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; F. Ambrosio

doi:10.1038/s41467-018-07253-3

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, F. Ambrosio

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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 language	English (US)
Article number	4859
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07253-3
State	Published - Dec 1 2018

ASJC Scopus subject areas

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

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Sahu, A., Mamiya, H., Shinde, S. N., Cheikhi, A., Winter, L. L., Vo, N. V., Stolz, D., Roginskaya, V., Tang, W. Y., St. Croix, C., Sanders, L. H., Franti, M., Van Houten, B., Rando, T. A., Barchowsky, A., & Ambrosio, F. (2018). Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. Nature communications, 9(1), [4859]. https://doi.org/10.1038/s41467-018-07253-3

Sahu, A, Mamiya, H, Shinde, SN, Cheikhi, A, Winter, LL, Vo, NV, Stolz, D, Roginskaya, V, Tang, WY, 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, 4859. https://doi.org/10.1038/s41467-018-07253-3

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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.",

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AU - Vo, N. V.

AU - Stolz, D.

AU - Roginskaya, V.

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AU - Sanders, L. H.

AU - Franti, M.

AU - Van Houten, B.

AU - Rando, T. A.

AU - Barchowsky, A.

AU - Ambrosio, F.

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N2 - 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.

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

Abstract

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