Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure

Detyrosinated microtubules (MTs) provide mechanical resistance that can impede the motion of contracting cardiomyocytes. However, the functional effects of MT 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 MTs in failing human hearts. As revealed by super-resolution imaging, failing cardiomyocytes are characterized by a dense, heavily detyrosinated MT network, which is associated with increased myocyte stiffness and impaired contractility. Pharmacological suppression of detyrosinated MTs lowers the viscoelasticity of failing myocytes and restores 40–50% of lost contractile function; reduction of MT 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 MTs could represent a new inotropic strategy for improving cardiac function.