Toward a novel muscle anabolic strategy for sarcopenia: targeting the interaction between long noncoding RNA lncRNA-3 and MyoD1 promoter to promote myogenesi

Sarcopenia, age-related loss of skeletal muscle mass and strength, is associated with serious health consequences, but there is no clinically established therapy for sarcopenia to date. Here, we identified a sarcopenia-related lncRNA (lncRNA-3), which was significantly up-regulated in gastrocnemius muscle of aged sarcopenic mice (Figure 1). LncRNA-3 neg- atively regulated muscle mass and MyoD protein level in skeletal muscles of mice (Figure 2). Mechanistically, lncRNA-3 could interact with RbAp46/48, a subunit of Polycomb re- pressive complex 2 (PRC2), guide PRC2 to MyoD1 promoter, in turns catalyze the methyl- ation of histone H3 at lysine 27 (H3K27) at MyoD1 promoter region and mediate MyoD1 gene silencing (Figure 3). Skeletal muscle-specific knockdown of lncRNA-3 promoted MyoD1 mRNA level and muscle mass in muscle-specific lncRNA-3 knockin mice (Figure 4). Low conservation in sequence limits the translation of lncRNA research. LncRNA-3 was functionally conserved in human (lncRNA-3H), which was also interacted with PRC2 and MyoD1 promoter. LncRNA-3H knockdown promoted MyoD1 mRNA level and ln- cRNA-3H overexpression inhibited MyoD1 mRNA level in human skeletal muscle cells (Figure 5). To interfere with the interaction between lncRNA-3 and MyoD1, the MyoD1 promoter sequence was overexpressed in C2C12 cells and the skeletal muscle of aged mice. The cell differentiation of C2C12 cells was enhanced after MyoD1 promoter overexpres- sion (Figure 6). Enhanced MyoD1 promoter expression in skeletal muscle suppressed the function of lncRNA-3 and counteract sarcopenia development in aged mice (Figure 7). The study uncovered the functional role of lncRNA-3 as an epigenetic regulator (Figure 8) and suggested the interaction between lncRNA-3 and MyoD1 promoter could be a potential therapeutic target to counteract sarcopenia development. It also provided a novel therapeutic strategy which to target the interaction between lncRNA and its conserved target protein or gene to overcome the limitation of low conservation of lncRNAs. Acknowledgments: This study was supported by the Hong Kong General Research Fund (14112915 and 14100218) and Direct Grant of The Chinese University of Hong Kong (2017.077).