Lin28a/miRNA let-7b-5p pathway has emerged as a key regulators of energy homeostasis in the skeletal muscle. However, the mechanism through which this pathway is regulated in the skeletal muscle has remained unclear. We have found that eight weeks of aerobic training (Tr) markedly decreased let-7b-5p expression in murine skeletal muscle, whereas high-fat diet (Hfd) decreased it's expression. Conversely, Lin28a expression, a well-known inhibitor of let-7b-5p, was induced by Tr and decreased by Hfd. Similarly, in human muscle biopsies, Tr increased LIN28 expression and decreased let-7b-5p expression. Bioinformatics analysis of LIN28a DNA sequence revealed that it is enrichment in PPARδ binding sites, which is a well-known metabolic regulator of exercise. Treatment of primary mouse skeletal muscle cells or C2C12 cells with PPARδ activators GW501516 and AICAR increased Lin28a expression. Lin28a and let-7b-5p expression were also regulated by PPARδ co-regulators. While co-activator PGC1α increased Lin28a expression, co-repressor NCoR1 decreased it's expression. Furthermore, PGC1α markedly reduced the let-7b-5p expression. PGC1α-mediated induction of Lin28a expression was blocked by PPARδ inhibitor GSK0660. In agreement, Lin28a expression was downregulated in PPARδ knocked-down cells leading to increased let-7b-5p expression. Finally, we show that modulation of Lin28a-let-7b-5p pathway in muscle cells leads to changes in mitochondrial metabolism in PGC1α dependent fashion. In summary, we demonstrate that Lin28a-let-7b-5p is a direct target of PPARδ in the skeletal muscle, where its impacts mitochondrial respiration.

中文翻译：

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过氧化物酶体增殖物激活受体δ对骨骼肌细胞中Lin28a-miRNA let-7b-5p通路的调节。

Lin28a/miRNA let-7b-5p 通路已成为骨骼肌能量稳态的关键调节因子。然而，该途径在骨骼肌中调节的机制仍不清楚。我们发现八周的有氧训练 (Tr) 显着降低了鼠骨骼肌中 let-7b-5p 的表达，而高脂饮食 (Hfd) 则降低了它的表达。相反，Lin28a 表达是一种众所周知的 let-7b-5p 抑制剂，它被 Tr 诱导并被 Hfd 降低。同样，在人类肌肉活检中，Tr 增加了 LIN28 表达并降低了 let-7b-5p 表达。LIN28a DNA序列的生物信息学分析表明，它富含PPARδ结合位点，这是众所周知的运动代谢调节剂。用 PPARδ 激活剂 GW501516 和 AICAR 处理原代小鼠骨骼肌细胞或 C2C12 细胞会增加 Lin28a 的表达。Lin28a 和 let-7b-5p 表达也受 PPARδ 共调节剂的调节。虽然共激活剂 PGC1α 增加了 Lin28a 的表达，但共阻遏物 NCoR1 降低了它的表达。此外，PGC1α 显着降低了 let-7b-5p 的表达。PPARδ 抑制剂 GSK0660 可阻断 PGC1α 介导的 Lin28a 表达诱导。一致地，Lin28a 表达在 PPARδ 敲低细胞中下调，导致 let-7b-5p 表达增加。最后，我们表明肌肉细胞中 Lin28a-let-7b-5p 通路的调节导致 PGC1α 依赖性方式的线粒体代谢发生变化。总之，我们证明 Lin28a-let-7b-5p 是骨骼肌中 PPARδ 的直接目标，