Insulin-Like Growth Factor-1 Receptor Is Regulated by microRNA-133 during Skeletal Myogenesis
Open Access
- 15 December 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (12), e29173
- https://doi.org/10.1371/journal.pone.0029173
Abstract
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. 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. 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.Keywords
This publication has 43 references indexed in Scilit:
- IGF-II is regulated by microRNA-125b in skeletal myogenesisThe Journal of cell biology, 2011
- Distinct roles for miR‐1 and miR‐133a in the proliferation and differentiation of rhabdomyosarcoma cellsThe FASEB Journal, 2010
- MicroRNA control of signal transductionNature Reviews Molecular Cell Biology, 2010
- Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486Proceedings of the National Academy of Sciences of the United States of America, 2010
- MicroRNA regulation of neuron-like differentiation of adipose tissue-derived stem cellsDifferentiation, 2009
- MicroRNAs: Target Recognition and Regulatory FunctionsCell, 2009
- An intragenic MEF2-dependent enhancer directs muscle-specific expression of microRNAs 1 and 133Proceedings of the National Academy of Sciences of the United States of America, 2007
- Myogenic factors that regulate expression of muscle-specific microRNAsProceedings of the National Academy of Sciences of the United States of America, 2006
- The functions of animal microRNAsNature, 2004
- MicroRNAs: small RNAs with a big role in gene regulationNature Reviews Genetics, 2004