NATURE COMMUNICATIONS 8:14718 (2017) 

Lnc-mg is a long non-coding RNA that promotes myogenesis

王晓刚


摘要:

Recent studies indicate important roles for long noncoding RNAs (lncRNAs) as essential regulators of myogenesis and adult skeletal muscle regeneration. However, the specific roles of lncRNAs in myogenic differentiation of adult skeletal muscle stem cells and myogenesis are still largely unknown. Here we identify a lncRNA that is specifically enriched in skeletal muscle (myogenesis-associated lncRNA, in short, lnc-mg). In mice, conditional knockout of lnc-mg in skeletal muscle results in muscle atrophy and the loss of muscular endurance during exercise. Alternatively, skeletal muscle-specific overexpression of lnc-mg promotes muscle hypertrophy. In vitro analysis of primary skeletal muscle cells shows that lnc-mg increases gradually during myogenic differentiation and its overexpression improves cell differentiation. Mechanistically, lnc-mg promotes myogenesis, by functioning as a competing endogenous RNA (ceRNA) for microRNA-125b to control protein abundance of insulin-like growth factor 2. These findings identify lnc-mg as a novel noncoding regulator for muscle cell differentiation and skeletal muscle development.To identify functional lncRNAs correlating with myogenesis, we isolated and induced mouse skeletal MuSCs to differentiation (Supplementary Fig. 1a). Microarray data from the original and differentiated MuSCs revealed that 70 lncRNAs were upregulated and 12 were downregulated during this change (Fig. 1a and Supplementary Table 1). Among the increased lncRNAs, we identified a lncRNA (named lnc-mg) enriched in skeletal muscle (Fig. 1b and Supplementary Fig. 1b). To validate whether lnc-mg expressed differently in various types of muscles, we examined the levels of lnc-mg in different types of muscles. It is found that the expression levels of lnc-mg have only a little difference among different types of muscles, while higher than in other tissues (Fig. 1c and Supplementary Fig. 1c). The general information and sequence of lnc-mg are supplied in Supplementary Fig. 1d,e. In addition, lnc-mg has a polyA tail and a 5′-cap structure (Supplementary Fig. 1f) but without coding capacity (Supplementary Fig. 1g). Consistent with the microarray data, lnc-mg is shown to be induced in MuSCs differentiation (Fig. 1d). Interestingly, in Gene Ontology analysis, lnc-mg-related genes are mainly clustered into muscle contraction and muscle system process classification categories (Fig. 1e).Animal protocol are approved by the Animal Ethics Committee of Peking Union Medical College, Beijing, China. Eight-week old, C57B/6J mice were used in our study, three for male and three for female in each group.Supplementary Figures and Supplementary Tables.This work was supported by National Natural Science Foundation Projects (81370971 to W.X.G., 81470715 to S.Y. and 31325012 to L.Y.X.) Guangdong Natural Science Funds (2014A030313358 and 2015A030313333), Major project in Guangdong Province of science (2014KZDXM011), Science and Technology Planning Project of Guangdong Province (2013B090500105 and 2014A020210015), Guangdong Natural Science Funds for Distinguished Young Scholar (S2013050013880), Key Project of Chinese National Programs for Research and Development(2016YFC1102705), National Key Technology Support Program (2014BAI04B07) and the Recruitment Program of Global Experts S.Y.The authors declare no competing financial interests.Author contributions M.Z. and J.L. constructed the lnc-mgSkl−/− and TG mice, and performed the molecular biological experiments. J.X. and L.Y. isolated and cultured mouse primary skeletal MuSCs, and performed cellular experiments. M.C. and H.S. raised the mice and conducted the animal experiments. X.C., Y.M., S.H., Z.W. and A.H. revised the manuscript. Y.L., Y.S. and X.W. designed this work and wrote this manuscript.
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