Delivering Klotho to Old Mice Partially Reverses Loss of Muscle Regenerative Capacity

In this study, we tested the hypothesis that age-related declines in α-Klotho drive dysfunctional muscle progenitor cell (MPC) mitochondrial bioenergetics, ultimately resulting in an impaired tissue regeneration. Our findings demonstrate that young skeletal muscle displays a robust increase in local α-Klotho expression following an acute muscle injury with transient demethylation of the Klotho promoter. However, aged muscle displays no change in Klotho promoter methylation and no increase in α-Klotho expression following injury. Levels of α-Klotho in MPCs derived from aged mice are decreased relative to those of young animals, and genetic knockdown of α-Klotho in young MPCs confers an aged phenotype with pathogenic mitochondrial ultrastructure, decreased mitochondrial bioenergetics, mitochondrial DNA damage, and increased senescence. Further supporting a role for α-Klotho in skeletal muscle vitality, mice heterozygously deficient for Klotho (Kl+/-) have impaired MPC bioenergetics that is consistent with a defective regenerative response following injury, but the regenerative defect of Kl+/- mice is rescued at the cellular and organismal level when mitochondrial ultrastructure is restored through treatment with the mitochondria-targeted peptide, SS-31. Finally, we demonstrate that systemic delivery of exogenous α-Klotho rejuvenates MPC bioenergetics and enhances functional myofiber regeneration in aged animals in a temporally dependent manner. Together, th...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs