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

• DOI: 10.1038/s41467-018-07253-3
• Publication Date: 2018-11-13T13:08:53Z
• 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
• Keywords: Klotho

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