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Adducin Regulates Sarcomere Disassembly During Cardiomyocyte Mitosis.

Feng Xiao1, Ngoc Uyen Nhi Nguyen1, Ping Wang1

  • 1Department of Internal Medicine (Cardiology) (F.X., N.U.N.N., P.W., S.L., C.-C.H., S.T., W.K., X.L., N.T.L., I.M.-M., W.M.E., A.C.C., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas.

Circulation
|May 6, 2024
PubMed
Summary

Adducin proteins regulate sarcomere disassembly in dividing cardiomyocytes. Phosphorylation of alpha-adducin induces neonatal cardiomyocyte sarcomere disassembly, a key process for cell division.

Keywords:
Irak4adducinalpha-actinincardiac proliferationsarcomere disassembly

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Area of Science:

  • Cardiovascular Biology
  • Cell Biology
  • Molecular Cardiology

Background:

  • Understanding cardiomyocyte cell cycle regulation is crucial for developing therapies for cardiomyopathy.
  • Cardiomyocyte mitosis and sarcomere disassembly mechanisms remain poorly understood.
  • The process of sarcomere disassembly during cardiomyocyte division requires further elucidation.

Purpose of the Study:

  • To identify novel regulators of sarcomere disassembly during cardiomyocyte mitosis.
  • To investigate the role of adducin proteins in cardiomyocyte cell cycle progression.
  • To explore therapeutic targets for enhancing cardiomyocyte regeneration.

Main Methods:

  • Proteomics screen to identify adducin as a sarcomere disassembly regulator.
  • Generation of adeno-associated virus and cardiomyocyte-specific genetic models.
  • In vitro and in vivo studies using neonatal and adult cardiomyocytes.

Main Results:

  • Adducin identified as a key regulator of sarcomere disassembly in mammalian cardiomyocyte mitosis.
  • Alpha/gamma-adducins are specifically expressed in neonatal mitotic cardiomyocytes.
  • Phosphorylation of alpha-adducin (Thr445/Thr480) strongly induces neonatal cardiomyocyte sarcomere disassembly.
  • Co-overexpression of alpha- and gamma-adducin leads to persistent sarcomere disassembly in adult mice via alpha-actinin interaction.

Conclusions:

  • Adducin plays a critical role in coordinating cytoskeletal changes during cardiomyocyte mitosis.
  • Identified a novel mechanism involving adducin phosphorylation and alpha-actinin interaction for sarcomere disassembly.
  • Findings provide insights into cardiomyocyte cell cycle regulation and potential therapeutic strategies.