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Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure

2018; Nature Portfolio; Volume: 24; Issue: 8 Linguagem: Inglês

10.1038/s41591-018-0046-2

1546-170X

Yingxian Chen, Matthew A. Caporizzo, Kenneth Bedi, Alexia Vite, Alexey Bogush, Patrick Robison, Julie Heffler, Alex Salomon, Neil Kelly, Apoorva Babu, Michael P. Morley, Kenneth B. Margulies, Benjamin L. Prosser,

Cardiovascular Effects of Exercise

Detyrosinated microtubules provide mechanical resistance that can impede the motion of contracting cardiomyocytes. However, the functional effects of microtubule detyrosination in heart failure or in human hearts have not previously been studied. Here, we utilize mass spectrometry and single-myocyte mechanical assays to characterize changes to the cardiomyocyte cytoskeleton and their functional consequences in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and microtubules in failing human hearts. As revealed by super-resolution imaging, failing cardiomyocytes are characterized by a dense, heavily detyrosinated microtubule network, which is associated with increased myocyte stiffness and impaired contractility. Pharmacological suppression of detyrosinated microtubules lowers the viscoelasticity of failing myocytes and restores 40–50% of lost contractile function; reduction of microtubule detyrosination using a genetic approach also softens cardiomyocytes and improves contractile kinetics. Together, these data demonstrate that a modified cytoskeletal network impedes contractile function in cardiomyocytes from failing human hearts and that targeting detyrosinated microtubules could represent a new inotropic strategy for improving cardiac function. Post-translational modification of microtubules by detyrosination is prevalent in failing human cardiomyocytes and inhibits cardiomyocyte contraction, suggesting a new therapeutic strategy for improving heart function.