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Updated: Apr 9, 2026

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Spastin-mediated severing of glutamylated microtubules controls cardiomyocyte coupling

Jiayin Zhang1,2,3,4, Xiaozhi Huang1,2,3, Zhichao Wu5

  • 1Department of Cardiology, Center for Genetic Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.

Nature Cardiovascular Research
|April 7, 2026
PubMed

Insights

Microtubule glutamylation disrupts connexin 43 (Cx43) trafficking, leading to arrhythmias during cardiac ischemia-reperfusion injury. Reducing glutamylation preserves Cx43 and mitigates injury, offering a new therapeutic target.

Area of Science:

  • Cardiovascular Biology
  • Cellular Biology
  • Molecular Medicine

Background:

  • Cardiac ischemia-reperfusion injury often causes malignant arrhythmias due to connexin 43 (Cx43) mislocalization and reduced cardiomyocyte coupling.
  • Current therapies targeting these mechanisms are limited.

Purpose of the Study:

  • To investigate the role of microtubule glutamylation in cardiac electrical stability during ischemia-reperfusion injury.
  • To identify potential therapeutic targets for preventing arrhythmias.

Main Methods:

  • Examined microtubule glutamylation and Cx43 trafficking in human ischemic cardiomyopathy and mouse models of ischemia-reperfusion.
  • Utilized cardiomyocyte-specific spastin knockout mice to assess the impact of spastin deficiency on microtubule dynamics and Cx43 transport.
  • Investigated the effects of genetic or pharmacological reduction of microtubule glutamylation before ischemia-reperfusion.

Main Results:

  • Ischemia-reperfusion promotes accumulation and stabilization of glutamylated microtubules, disrupting Cx43 trafficking.
  • Spastin deficiency leads to stabilized, glutamylated microtubules and impaired Cx43 transport, increasing susceptibility to arrhythmias.
  • Reducing microtubule glutamylation preserved Cx43 localization and reduced oxidative stress-induced injury.

Conclusions:

  • Microtubule glutamylation is a key regulator of cardiac electrical stability.
  • Targeting microtubule glutamylation represents a promising therapeutic strategy for ischemia-reperfusion injury and associated arrhythmias.

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