Abstract

Acetoacetate (AA) is an important ketone body that is used as an oxidative fuel to supply energy for the cellular activities of various tissues, including the brain and skeletal muscle. We recently revealed a new signaling role for AA by showing that it promotes muscle cell proliferation in vitro, enhances muscle regeneration in vivo, and ameliorates the dystrophic muscle phenotype of Mdx mice. In this study, we provide new molecular insight into this function of AA. We show that AA promotes C2C12 cell proliferation by transcriptionally upregulating the expression of muscle-specific miR-133b, which in turn stimulates muscle cell proliferation by targeting serum response factor. Furthermore, we show that the AA-induced upregulation of miR-133b is transcriptionally mediated by MEF2 via the Mek-Erk1/2 signaling pathway. Mechanistically, our findings provide further convincing evidence that AA acts as signaling metabolite to actively regulate various cellular activities in mammalian cells.

中文翻译：

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乙酰乙酸盐通过 miR-133b/SRF 轴通过 Mek-Erk-MEF2 通路促进肌肉细胞增殖

摘要

乙酰乙酸 (AA) 是一种重要的酮体，用作氧化燃料，为各种组织的细胞活动提供能量，包括大脑和骨骼肌。我们最近通过显示它在体外促进肌肉细胞增殖，在体内增强肌肉再生，并改善Mdx的营养不良肌肉表型，揭示了 AA 的新信号作用。老鼠。在这项研究中，我们为 AA 的这种功能提供了新的分子见解。我们表明 AA 通过转录上调肌肉特异性 miR-133b 的表达来促进 C2C12 细胞增殖，进而通过靶向血清反应因子刺激肌肉细胞增殖。此外，我们表明 AA 诱导的 miR-133b 上调是由 MEF2 通过 Mek-Erk1/2 信号通路转录介导的。从机制上讲，我们的研究结果提供了进一步令人信服的证据，表明 AA 作为信号代谢物，可以主动调节哺乳动物细胞中的各种细胞活动。