LncRNA RMG controls liquid-liquid phase separation of MEIS2 to regulate myogenesis

Long non-coding RNAs (lncRNAs) regulate liquid-liquid phase separation (LLPS), driving the formation of biomolecular condensates essential for cellular function. However, this regulatory mechanism is yet to be reported in skeletal muscles. In this study, we comprehensively analyzed lncRNAs in skeletal muscle across multiple pig breeds, developmental stages, and tissues. Our analysis identified over 10,000 novel lncRNAs. We found that the lnc-regulator of muscle growth (lnc-RMG) regulates myogenesis by modulating the LLPS of Meis homeobox 2 (MEIS2). Lnc-RMG was specifically expressed in the skeletal muscle, with significantly higher expression in the fetal stage than in the embryonic stage. Notably, lnc-RMG was highly conserved between pigs and humans and exhibits similar biological functions in myogenesis. Furthermore, lnc-RMG knockdown promoted skeletal muscle regeneration. Mechanistically, lnc-RMG produces mature microRNA (miR)-133a-3p, which targets and inhibits MEIS2 expression, thereby inhibiting MEIS2 LLPS. This inhibition promoted the transcription of transforming growth factor-β receptor II (TGFβR2), ultimately regulating myogenesis. Overall, our findings revealed a novel lnc-RMG/miR-133a-3p/MEIS2/TGFβR2 axis that regulated myogenesis through LLPS and provided new insights into the molecular mechanisms that drive muscle development and regeneration. These findings highlight potential therapeutic targets for muscle-related diseases and novel strategies for livestock improvement.