Department of Pharmacology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan.
Department of Neurology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Sci Rep. 2024 Jan 16;14(1):1365. doi: 10.1038/s41598-024-51746-9.
It has been reported that autophagic activity is disturbed in the skeletal muscles of dystrophin-deficient mdx mice and patients with Duchenne muscular dystrophy (DMD). Transcriptional regulations of autophagy by FoxO transcription factors (FoxOs) and transcription factor EB (TFEB) play critical roles in adaptation to cellular stress conditions. Here, we investigated whether autophagic activity is dysregulated at the transcription level in dystrophin-deficient muscles. Expression levels of autophagy-related genes were globally decreased in tibialis anterior and soleus muscles of mdx mice compared with those of wild-type mice. DNA microarray data from the NCBI database also showed that genes related to autophagy were globally downregulated in muscles from patients with DMD. These downregulated genes are known as targets of FoxOs and TFEB. Immunostaining showed that nuclear localization of FoxO1 and FoxO3a was decreased in mdx mice. Western blot analyses demonstrated increases in phosphorylation levels of FoxO1 and FoxO3a in mdx mice. Nuclear localization of TFEB was also reduced in mdx mice, which was associated with elevated phosphorylation levels of TFEB. Collectively, the results suggest that autophagy is disturbed in dystrophin-deficient muscles via transcriptional downregulation due to phosphorylation-mediated suppression of FoxOs and TFEB.
已有报道称，在肌营养不良蛋白缺乏的 mdx 小鼠和杜氏肌营养不良症（DMD）患者的骨骼肌中，自噬活性受到干扰。FoxO 转录因子（FoxOs）和转录因子 EB（TFEB）对自噬的转录调控在适应细胞应激条件方面起着关键作用。在这里，我们研究了肌营养不良蛋白缺乏的肌肉中自噬活性是否在转录水平上失调。与野生型小鼠相比，mdx 小鼠的比目鱼肌和跖肌中的自噬相关基因的表达水平整体下降。NCBI 数据库的 DNA 微阵列数据还显示，DMD 患者肌肉中的自噬相关基因整体下调。这些下调的基因是 FoxO 和 TFEB 的已知靶点。免疫染色显示 FoxO1 和 FoxO3a 的核定位在 mdx 小鼠中减少。Western blot 分析表明，mdx 小鼠中 FoxO1 和 FoxO3a 的磷酸化水平增加。TFEB 的核定位也减少，这与 TFEB 的磷酸化水平升高有关。总之，这些结果表明，由于 FoxO 和 TFEB 的磷酸化介导的抑制作用，自噬在肌营养不良蛋白缺乏的肌肉中通过转录下调而受到干扰。
