Gu Yuming, Lin Yinghao, Li Ming, Zong Chenyu, Sun Hualin, Shen Yuntian, Zhu Jianwei
Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, China.
Department of Laboratory Medicine, Binhai County People's Hospital affiliated to Kangda College of Nanjing Medical University, Yancheng, China.
Ann Transl Med. 2022 May;10(9):516. doi: 10.21037/atm-21-6512.
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.
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.
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.
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.
周围神经损伤所致肌肉萎缩是一种常见的临床疾病，目前尚无有效的治疗方法。我们之前的研究发现，抑制组蛋白去乙酰化酶4（HDAC4）可减轻去神经支配诱导的肌肉萎缩。越来越多的证据表明，微小RNA（miRNA）和长链非编码RNA（lncRNA）参与了肌肉萎缩的发生。本研究旨在基于lncRNA相关的竞争性内源RNA（ceRNA）网络，探寻HDAC4调节去神经支配诱导的肌肉萎缩的机制。
我们使用RNA测序分析了短发夹RNA（shRNA）敲低HDAC4对去神经支配肌肉萎缩后lncRNA和miRNA的影响。采用Pearson相关热图和主成分分析来分析差异表达的miRNA和lncRNA。对靶基因进行基因本体论和京都基因与基因组百科全书富集分析。构建lncRNA-miRNA-mRNA的ceRNA网络，并分析ceRNA网络中的核心调控分子。
我们发现32个与HDAC4调节的去神经支配肌肉萎缩相关的miRNA和111个lncRNA。此外，15个下调的lncRNA、14个上调的miRNA和61个下调的mRNA构成了一个ceRNA调控网络，参与包括对去神经支配的反应等涉及肌肉适应性调节的生物学过程，以及自噬、FoxO信号通路和Jak-STAT信号通路等信号通路。另外，6个上调的lncRNA、8个下调的miRNA和66个上调的mRNA构成了另一个ceRNA调控网络，主要参与细胞周期相关的生物学过程和通路。最后，3个lncRNA、4个miRNA和12个mRNA构成了一个ceRNA子网，XR_377582.2和ENSMUST00000143649被认为是关键lncRNA。
在ceRNA网络中，所有节点都直接或间接参与HDAC4调节周围神经损伤所致骨骼肌萎缩的过程。XR_377582.2和ENSMUST00000143649可能是与HDAC4参与肌肉萎缩调节相关的关键lncRNA。
