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

A. Sahu, H. Mamiya, S. N. Shinde, A. Cheikhi, L. L. Winter, N. V. Vo, D. Stolz, V. Roginskaya, Wan-Yee Tang, C. St Croix, L. H. Sanders, M. Franti, B. Van Houten, T. A. Rando, A. Barchowsky, F. Ambrosio

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Number of pages1
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Nov 19 2018

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muscles
regeneration
Muscle
Regeneration
Stem Cells
Muscles
cells
Energy Metabolism
Aging of materials
Cell Lineage
Epigenomics
progressions
integrity
DNA Damage
cascades
deoxyribonucleic acid
damage
proteins
DNA

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. / Sahu, A.; Mamiya, H.; Shinde, S. N.; Cheikhi, A.; Winter, L. L.; Vo, N. V.; Stolz, D.; Roginskaya, V.; Tang, Wan-Yee; St Croix, C.; Sanders, L. H.; Franti, M.; Van Houten, B.; Rando, T. A.; Barchowsky, A.; Ambrosio, F.

In: Nature Communications, Vol. 9, No. 1, 19.11.2018.

Research output: Contribution to journalArticle

Sahu, A, Mamiya, H, Shinde, SN, Cheikhi, A, Winter, LL, Vo, NV, Stolz, D, Roginskaya, V, Tang, W-Y, St Croix, C, Sanders, LH, Franti, M, Van Houten, B, Rando, TA, Barchowsky, A & Ambrosio, F 2018, 'Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration', Nature Communications, vol. 9, no. 1. https://doi.org/10.1038/s41467-018-07253-3
Sahu, A. ; Mamiya, H. ; Shinde, S. N. ; Cheikhi, A. ; Winter, L. L. ; Vo, N. V. ; Stolz, D. ; Roginskaya, V. ; Tang, Wan-Yee ; St Croix, C. ; Sanders, L. H. ; Franti, M. ; Van Houten, B. ; Rando, T. A. ; Barchowsky, A. ; Ambrosio, F. / Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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