Down-regulation of human-specific lncRNA TMEM9B-AS1 in skeletal muscle of people with type 2 diabetes affects ribosomal biogenesis
Ilke Sen, Jonathon A. B. Smith, E Caria, Iurii A. Orlov, Mladen Savikj, Aidan J. Brady, Kristian Lian, Stian Ellefsen, Juleen R. Zierath, Anna Krook
Abstract
Long noncoding RNAs (lncRNAs) are important regulators of skeletal muscle physiology, with altered expression noted in several human diseases including type 2 diabetes. We report that TMEM9B-AS1, a previously uncharacterized lncRNA, is down-regulated in skeletal muscle of men with type 2 diabetes and skeletal muscle from individuals with sarcopenia. Silencing of TMEM9B-AS1 in primary human myotubes attenuated protein synthesis, concomitant with reduced phosphorylation of ribosomal protein S6. Moreover, we show that TMEM9B-AS1 plays a pivotal role in regulation of ribosomal biogenesis by facilitating messenger RNA stabilization of the transcription factor MYC through direct physical interaction with the RNA binding protein, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1). Disrupted ribosomal biogenesis resulting from TMEM9B-AS1 silencing leads to decreased expression of muscle contractile and structural proteins important for maintenance of skeletal muscle mass and function. Collectively, our data reveal a role of TMEM9B-AS1 in skeletal muscle loss associated with metabolic disorders.