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

Authors: 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


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.

Source: Nature Communications; Volume 9, Article number: 4859 (2018)