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Long non\u2010coding RNAs (lncRNAs) have emerged as key regulators in muscle biology; however, their precise roles in muscle function and pathology remain to be fully elucidated. This study demonstrates that lncRNA maternally expressed gene 3 (MEG3)\u00a0is preferentially expressed in slow\u2010twitch muscle fibers and dynamically regulated during muscle development, aging, and in the context of Duchenne muscular dystrophy (DMD). Using both loss\u2010 and gain\u2010of\u2010function mice models, this study shows that lncRNA\u2010MEG3 is critical for preserving muscle mass and function. Its depletion leads to muscle atrophy, mitochondrial dysfunction, and impaired regenerative capacity, while overexpression enhances muscle mass, increases oxidative muscle fiber content, and improves endurance. Notably, lncRNA\u2010MEG3 overexpression in MDX mice significantly alleviates muscle wasting and adipose tissue infiltration. Mechanistically, this study uncovers a novel interaction between lncRNA\u2010MEG3 and the polycomb repressive complex 2 (PRC2), where lncRNA\u2010MEG3 binds to SUZ12 polycomb repressive complex 2 subunit (Suz12), stabilizes PRC2, facilitates SUZ12 liquid\u2013liquid phase separation (LLPS), and regulates the epigenetic modulation of four and a half lim domains 3 (Fhl3) and ring finger protein 128 (Rnf128). These findings not only highlight the crucial role of lncRNA\u2010MEG3 in muscle homeostasis but also provide new insights into lncRNA\u2010based therapeutic strategies for muscle\u2010related diseases.<\/jats:p>","DOI":"10.1002\/advs.202417715","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T06:06:24Z","timestamp":1745647584000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["LncRNA\u2010MEG3 Regulates Muscle Mass and Metabolic Homeostasis by Facilitating SUZ12 Liquid\u2013Liquid Phase Separation"],"prefix":"10.1002","volume":"12","author":[{"given":"Yilong","family":"Yao","sequence":"first","affiliation":[{"name":"Shenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi\u2010omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences  Shenzhen 518124 China"},{"name":"Kunpeng 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