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

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Abstract

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.

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Funding

This study was funded by the National Natural Science Foundation of China (81702241), the Natural Science Foundation of Hunan Province (2018JJ3847), China Postdoctoral Science Foundation (2020M682597) and the Natural Science Foundation of Hunan Province (2021JJ31129).

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Authors and Affiliations

  1. Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, No. 87, Xiang-Ya Road, Changsha, 410008, Hunan Province, China

    Kai Wu & Yuan Liu

  2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, 410008, Hunan Province, China

    Kai Wu, Sha Huang, Fan Zheng & Yuan Liu

  3. Department of Neurology, Xiangya Hospital of Central South University, Changsha, 410008, China

    Sha Huang

  4. Health Management Department, Xiangya Hospital of Central South University, Changsha, 410008, China

    Fan Zheng

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  1. Kai Wu
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Contributions

KW and SH designed the study. FZ and YL collated the data, designed and developed the database, carried out data analyses and produced the initial draft of the manuscript. KW and SH contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Yuan Liu.

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This study protocol was approved by the Experimental Animal Ethics Committee of Xiangya Hospital of Central South University.

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Clinical data was primarily obtained from public databases.

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Wu, K., Huang, S., Zheng, F. et al. The CEBPA-FGF21 regulatory network may participate in the T2DM-induced skeletal muscle atrophy by regulating the autophagy-lysosomal pathway. Acta Diabetol 60, 1491–1503 (2023). https://doi.org/10.1007/s00592-023-02131-x

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