Insulin-like growth factor-1 receptor is regulated by microRNA-133 during skeletal myogenesis

PLoS One. 2011;6(12):e29173. doi: 10.1371/journal.pone.0029173. Epub 2011 Dec 15.


Background: The insulin-like growth factor (IGF) signaling pathway has long been established as playing critical roles in skeletal muscle development. However, the underlying regulatory mechanism is poorly understood. Recently, a large family of small RNAs, named microRNAs (miRNAs), has been identified as key regulators for many developmental processes. Because miRNAs participate in the regulation of various signaling pathways, we hypothesized that miRNAs may be involved in the regulation of IGF signaling in skeletal myogenesis.

Methodology/principal findings: In the present study, we determined that the cell-surface receptor IGF-1R is directly regulated by a muscle-specific miRNA, microRNA-133 (miR-133). A conserved and functional binding site for miR-133 was identified in the 3'untranslated region (3'UTR) of IGF-1R. During differentiation of C2C12 myoblasts, IGF-1R protein, but not messenger RNA (mRNA) expression, was gradually reduced, concurrent with the upregulation of miR-133. Overexpression of miR-133 in C2C12 cells significantly suppressed IGF-1R expression at the posttranscriptional level. We also demonstrated that both overexpression of miR-133 and knockdown of IGF-1R downregulated the phosphorylation of Akt, the central mediator of the PI3K/Akt signaling pathway. Furthermore, upregulation of miR-133 during C2C12 differentiation was significantly accelerated by the addition of IGF-1. Mechanistically, we found that the expression of myogenin, a myogenic transcription factor reported to transactivate miR-133, was increased by IGF-1 stimulation.

Conclusion/significance: Our results elucidate a negative feedback circuit in which IGF-1-stimulated miR-133 in turn represses IGF-1R expression to modulate the IGF-1R signaling pathway during skeletal myogenesis. These findings also suggest that miR-133 may be a potential therapeutic target in muscle diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Line
  • Gene Expression Regulation, Developmental* / drug effects
  • HEK293 Cells
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Biological
  • Molecular Sequence Data
  • Muscle Development / drug effects
  • Muscle Development / genetics*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / growth & development*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / genetics*
  • Receptor, IGF Type 1 / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics


  • 3' Untranslated Regions
  • MicroRNAs
  • Mirn133 microRNA, mouse
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt