Identification of novel immune related transcriptional regulatory network in sarcopenia

Abstract

Abstract Background: Sarcopenia is highly prevalent in elderly and has a significant adverse effect on their physical health and quality of life, but the mechanisms remain unclear. Studies have indicated that transcription factors (TFs) and immune microenvironment played a vital role in skeletal muscle atrophy. Methods: RNA-seq data of 40 muscle samples were downloaded from GEO database. Then differential expressed genes (DEGs), TFs, pathways, and immune gene sets were identified with edgeR package, Cistrome Database, GO, KEGG, ORA, GSVA, and ssGAES, respectively. In silico regulatory network was built by Cytoscape and the potential medicine was screened by Connectivity Map. Finally, regulatory mechanisms and RNA expression of DEGs and TFs were identified by multiple online databases and RT-qPCR. Results: We primary screened 808 DEGs (log2 fold change (FC) > 1or < −1, p < 0.05), 4 differential expressed transcription factors (DETFs) (log2FC > 0.7 or < −0.7, p < 0.05), 304 differential expressed pathways (DEPs) (enrichment scores (ES) > 1or < −1, p < 0.05 or), and 1208 differential expressed immune genes sets (p < 0.01). Based on the results of Pearson correlation analysis (Correlation coefficient (CC) > 0.4 or < -0.4, p < 0.01), we then structured immune related network with 4 DETFs, 9 key DEGs, 11 DEPs, 5 immune cells and 1 immune reaction. Combining the results of online databases and vitro experiments, we found that PAX5-SERPINA5-PI3K/Akt (CC≤0.444, p≤ 0.004) was a potential transcriptional regulation axis, and the B cells (R = 0.437, p = 0.005) may play a vital role in this signal transduction. Finally, the compound of Tanespimycin (enrichment = -0.403, p < 0.0001) might be a potential medicine for sarcopenia based on mechanism of actions database and the result of literature review. Conclusions: We firstly identified immune related transcriptional regulatory network with High-throughput RNA-seq data in sarcopenia. We supposed that PAX5-SERPIAN5-PI3K/Akt axis was a potential mechanism in sarcopenia, and the B cells may play a vital role in this signal transduction. Besides, Tanespimycin is a potential medicine for sarcopenia by targeting Akt degradation.