s41591-018-0046-2 (2018)
Further reading
Kim, G. H. et al. Reverse remodelling and myocardial recovery in heart failure. Nat. Rev. Cardiol. 15, 83–96 (2018)
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Fernández-Ruiz, I. Targeting the cytoskeleton in heart failure. Nat Rev Cardiol 15, 503 (2018). https://doi.org/10.1038/s41569-018-0056-2
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DOI: https://doi.org/10.1038/s41569-018-0056-2