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

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.

Divergent Roles of Inflammation in Skeletal Muscle Recovery From Injury

“…Agerelated perturbations in IL-33 expression may similarly disrupt regeneration by altering the accumulation of T reg cells in the satellite cell niche (Kuswanto et al, 2016). Additional changes to the satellite cell microenvironment including increased fibroblast growth factor-2 (FGF-2) expression, loss of fibronectin, systemic increases in GDF11, impaired β1-Integrin signaling, and attenuated levels of the anti-aging hormone Klotho have all been implicated in the poor repair of skeletal muscle with aging (Chakkalakal et al, 2012;Egerman et al, 2015;Lukjanenko et al, 2016;Rozo et al, 2016;Sahu et al, 2018;Welc et al, 2020).…”

Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells

“…It is thus imperative to investigate mechanisms accounting for the age‐related muscle loss and functional decline. Changes at all levels, including gene expression, histone modification, DNA methylation, and physical changes in muscle stem cell environment, or niche, have been found to be associated with aging (Liu et al, ; Sahu et al, ; Stearns‐Reider et al, ; Su et al, ; Vinel et al, ; Zykovich et al, ). For instance, one of the studies of gene expression in aging muscle revealed that mitochondrial dysfunction is a major age‐related phenomenon and highlighted the beneficial effects of maintaining a high physical capacity in the prevention of age‐related muscle function decline (Su et al, ).…”

Reprogramming of human fibroblasts into osteoblasts by insulin-like growth factor-binding protein 7

“…Cell senescence is a form of cell cycle arrest characterized by the activation of tumor suppressor networks including p53, p16, and p21, and production of SASP factors. Cellular senescence is regarded as detrimental for tissue repair and regeneration since it induces replicative aging in cells, which directly contributes to their loss of regenerative capacity in tissue repair . Additionally, SASP proteins released by senescent cells can disrupt tissue homeostasis and potentially act on neighboring cells in a paracrine signaling manner .…”

“…Cellular senescence is regarded as detrimental for tissue repair and regeneration since it induces replicative aging in cells, 42 which directly contributes to their loss of regenerative capacity in tissue repair. [43][44][45][46] Additionally, SASP proteins released by senescent cells can disrupt tissue homeostasis and potentially act on neighboring cells in a paracrine signaling manner. 45,[47][48][49] Thus, induction of cell senescence in the reprograming of fibroblast into OB appears contradictory.…”

“…[43][44][45][46] Additionally, SASP proteins released by senescent cells can disrupt tissue homeostasis and potentially act on neighboring cells in a paracrine signaling manner. 45,[47][48][49] Thus, induction of cell senescence in the reprograming of fibroblast into OB appears contradictory. Nevertheless, emerging evidence in embryonic and adult tissues indicates that cell senescence is beneficial in tissue homeostasis.…”