Myostatin signaling regulates Akt activity via the regulation of miR-486 expression

Int J Biochem Cell Biol. 2014 Feb;47:93-103. doi: 10.1016/j.biocel.2013.12.003. Epub 2013 Dec 14.


Myostatin, also known as growth and differentiation factor-8, is a pivotal negative regulator of skeletal muscle mass and reduces muscle protein synthesis by inhibiting the insulin-like growth factor-1 (IGF-1)/Akt/mammalian target of rapamycin (mTOR) pathway. However, the precise mechanism by which myostatin inhibits the IGF-1/Akt/mTOR pathway remains unclear. In this study, we investigated the global microRNA expression profile in myostatin knockout mice and identified miR-486, a positive regulator of the IGF-1/Akt pathway, as a novel target of myostatin signaling. In myostatin knockout mice, the expression level of miR-486 in skeletal muscle was significantly increased. In addition, we observed increased expression of the primary transcript of miR-486 (pri-miR-486) and Ankyrin 1.5 (Ank1.5), the host gene of miR-486, in myostatin knockout mice. In C2C12 cells, myostatin negatively regulated the expression of Ank1.5. Moreover, canonical myostatin signaling repressed the skeletal muscle-specific promoter activity of miR-486/Ank1.5. This repression was partially mediated by the E-box elements in the proximal region of the promoter. We also show that overexpression of miR-486 induced myotube hypertrophy in vitro and that miR-486 was essential to maintain skeletal muscle size both in vitro and in vivo. In addition, inhibition of miR-486 led to a decrease in Akt activity in C2C12 myotubes. Our findings indicate that miR-486 is one of the intermediary molecules connecting myostatin signaling and the IGF-1/Akt/mTOR pathway in the regulation of skeletal muscle size.

Keywords: Akt; Ank1.5; Myostatin; Smad3; miR-486.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ankyrins / genetics
  • Ankyrins / metabolism
  • Cell Line
  • Gene Expression Regulation
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Muscle, Skeletal / metabolism
  • Myostatin / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transfection


  • Ank1 protein, mouse
  • Ankyrins
  • MIRN486 microRNA, mouse
  • MicroRNAs
  • Mstn protein, mouse
  • Myostatin
  • Insulin-Like Growth Factor I
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt