Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, No. 87, Xiang-Ya Road, Changsha, 410008, Hunan Province, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, 410008, Hunan Province, China.
Acta Diabetol. 2023 Nov;60(11):1491-1503. doi: 10.1007/s00592-023-02131-x. Epub 2023 Jul 1.
Recent years have witnessed an increasing research interest in the roles of transcription factor (TF)-gene regulatory network in type 2 diabetes mellitus (T2DM). Thus, we sought to characterize the mechanistic insights based on the TF-gene regulatory network in skeletal muscle atrophy in T2DM.
Differentially expressed TFs (DETFs) and mRNAs (DEmRNAs) were obtained in T2DM-related gene expression profiles (GSE12643, GSE55650, GSE166502, and GSE29221), followed by WGCNA, and GO and KEGG enrichment analyses. Next, the iRegulon plug-in unit of Cytoscape software was used to construct a TF-mRNA regulatory network. Besides, RT-qPCR and ChIP-seq were utilized to measure the expression of CEBPA and FGF21 in the skeletal muscle tissues or cells of T2DM rat models. At last, the effect of overexpression of FGF21 on the autophagy-lysosomal pathway was examined in skeletal muscle cells of T2DM rats.
Totally, 12 DETFs and 102 DEmRNAs were found in the skeletal muscle tissues of T2DM samples. The DEmRNAs were mainly enriched in the autophagy-lysosomal pathway. CEBPA affected the skeletal muscle atrophy in T2DM by regulating 5 target genes via the autophagy-lysosomal pathway. CEBPA could target FGF21. In addition, the expression of CEBPA was elevated, while the expression of FGF21 was diminished in the skeletal muscle tissues or cells of T2DM rats. The CEBPA-FGF21 regulatory network promoted skeletal muscle atrophy in T2DM by activating the autophagy-lysosomal pathway.
The CEBPA-FGF21 regulatory network may participate in the T2DM-induced skeletal muscle atrophy by regulating the autophagy-lysosomal pathway. Thus, our study provides interesting targets for prevention of skeletal muscle atrophy in T2DM.
近年来，转录因子（TF）-基因调控网络在 2 型糖尿病（T2DM）中的作用研究日益受到关注。因此，我们试图基于 TF-基因调控网络来描述 T2DM 骨骼肌萎缩的机制。
从 T2DM 相关基因表达谱（GSE12643、GSE55650、GSE166502 和 GSE29221）中获取差异表达的 TF（DETFs）和 mRNAs（DEmRNAs），然后进行 WGCNA、GO 和 KEGG 富集分析。接下来，使用 Cytoscape 软件的 iRegulon 插件单元构建 TF-mRNA 调控网络。此外，还利用 RT-qPCR 和 ChIP-seq 测量 T2DM 大鼠模型骨骼肌组织或细胞中 CEBPA 和 FGF21 的表达。最后，在 T2DM 大鼠骨骼肌细胞中检查 FGF21 过表达对自噬溶酶体途径的影响。
T2DM 样本骨骼肌组织中发现 12 个 DETFs 和 102 个 DEmRNAs。DEmRNAs 主要富集在自噬溶酶体途径中。CEBPA 通过调节自噬溶酶体途径中的 5 个靶基因影响 T2DM 中的骨骼肌萎缩。CEBPA 可以靶向 FGF21。此外，在 T2DM 大鼠骨骼肌组织或细胞中，CEBPA 的表达增加，而 FGF21 的表达减少。CEBPA-FGF21 调控网络通过激活自噬溶酶体途径促进 T2DM 中的骨骼肌萎缩。
CEBPA-FGF21 调控网络可能通过调节自噬溶酶体途径参与 T2DM 诱导的骨骼肌萎缩。因此，我们的研究为预防 T2DM 中的骨骼肌萎缩提供了有趣的靶点。
