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Published on: February 24, 2017
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.
Background:
Recent interest in understanding cardiomyocyte cell cycle has been driven by potential therapeutic applications in cardiomyopathy. However, despite recent advances, cardiomyocyte mitosis remains a poorly understood process. For example, it is unclear how sarcomeres are disassembled during mitosis to allow the abscission of daughter cardiomyocytes.
Methods:
Here, we use a proteomics screen to identify adducin, an actin capping protein previously not studied in cardiomyocytes, as a regulator of sarcomere disassembly. We generated many adeno-associated viruses and cardiomyocyte-specific genetic gain-of-function models to examine the role of adducin in neonatal and adult cardiomyocytes in vitro and in vivo.
Results:
We identify adducin as a regulator of sarcomere disassembly during mammalian cardiomyocyte mitosis. α/γ-adducins are selectively expressed in neonatal mitotic cardiomyocytes, and their levels decline precipitously thereafter. Cardiomyocyte-specific overexpression of various splice isoforms and phospho-isoforms of α-adducin in vitro and in vivo identified Thr445/Thr480 phosphorylation of a short isoform of α-adducin as a potent inducer of neonatal cardiomyocyte sarcomere disassembly. Concomitant overexpression of this α-adducin variant along with γ-adducin resulted in stabilization of the adducin complex and persistent sarcomere disassembly in adult mice, which is mediated by interaction with α-actinin.
Conclusions:
These results highlight an important mechanism for coordinating cytoskeletal morphological changes during cardiomyocyte mitosis.
Insights
Adducin proteins regulate sarcomere disassembly in dividing cardiomyocytes. Phosphorylation of alpha-adducin induces neonatal cardiomyocyte sarcomere disassembly, a key process for cell division.
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.
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