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The role of MiR biogenesis in myogenesis has not been characterized yet. RNA\u2010binding protein Musashi 2 (Msi2) is considered to be one of the major drivers for oncogenesis and stem cell proliferation. The functions of Msi2 in myogenesis have not been explored yet. We sought to investigate Msi2\u2010regulated biogenesis of MiRs in myogenesis and muscle stem cell (MuSC) ageing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We detected the expression of Msi2 in MuSCs and differentiated myotubes by quantitative reverse transcription PCR (RT\u2010qPCR) and western blot. Msi2\u2010binding partner human antigen R (HuR) was identified by immunoprecipitation followed by mass spectrometry analysis. The cooperative binding of Msi2 and HuR on MiR7a\u20101 was analysed by RNA immunoprecipitation and electrophoresis mobility shift assays. The inhibition of the processing of <jats:italic>pri\u2010MiR7a\u20101<\/jats:italic> mediated by Msi2 and HuR was shown by Msi2 and HuR knockdown. Immunofluorescent staining, RT\u2010qPCR and immunoblotting were used to characterize the function of MiR7a\u20101 in myogenesis. Msi2 and HuR up\u2010regulate cryptochrome circadian regulator 2 (Cry2) via MiR7a\u20101 was confirmed by the luciferase assay and western blot. The post\u2010transcriptional regulatory cascade was further confirmed by RNAi and overexpressing of Msi2 and HuR in MuSCs, and the <jats:italic>in vivo<\/jats:italic> function was characterized by histopathological and molecular biological methods in Msi2 knockout mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a post\u2010transcription regulatory cascade governed by a pair of RNA\u2010binding proteins Msi2 and HuR. Msi2 is enriched in differentiated muscle cells and promotes MuSC differentiation despite its pro\u2010proliferation functions in other cell types. Msi2 works synergistically with another RNA\u2010binding protein HuR to repress the biogenesis of MiR7a\u20101 in an Msi2 dose\u2010dependent manner to regulate the translation of the key component of the circadian core oscillator complex Cry2. Down\u2010regulation of Cry2 (0.6\u2010fold, vs. control, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) mediated by MiR7a\u20101 represses MuSC differentiation. The disruption of this cascade leads to differentiation defects of MuSCs. In aged muscles, Msi2 (0.3\u2010fold, vs. control, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) expression declined, and the Cry2 protein level also decreases (0.5\u2010fold, vs. control, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), suggesting that the disruption of the Msi2\u2010mediated post\u2010transcriptional regulatory cascade could attribute to the declined ability of muscle regeneration in aged skeletal muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings have identified a new post\u2010transcriptional cascade regulating myogenesis. The cascade is disrupted in skeletal muscle ageing, which leads to declined muscle regeneration ability.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12882","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T09:21:22Z","timestamp":1638955282000},"page":"728-742","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Msi2\u2010mediated MiR7a\u20101 processing repression promotes myogenesis"],"prefix":"10.1002","volume":"13","author":[{"given":"Wenjun","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pediatric Orthopedics Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lele","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangzhou Laboratory  Guangzhou China"},{"name":"Max Planck Center for Tissue Stem Cells and Regenerative Medicine 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