The anti-aging protein Klotho affects early postnatal myogenesis by downregulating Jmjd3 and the canonical Wnt pathway.
The anti-aging protein Klotho affects early postnatal myogenesis by downregulating Jmjd3 and the canonical Wnt pathway.
复制标题
DOI：
10.1096/fj.202101298r
复制
发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
在出生后早期发育过程中调节肌肉干细胞（称为卫星细胞）的数量，对肌肉生长产生长期影响。我们验证了一种假说，即抗衰老蛋白Klotho在出生后早期肌肉发生时的高表达水平通过影响调节肌肉发生的基因的表观遗传调控来增加卫星细胞数量。我们的研究结果表明，klotho表达的升高导致卫星细胞数量的短暂增加，肌肉纤维的生长减慢，随后一段时间的肌肉生长加速，导致纤维变大。Klotho还通过转录下调H3K27去甲基化酶Jmjd3，导致H3K27甲基化增加和典型Wnt通路中基因表达减少，这与肌肉分化延迟有关。此外，Klotho刺激和Jmjd3下调对肌源性细胞中Wnt4、Wnt9a和Wnt10a的表达产生相似但不加在一起的降低，表明抑制是通过共同的途径发生的。总之，我们的研究结果确定了Klotho通过降低Jmjd3的表达来影响肌生成的新途径，从而导致Wnt基因表达的减少和典型Wnt信号的抑制。
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 leads to larger fibers. Klotho also transcriptionally downregulated the H3K27 demethylase Jmjd3, leading to increased H3K27 methylation and decreased expression of genes in the canonical Wnt pathway, which was associated with a delay in muscle differentiation. In addition, Klotho stimulation and Jmjd3 downregulation 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 the expression of Jmjd3, leading to reductions in the expression of Wnt genes and inhibition of canonical Wnt signaling.