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BECN1 F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner

View ORCID ProfileSalwa Sebti, View ORCID ProfileZhongju Zou, View ORCID ProfileMichael U. Shiloh
doi: https://doi.org/10.1101/2022.01.12.475960
Salwa Sebti
1Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
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  • For correspondence: salwa.sebti@utsouthwestern.edu
Zhongju Zou
1Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
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Michael U. Shiloh
1Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
2Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
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Abstract

Autophagy is necessary for lifespan extension in multiple model organisms and autophagy dysfunction impacts age-related phenotypes and diseases. Introduction of an F121A mutation into the essential autophagy protein BECN1 constitutively increases basal autophagy in young mice and reduces cardiac and renal age-related changes in longer-lived Becn1F121A mutant mice. However, both autophagic and lysosomal activity have been described to decline with age. Thus, whether autophagic flux is maintained during aging and whether it is enhanced in Becn1F121A mice is unknown. Here we demonstrate that old wild type mice maintained functional autophagic flux in heart, kidney and skeletal muscle but not liver, and old Becn1F121A mice had increased autophagic flux in those same organs compared to wild type. In parallel, Becn1F121A mice were not protected against age-associated hepatic phenotypes but demonstrated reduced skeletal muscle fiber atrophy. These findings identify an organ-specific role for the ability of autophagy to impact organ aging phenotypes.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations
    CQ
    chloroquine
    GFP
    green fluorescent protein
    KI
    BECN1F121A knock-in mutation
    MAP1LC3/LC3
    microtubule associated protein 1 light chain 3
    PCT
    Renal proximal convoluted tubules
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted January 12, 2022.
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    BECN1 F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner
    Salwa Sebti, Zhongju Zou, Michael U. Shiloh
    bioRxiv 2022.01.12.475960; doi: https://doi.org/10.1101/2022.01.12.475960
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    BECN1 F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner
    Salwa Sebti, Zhongju Zou, Michael U. Shiloh
    bioRxiv 2022.01.12.475960; doi: https://doi.org/10.1101/2022.01.12.475960

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