Professor Baoting ZHANG from School of Chinese Medicine, CUHK discovers a novel long noncoding RNA that regulates muscle differentiation and growth
A joint research team led by Professor Baoting ZHANG from School of Chinese Medicine of the Faculty of Medicine at The Chinese University of Hong Kong (CUHK) has achieved a breakthrough in the mechanism of skeletal muscle atrophy. The team consisting of investigators from School of Chinese Medicine at CUHK and Hong Kong Baptist University discovers a novel long noncoding RNA (lncRNA) MAR1 in mice skeletal muscle, functioning as a microRNA-487b (miR-487b) sponge to promote skeletal muscle differentiation and regeneration, which could be a novel therapeutic target for treating muscle atrophy induced by either aging or mechanical unloading. The study has been published in the Journal of Cachexia, Sarcopenia and Muscle (Impact factor: 12.511).
Down-regulation of lncRNA MAR1 level in muscle is associated with skeletal muscle atrophy in mice
Various causes, including aging and mechanical unloading, can lead to skeletal muscle atrophy, which increases the risk of falls, disability, hospitalization, and even mortality. So far, there is no effective therapeutic approach for counteracting muscle atrophy in clinical practice. Anti-resistance training and drug therapy have limited clinical application due to the unclear effects and potential adverse reactions. LncRNAs are longer than 200 nucleotides in length and have no capacity to be translated into proteins. They play important roles in many physiological and pathological processes. In skeletal muscle, several lncRNAs have been found to play functional roles in the physiological processes of muscle. However, there are no study to investigate the pathological roles of lncRNAs in skeletal muscle atrophy yet, especially induced by either aging or mechanical unloading.
Professor Baoting ZHANG, Associate Professor and Assistant Director of School of Chinese Medicine, Faculty of Medicine, CUHK, stated that, “Our study compared the gene expression between skeletal muscles from old and adult mice by microarray analysis. The most down-regulated lncRNA (MAR1) in the aged muscle was identified. The in vitro and in vivo studies demonstrated that MAR1 played an important role during the muscle growth and differentiation. The decrease of MAR1 level in skeletal muscle would induce skeletal muscle atrophy. The findings provide a novel molecular target for counteracting skeletal muscle atrophy.”
MAR1 functions as a miR-487b sponge to promote skeletal muscle differentiation
The compromised muscle anabolism is a major cause of muscle atrophy. Therefore, it is important to explore the molecular mechanism of muscle atrophy and discover the novel molecular targets to meet the urgent need of developing effective muscle anabolic agent to counteract muscle atrophy. The research team found that muscle-specific over-expression of MAR1 could successfully relieve the decreases in muscle cell differentiation, myotube formation, muscle weight, muscle fiber cross-sectional area, muscle strength, and the expression of muscle anabolic proteins in mice with skeletal muscle atrophy induced by either aging or mechanical unloading. Furthermore, the research team found that MAR1 could function as competing endogenous RNA (ceRNA) to sponge miR-487b, thereby promoting the expression of Wnt5a, the target protein of miR-487b, and in turns enhancing muscle growth and differentiation. Interestingly, this study also identified miR-487b as a negative regulator during muscle differentiation. The findings expand the understanding of noncoding RNAs function as key regulators and potential therapeutic targets during skeletal muscle atrophy.
Further lncRNA-based muscle anabolic strategy to counteract muscle atrophy is still ongoing
Professor Baoting ZHANG further remarked, “The structural diversity and biological activity of traditional Chinese medicines and natural products make them a vital source of lead compounds for treating diseases. Our joint research team of CUHK and HKBU has initiated the study of noncoding RNA-based high-throughput screening for drug discovery in the Chinese medicine and natural product database. We hope that we could discover small molecules that target key lncRNAs and develop innovative drugs for counteracting muscle atrophy.”
Zhang ZK, Li J, Guan D, Liang C, Zhuo Z, Liu J, Lu A, Zhang G, Zhang BT. A newly identified lncRNA MAR1 acts as a miR-487b sponge to promote skeletal muscle differentiation and regeneration. Journal of Cachexia, Sarcopenia and Muscle 9(3):613-626, 2018.