The CEBPA-FGF21 regulatory network may participate in the T2DM-induced skeletal muscle atrophy by regulating the autophagy-lysosomal pathway.

Aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.