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, W. Y. Tang, C. St. Croix, L. H. Sanders, M. Franti, B. Van Houten, T. A. Rando, A. Barchowsky and F. Ambrosio ()
Additional contact information
A. Sahu: University of Pittsburgh
H. Mamiya: University of Pittsburgh
S. N. Shinde: University of Pittsburgh
A. Cheikhi: University of Pittsburgh
L. L. Winter: University of Pittsburgh
N. V. Vo: 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
A. Barchowsky: University of Pittsburgh
F. Ambrosio: University of Pittsburgh

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07253-3

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