Abstract
Skeletal muscle is a highly plastic tissue and decreased skeletal muscle mass (muscle atrophy) results in deteriorated motor function and perturbed body homeostasis. Myogenin promoter-associated long non-coding RNA (lncRNA) Myoparr promotes skeletal muscle atrophy caused by surgical denervation; however, the precise molecular mechanism remains unclear. Here, we examined the downstream genes of Myoparr during muscle atrophy following denervation of tibialis anterior (TA) muscles in C57BL/6J mice. Myoparr knockdown affected the expression of 848 genes. Sixty-five of the genes differentially regulated by Myoparr knockdown coded secretory proteins. Among these 65 genes identified in Myoparr-depleted skeletal muscles after denervation, we focused on the increased expression of growth/differentiation factor 5 (GDF5), an inhibitor of muscle atrophy. Myoparr knockdown led to activated bone morphogenetic protein (BMP) signaling in denervated muscles, as indicated by the increased levels of phosphorylated Smad1/5/8. Our detailed evaluation of downstream genes of Myoparr also revealed that Myoparr regulated differential gene expression between myogenic differentiation and muscle atrophy. This is the first report demonstrating the in vivo role of Myoparr in regulating BMP signaling in denervated muscles. Therefore, lncRNAs that have inhibitory activity on BMP signaling may be putative therapeutic targets for skeletal muscle atrophy.
Highlights
Long non-coding RNAs, which exceed 200 nucleotides in length, are derived from intergenic regions, intronic regions, and cis-regulatory regions [1], and show tissue-specific expression patterns compared to protein-coding RNAs [2,3]
Before RNA-seq analysis, Myoparr expression was quantified by quantitative reverse transcription polymerase chain reaction
We observed that Myoparr knockdown significantly decreased myogenin expression, which we previously identified as a Myoparr target gene [22] (Figure 1c), indicating that electroporation-mediated Myoparr knockdown in tibialis anterior (TA) muscles altered the expression of the downstream gene of Myoparr
Summary
Long non-coding RNAs (lncRNAs), which exceed 200 nucleotides in length, are derived from intergenic regions, intronic regions, and cis-regulatory regions (enhancers and promoters) [1], and show tissue-specific expression patterns compared to protein-coding RNAs [2,3]. Gain-of-function and loss-of-function of lncRNAs in cell culture systems have revealed that lncRNAs exhibit multiple biological roles, such as epigenetic regulation, transcriptional regulation, translational regulation, and functioning as structural cores, among others [5,6]. Correlations between mutations and dysregulation of lncRNAs and human diseases have been identified [7,8,9]. Other in vivo functions of several lncRNAs have been experimentally demonstrated using knockout mice. Several genetic studies have raised questions about the roles of multiple lncRNAs in the development of mice [18,19,20]. In vivo analysis of the molecular function of lncRNAs is essential in order to reveal the physiological roles of lncRNAs in differentiation, development, and various diseases
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