Date Published: January 30, 2019
Publisher: Public Library of Science
Author(s): Hiroyuki Shibasaki, Michihiro Imamura, Sayuri Arima, Jun Tanihata, Mutsuki Kuraoka, Yasunari Matsuzaka, Fumiaki Uchiumi, Sei-ichi Tanuma, Shin’ichi Takeda, Atsushi Asakura.
MicroRNAs (miRNAs) are non-coding small RNAs that regulate gene expression at the post-transcriptional level. Several miRNAs are exclusively expressed in skeletal muscle and participate in the regulation of muscle differentiation by interacting with myogenic factors. These miRNAs can be found at high levels in the serum of patients and animal models for Duchenne muscular dystrophy, which is expected to be useful as biomarkers for their clinical conditions. By miRNA microarray analysis, we identified miR-188 as a novel miRNA that is elevated in the serum of the muscular dystrophy dog model, CXMDJ. miR-188 was not muscle-specific miRNA, but its expression was up-regulated in skeletal muscles associated with muscle regeneration induced by cardiotoxin-injection in normal dogs and mice. Manipulation of miR-188 expression using antisense oligo and mimic oligo RNAs alters the mRNA expression of the myogenic regulatory factors, MRF4 and MEF2C. Our results suggest that miR-188 is a new player that participates in the gene regulation process of muscle differentiation and that it may serve as a serum biomarker reflecting skeletal muscle regeneration.
MicroRNAs (miRNAs) are evolutionary conserved small non-coding RNAs composed of approximately 22 nucleotides, and that function in the post-transcriptional regulation of gene expression. Specific interaction of miRNAs with complementary sequences at 3’ noncoding regions of messenger RNAs (mRNAs) causes mRNA degradation or inhibition of protein translation, resulting in negative regulation of gene expression. [1, 2] The miRNA database, miRBase (http://www.mirbase.org/), has recently listed more than 35,000 miRNAs from a variety of species. In mammals, miRNAs are predicted to regulate about 60% of genes , which means that various biological phenomena are relevant to miRNA expression and comprehensive studies of miRNA function are thus important.
In this study, we found that miR-188 was specifically elevated in the serum of CXMDJ dogs with onset of muscular dystrophy. Significant elevation of serum miR-188 was observed until around 9 months of age, and which was compatible with the results of expression analysis using skeletal muscle. The period of miR-188 elevation with CXMDJ growth was corresponding to the time when the muscle regeneration was vigorous. Even in normal animals, induction of muscle regeneration by CTX-injury indicated significant miR-188 elevation. Taken together with the fact that miR-188 was up-regulated in C2C12 cells during differentiation, our results revealed that miR-188 elevation in CXMDJ serum reflects muscle regeneration, implying that miR-188 is useful as a marker for such regeneration.