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Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration

Author

Listed:
  • A. Sahu

    (University of Pittsburgh
    University of Pittsburgh)

  • H. Mamiya

    (University of Pittsburgh
    University of Pittsburgh)

  • S. N. Shinde

    (University of Pittsburgh)

  • A. Cheikhi

    (University of Pittsburgh
    University of Pittsburgh)

  • L. L. Winter

    (University of Pittsburgh
    University of Pittsburgh)

  • N. V. Vo

    (University of Pittsburgh
    University of Pittsburgh)

  • D. Stolz

    (University of Pittsburgh)

  • V. Roginskaya

    (University of Pittsburgh)

  • W. Y. Tang

    (Johns Hopkins Bloomberg School of Public Health)

  • C. St. Croix

    (University of Pittsburgh)

  • L. H. Sanders

    (Duke University School of Medicine)

  • M. Franti

    (Research Beyond Borders: Boehringer-Ingelheim Pharmaceuticals)

  • B. Van Houten

    (University of Pittsburgh)

  • T. A. Rando

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Veterans Affairs Hospital)

  • A. Barchowsky

    (University of Pittsburgh
    University of Pittsburgh)

  • F. Ambrosio

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

Abstract

While young muscle is capable of restoring the original architecture of damaged myofibers, aged muscle displays a markedly reduced regeneration. We show that expression of the “anti-aging” protein, α-Klotho, is up-regulated within young injured muscle as a result of transient Klotho promoter demethylation. However, epigenetic control of the Klotho promoter is lost with aging. Genetic inhibition of α-Klotho in vivo disrupted muscle progenitor cell (MPC) lineage progression and impaired myofiber regeneration, revealing a critical role for α-Klotho in the regenerative cascade. Genetic silencing of Klotho in young MPCs drove mitochondrial DNA (mtDNA) damage and decreased cellular bioenergetics. Conversely, supplementation with α-Klotho restored mtDNA integrity and bioenergetics of aged MPCs to youthful levels in vitro and enhanced functional regeneration of aged muscle in vivo in a temporally-dependent manner. These studies identify a role for α-Klotho in the regulation of MPC mitochondrial function and implicate α-Klotho declines as a driver of impaired muscle regeneration with age.

Suggested Citation

  • A. Sahu & H. Mamiya & S. N. Shinde & A. Cheikhi & L. L. Winter & N. V. Vo & D. Stolz & V. Roginskaya & W. Y. Tang & C. St. Croix & L. H. Sanders & M. Franti & B. Van Houten & T. A. Rando & A. Barchows, 2018. "Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07253-3
    DOI: 10.1038/s41467-018-07253-3
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    Cited by:

    1. Hirotaka Iijima & Gabrielle Gilmer & Kai Wang & Allison C. Bean & Yuchen He & Hang Lin & Wan-Yee Tang & Daniel Lamont & Chia Tai & Akira Ito & Jeffrey J. Jones & Christopher Evans & Fabrisia Ambrosio, 2023. "Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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