Skeletal muscle development is a highly ordered process orchestrated transcriptionally by the myogenic regulatory factors. However, the downstream molecular mechanisms of myogenic regulatory factor functions in myogenesis are not fully understood. Here, we identified the RNA-binding protein Musashi2 (Msi2) as a myogenin target gene and a post-transcriptional regulator of myoblast differentiation. Msi2 knockdown in murine myoblasts blocked differentiation without affecting the expression of MyoD or myogenin. Msi2 overexpression was also sufficient to promote myoblast differentiation and myocyte fusion. Msi2 loss attenuated autophagosome formation via down-regulation of the autophagic protein MAPL1LC3/ATG8 (LC3) at the early phase of myoblast differentiation. Moreover, forced activation of autophagy effectively suppressed the differentiation defects incurred by Msi2 loss. Consistent with its functions in myoblasts in vitro, mice deficient for Msi2 exhibited smaller limb skeletal muscles, poorer exercise performance, and muscle fiber-type switching in vivo. Collectively, our study demonstrates that Msi2 is a novel regulator of mammalian myogenesis and establishes a new functional link between muscular development and autophagy regulation.

中文翻译：

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RNA 结合蛋白 Msi2 在肌原性分化过程中调节自噬。

骨骼肌发育是一个由生肌调节因子转录精心安排的高度有序的过程。然而，肌生成调节因子在肌生成中发挥作用的下游分子机制尚不完全清楚。在这里，我们将 RNA 结合蛋白 Musashi2 (Msi2) 鉴定为肌细胞生成素靶基因和成肌细胞分化的转录后调节因子。小鼠成肌细胞中 Msi2 敲低可阻止分化，但不影响 MyoD 或肌细胞生成素的表达。Msi2 过度表达也足以促进成肌细胞分化和肌细胞融合。Msi2 缺失通过在成肌细胞分化早期下调自噬蛋白 MAPL1LC3/ATG8 (LC3) 来减弱自噬体形成。此外，强制激活自噬有效抑制了 Msi2 缺失引起的分化缺陷。与其在体外成肌细胞中的功能一致，缺乏 Msi2 的小鼠在体内表现出较小的肢体骨骼肌、较差的运动表现和肌纤维类型转换。总的来说，我们的研究表明 Msi2 是哺乳动物肌肉生成的新型调节剂，并在肌肉发育和自噬调节之间建立了新的功能联系。