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However, the role of tsRNAs in skeletal muscle regeneration remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Small RNA sequencing revealed the relationship between tsRNAs and skeletal muscle injury. The dynamic expression level of 5'tiRNA\u2010Gly after muscle injury was confirmed by real\u2010time quantitative PCR (q\u2010PCR). In addition, q\u2010PCR, flow cytometry, the 5\u2010ethynyl\u20102'\u2010deoxyuridine (Edu), cell counting kit\u20108, western blotting and immunofluorescence were used to explore the biological function of 5'tiRNA\u2010Gly. Bioinformatics analysis and dual\u2010luciferase reporter assay were used to further explore the mechanism of action under the biological function of 5'tiRNA\u2010Gly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Transcriptome analysis revealed that tsRNAs were significantly enriched during inflammatory response immediately after muscle injury. Interestingly, we found that 5'tiRNA\u2010Gly was significantly up\u2010regulated after muscle injury (<jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.0001) and had a strong positive correlation with inflammation in vivo. In vitro experiments showed that 5'tiRNA\u2010Gly promoted the mRNA expression of proinflammatory cytokines (<jats:italic>IL\u20101\u03b2<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0468; <jats:italic>IL\u20106<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0369) and the macrophages of M1 markers (<jats:italic>TNF\u2010\u03b1<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0102; <jats:italic>CD80<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0056; <jats:italic>MCP\u20101<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0002). On the contrary, 5'tiRNA\u2010Gly inhibited the mRNA expression of anti\u2010inflammatory cytokines (<jats:italic>IL\u20104<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0009; <jats:italic>IL\u201010<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0007; <jats:italic>IL\u201013<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0008) and the mRNA expression of M2 markers (<jats:italic>TGF\u2010\u03b21<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0016; <jats:italic>ARG1<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0083). Flow cytometry showed that 5'tiRNA\u2010Gly promoted the percentage of CD86<jats:sup>+<\/jats:sup> macrophages (16%, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.011) but inhibited that of CD206<jats:sup>+<\/jats:sup> macrophages (10.5%, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.012). Immunofluorescence showed that knockdown of 5'tiRNA\u2010Gly increased the infiltration of M2 macrophages to the skeletal muscles (13.9%, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0023) and inhibited the expression of <jats:italic>Pax7<\/jats:italic> (<jats:italic>P\u00a0=<\/jats:italic>\u00a00.0089) in vivo. 5'tiRNA\u2010Gly promoted myoblast the expression of myogenic differentiation marker genes (<jats:italic>MyoD<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0002; <jats:italic>MyoG<\/jats:italic>, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0037) and myotube formation (21.3%, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0016) but inhibited the positive rate of Edu (27.7%, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0001), cell viability (22.6%, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.003) and the number of myoblasts in the G2 phase (26.3%, <jats:italic>P\u00a0=<\/jats:italic>\u00a00.0016) in vitro. Mechanistically, we found that the <jats:italic>Tgfbr1<\/jats:italic> gene is a direct target of 5'tiRNA\u2010Gly mediated by AGO1 and AGO3. 5'tiRNA\u2010Gly dysregulated the expression of downstream genes related to inflammatory response, activation of satellite cells and differentiation of myoblasts through the TGF\u2010\u03b2 signalling pathway by targeting <jats:italic>Tgfbr1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results reveal that 5'tiRNA\u2010Gly potentially regulated skeletal muscle regeneration by inducing inflammation via the TGF\u2010\u03b2 signalling pathway. The findings of this study uncover a new potential target for skeletal muscle regeneration treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13187","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T04:42:30Z","timestamp":1675917750000},"page":"1033-1045","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["<scp>tRNA<\/scp>\u2010derived small RNA, <scp>5'tiRNA\u2010Gly\u2010CCC<\/scp>, promotes skeletal muscle regeneration through the inflammatory response"],"prefix":"10.1002","volume":"14","author":[{"given":"Linyuan","family":"Shen","sequence":"first","affiliation":[{"name":"College of Animal Science and Technology Sichuan Agricultural University  Chengdu China"},{"name":"Key Laboratory of Livestock and Poultry Multi\u2010omics, Ministry of Agriculture and Rural Affairs, Institute of Animal Genetics and Breeding Sichuan Agricultural University  Chengdu 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