The anti-aging protein Klotho affects early postnatal myogenesis by down-regulating Jmjd3 and the canonical Wnt pathway

Modulating the number of muscle stems cells, called satellite cells, during early postnatal development produces long-term effects on muscle growth. We tested the hypothesis that high expression levels of the anti-aging protein Klotho in early postnatal myogenesis increase satellite cell numbers by influencing the epigenetic regulation of genes that regulate myogenesis. Our findings show that elevated klotho expression caused a transient increase in satellite cell numbers and slowed muscle fiber growth, followed by a period of accelerated muscle growth that resulted in larger fibers. Klotho also transcriptionally down-regulated the H3K27 demethylase Jmjd3, increased H3K27 methylation and decreased expression of genes in the canonical Wnt pathway, which was associated with a significant delay in muscle differentiation. In addition, Klotho stimulation and subsequent Jmjd3 down-regulation produced similar but not additive reductions in the expression of Wnt4, Wnt9a and Wnt10a in myogenic cells, indicating that inhibition occurred through a common pathway. Together, our results identify a novel pathway through which Klotho influences myogenesis by reducing expression of Jmjd3, leading to reductions in the expression of Wnt genes and inhibition of canonical Wnt signaling. Overall design: H3K27me2/3 ChIP-seq experiment in either vehicle or Klotho treated C2C12 myoblasts.