An analysis of lncRNA-miRNA-mRNA networks to investigate the effects of HDAC4 inhibition on skeletal muscle atrophy caused by peripheral nerve injury.

Background: Muscle atrophy caused by peripheral nerve injury is a common clinical disease, with no effective treatments currently available. Our previous studies have found that denervation-induced muscle atrophy can be alleviated by inhibiting histone deacetylase 4 (HDAC4). An increasing amount of evidence shows that microRNA (miRNA) and long noncoding RNA (lncRNA) are involved in the occurrence of muscle atrophy. This study aimed to find the mechanism by which HDAC4 regulates denervation-induced muscle atrophy based on lncRNA-associated competing endogenous RNA (ceRNA) networks. Methods: We analyzed the influence of short hairpin RNA (shRNA) knockdown of HDAC4 on lncRNAs and miRNAs after denervated muscle atrophy using RNA sequencing. A Pearson's correlation heat map and principal component analysis were employed to analyze differentially expressed miRNAs and lncRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of target genes were conducted. The ceRNA network of lncRNA-miRNA-mRNA was constructed, and the core regulatory molecules in the ceRNA network were analyzed. Results: We found 32 miRNAs and 111 lncRNAs related to denervated muscle atrophy regulated by HDAC4. Moreover, 15 downregulated lncRNAs, 14 upregulated miRNAs, and 61 downregulated mRNAs constituted a ceRNA regulatory network, participating in the biological processes including response to denervation involved in regulation of muscle adaptation, along with the signaling pathways including autophagy, FoxO signaling pathways, and Jak-STAT signaling pathways. Additionally, 6 upregulated lncRNAs, 8 downregulated miRNAs, and 66 upregulated mRNAs constituted another ceRNA regulatory network, which was mainly involved in cell cycle-related biological processes and pathways. Finally, 3 lncRNAs, 4 miRNAs, and 12 mRNAs constituted a ceRNA sub-network, and XR_377582.2 and ENSMUST00000143649 were considered to be the key lncRNAs. Conclusions: In the ceRNA network, all nodes are directly or indirectly involved in the process by which HDAC4 regulates skeletal muscle atrophy caused by peripheral nerve injury. XR_377582.2 and ENSMUST00000143649 may be the key lncRNAs related to HDAC4 involved in the regulation of muscle atrophy.