IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-47847-8.html
   My bibliography  Save this article

BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts

Author

Listed:
  • Maartje Westhoff

    (University of California Davis)

  • Silvia G. Villar

    (University of California Davis)

  • Taylor L. Voelker

    (University of California Davis)

  • Phung N. Thai

    (Davis)

  • Heather C. Spooner

    (University of California Davis)

  • Alexandre D. Costa

    (University of California Davis)

  • Padmini Sirish

    (Davis)

  • Nipavan Chiamvimonvat

    (Davis
    Northern California Health Care System
    University of California Davis)

  • Eamonn J. Dickson

    (University of California Davis)

  • Rose E. Dixon

    (University of California Davis)

Abstract

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Suggested Citation

  • Maartje Westhoff & Silvia G. Villar & Taylor L. Voelker & Phung N. Thai & Heather C. Spooner & Alexandre D. Costa & Padmini Sirish & Nipavan Chiamvimonvat & Eamonn J. Dickson & Rose E. Dixon, 2024. "BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47847-8
    DOI: 10.1038/s41467-024-47847-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-47847-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-47847-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Guoxia Liu & Arianne Papa & Alexander N. Katchman & Sergey I. Zakharov & Daniel Roybal & Jessica A. Hennessey & Jared Kushner & Lin Yang & Bi-Xing Chen & Alexander Kushnir & Katerina Dangas & Steven P, 2020. "Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics," Nature, Nature, vol. 577(7792), pages 695-700, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Declan Manning & L. Fernando Santana, 2022. "Regulating voltage-gated ion channels with nanobodies," Nature Communications, Nature, vol. 13(1), pages 1-2, December.
    2. Travis J. Morgenstern & Neha Nirwan & Erick O. Hernández-Ochoa & Hugo Bibollet & Papiya Choudhury & Yianni D. Laloudakis & Manu Johny & Roger A. Bannister & Martin F. Schneider & Daniel L. Minor & Hen, 2022. "Selective posttranslational inhibition of CaVβ1-associated voltage-dependent calcium channels with a functionalized nanobody," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Dingxi Zhou & Mariana Borsa & Daniel J. Puleston & Susanne Zellner & Jesusa Capera & Sharon Sanderson & Martina Schifferer & Svenja S. Hester & Xin Ge & Roman Fischer & Luke Jostins & Christian Behren, 2022. "Mapping autophagosome contents identifies interleukin-7 receptor-α as a key cargo modulating CD4+ T cell proliferation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47847-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.