Human-specific lncRNA TMEM9B-AS1 is downregulated in skeletal muscle of individuals with type 2 diabetes and regulates ribosomal biogenesis

Long non-coding RNAs (lncRNAs) are important regulators of skeletal muscle physiology, with altered expression noted in several human diseases including type 2 diabetes. Here we report TMEM9B-AS1, a previously uncharacterized lncRNA, is downregulated in skeletal muscle of men with type 2 diabetes. Silencing of TMEM9B-AS1 in primary human myotubes attenuated protein synthesis, concomitant with reduced phosphorylation of ribosomal protein S6, a downstream target of ERK and mTOR pathways. Moreover, we provide evidence that TMEM9B-AS1 plays a pivotal role in the regulation of ribosomal biogenesis by facilitating mRNA stabilization of the transcription factor MYC through a direct physical interaction with the RNA-binding protein IGF2BP1. Disrupted ribosomal biogenesis resulting from TMEM9B-AS1 silencing is linked reduced skeletal muscle mass in type 2 diabetes, elucidating molecular mechanisms contributing to skeletal muscle loss in metabolic disease.