It has been established that Long noncoding RNAs (lncRNAs) play a pivotal role in regulating systemic glucose and lipid homeostasis. Previously, we identified a insulin-resistance (IR) related lncRNA named Gm15441, which was upregualted in skeletal muscle from db/db mice by RNA-sequencing. Here, we explored the relationship between Gm15441 and skeletal muscle function in vitro and in vivo and the possible mechanism involved in that process. Real-time PCR analyses revealed Gm15441 was abundant in skeletal muscle compared to other metabolic tissues. Additionally, Gm15441 expression was observed upregualted in IR cells (pamitate-treated C2C12 myotubes) and mice (db/db, ob/ob and aged mice). Overexpression of Gm15441 by plasmid transfection in C2C12 myotubes decreased Glut4, p-Akt/Akt and p-Irs1/Irs1 protein levels and attenuated glucose uptake capacity by the 2-NBDG method. Gm15441 overexpression also impaired mitochondrial oxygen consumption and Pgc1α expression. Moreover, adeno-associated viral (AAV) vectors to induce Gm15441 expression in skeletal muscles. Six-week-old male mice were administered with AAV-GFP or AAV-Gm15441 vectors followed with or without high-fat diet (HFD) for 14 weeks. Body weight gain and food intake were not different among the groups, but AAV-Gm15441 mice under HFD showed decreased glucose tolerance and insulin sensitivity. These mice exhibited ectopic lipid accumulation in skeletal muscle by HE staining, although no difference was observed in skeletal muscle weights and serum TG. A global mRNA analysis further indicated a possible regulatory role of Pparα-Pgc1α pathway in Gm15441-mediated dysregulation of glucose-lipid metabolism. Collectively, these findings improve our understanding of lncRNAs involved in skeletal muscle glucose-lipid metabolism and represent potential therapeutic targets to IR and associated metabolic diseases. Key words: lncRNA, Gm15441, skeletal muscle, insulin resistance, Pgc1α.
L. You: None. Y. Zeng: None. N. Gu: None. C. Ji: None.
