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Super-resolution microscopy images of microtubules in heart cells

The STED imaging system built by Allgeyer and Sirinakis at the Gurdon Institute has proved crucial in a research collaboration to understand why heart muscle weakens after a heart attack. By visualising microtubules in cardiac cells, the St Johnston lab researchers helped an international team to identify a new target for drugs to improve heart pumping strength after damage.

 

MARK4 controls ischaemic heart failure through microtubule detyrosination

Yu X et al. (2021) Nature  DOI: 10.1038/s41586-021-03573-5.

Read the press release from the British Heart Foundation & University of Cambridge

 

Summary from the paper

Myocardial 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 annual mortality rate. 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 failure.

Microtubule detyrosination is emerging as an important mechanism of regulating cardiomyocyte contractility. Here, we show that deficiency of Microtubule-Affinity Regulating Kinase 4 (MARK4) substantially limits the reduction of left ventricular ejection fraction 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 tubulin carboxypeptidase (Vasohibin) to microtubules for α-tubulin detyrosination.

Our results show how microtubule detyrosination is finely tuned by MARK4 in the cardiomyocytes to regulate cardiac inotropy, and identify MARK4 as a promising druggable therapeutic target to improve cardiac function after MI.

 

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Read about research in the St Johnston lab.

Watch Allgeyer and Sirinakis describe their research in our video, Microscope Builders.

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The Gurdon Institute reopened on Monday 15th June. Many staff will continue to work from home, and all staff may be contacted by email.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.
 

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