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Long noncoding RNA (lncRNA) play important roles in various stages of muscle development. We previously reported that <jats:italic>Synaptopodin\u20102<\/jats:italic> (<jats:italic>SYNPO2<\/jats:italic>) intron sense\u2010overlapping lncRNA (<jats:italic>SYISL<\/jats:italic>) regulates myogenesis through an interaction with enhancer of zeste homologue 2 (EZH2). However, it remains unclear whether <jats:italic>SYISL<\/jats:italic> homologues exist in humans and pigs, and whether the functions and mechanisms of these homologues are conserved among species.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Bioinformatics, cell fractionation, and quantitative real\u2010time polymerase chain reaction (qRT\u2010PCR) analyses were used for the identification and molecular characterization of <jats:italic>SYISL<\/jats:italic> homologues in humans and pigs. Effects on myogenesis and muscle atrophy were determined via loss\u2010of\u2010function or gain\u2010of\u2010function experiments using C2C12 myoblasts, myogenic progenitor cells, dexamethasone (DEX), and aging\u2010induced muscle atrophy models. RNA pulldown, RNA immunoprecipitation, dual luciferase reporting, and co\u2010transfection experiments were used to explore the mechanisms of <jats:italic>SYISL<\/jats:italic> interactions with proteins and miRNAs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified <jats:italic>SYISL<\/jats:italic> homologues in humans (designated <jats:italic>hSYISL<\/jats:italic>) and pigs (designated <jats:italic>pSYISL<\/jats:italic>). Functional experiments demonstrated that <jats:italic>hSYISL<\/jats:italic> and <jats:italic>pSYISL<\/jats:italic> regulate myogenesis through interactions with EZH2. Interestingly, we showed that <jats:italic>SYISL<\/jats:italic> functions to regulate muscle atrophy and sarcopenia through comparative analysis. <jats:italic>SYISL<\/jats:italic> is significantly up\u2010regulated after muscle atrophy (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01); it significantly promotes muscle atrophy in DEX\u2010induced muscle atrophy models (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). <jats:italic>SYISL<\/jats:italic> knockdown or knockout alleviates muscle atrophy and sarcopenia in DEX\u2010induced and aged mice. The tibialis anterior (TA) muscle weight of 3\u2010month\u2010old wild\u2010type (WT) mice decreased by 33.24% after DEX treatment (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), while the muscle weight loss of 3\u2010month\u2010old <jats:italic>SYISL<\/jats:italic> knockout mice was only 18.20% after DEX treatment (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). <jats:italic>SYISL<\/jats:italic> knockout in 18\u2010month\u2010old WT mice significantly increased the weights of quadriceps (Qu), gastrocnemius (Gas), and TA muscles by 10.45% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), 13.95% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), and 24.82% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), respectively. Mechanistically, <jats:italic>SYISL<\/jats:italic> increases the expression levels of the muscle atrophy genes <jats:italic>forkhead box protein O3a<\/jats:italic> (<jats:italic>FoxO3a<\/jats:italic>), <jats:italic>muscle ring finger 1<\/jats:italic> (<jats:italic>MuRF1<\/jats:italic>), and <jats:italic>muscle atrophy\u2010related F\u2010box<\/jats:italic> (<jats:italic>Atrogin\u20101<\/jats:italic>) via sponging of <jats:italic>miR\u201023a\u20103p\/miR\u2010103\u20103p\/miR\u2010205\u20105p<\/jats:italic> and thus promotes muscle atrophy. Additionally, we verified that human <jats:italic>SYISL<\/jats:italic> overexpression in muscles of 18\u2010month\u2010old WT mice significantly decreased the weights of Gas, Qu, and TA muscles by 7.76% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), 12.26% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), and 13.44% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), respectively, and accelerates muscle atrophy through conserved mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results identify <jats:italic>SYISL<\/jats:italic> as a conserved lncRNA that modulates myogenesis in mice, pigs, and humans. We also demonstrated its previously unknown ability to promote muscle atrophy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13012","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T07:00:03Z","timestamp":1653030003000},"page":"2017-2030","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Conservative analysis of <i>Synaptopodin\u20102<\/i> intron sense\u2010overlapping lncRNA reveals its novel function in promoting muscle atrophy"],"prefix":"10.1002","volume":"13","author":[{"given":"Jianjun","family":"Jin","sequence":"first","affiliation":[{"name":"Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs Huazhong Agricultural University  Wuhan China"},{"name":"Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education Huazhong Agricultural University  Wuhan China"},{"name":"Key Laboratory of Animal 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