MARK4 controls ischaemic heart failure through microtubule detyrosination.

Abstract

SummaryMyocardial infarction (MI) is a major cause of premature adult death. Compromised cardiac function after MI leads to chronic heart failure with systemic health complications and high mortality rate1. Effective therapeutic strategies are highly needed to improve the recovery of cardiac function after MI. More specifically, there is a major unmet need for a new class of drugs that improve cardiomyocyte contractility, because currently available inotropic therapies have been associated with high morbidity and mortality in patients with systolic heart failure2,3, or have shown a very modest risk reduction4. Microtubule detyrosination is emerging as an important mechanism of regulation of cardiomyocyte contractility5. Here, we show that deficiency of Microtubule-Affinity Regulating Kinase 4 (MARK4) substantially limits the reduction of left ventricular ejection fraction (LVEF) after acute MI in mice, without affecting infarct size or cardiac remodeling. Mechanistically, we provide evidence that MARK4 regulates cardiomyocyte contractility through promoting microtubule-associated protein 4 (MAP4) phosphorylation, thereby facilitating the access of Vasohibin 2 (VASH2), a tubulin carboxypeptidase (TCP), to microtubules for α-tubulin detyrosination. Our results show how cardiomyocyte microtubule detyrosination is finely tuned by MARK4 to regulate cardiac inotropy, and identify MARK4 as a promising druggable therapeutic target for improving cardiac function after MI.