The microRNA Signature in Response to Insulin Reveals Its Implication in the Transcriptional Action of Insulin in Human Skeletal Muscle and the Role of a Sterol Regulatory Element–Binding Protein-1c/Myocyte Enhancer Factor 2C Pathway

  1. Aurélie Granjon1,
  2. Marie-Paule Gustin2,
  3. Jennifer Rieusset1,
  4. Etienne Lefai1,
  5. Emmanuelle Meugnier1,
  6. Isabelle Güller1,
  7. Catherine Cerutti2,
  8. Christian Paultre2,
  9. Emmanuel Disse3,4,
  10. Rémi Rabasa-Lhoret5,
  11. Martine Laville1,3,4,
  12. Hubert Vidal1,3,4 and
  13. Sophie Rome1
  1. 1Institut de la Recherche Agronomique (INRA) 1235, INSERM 870, INSA-Lyon, Régulations Métaboliques Nutrition et Diabète, Université Lyon, Oullins, France;
  2. 2INSERM ERI22/EA 4173, Biostatistiques, Université Lyon, Lyon, France;
  3. 3Hospices Civils de Lyon, Service de Diabétologie et Nutrition, Hôpital Edouard-Herriot, Lyon, France;
  4. 4Centre de Recherche en Nutrition Humaine Rhône-Alpes, Oullins, France;
  5. 5Chaire de recherche J-A DeSève, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada.
  1. Corresponding author: Sophie Rome, srome{at}univ-lyon1.fr.

Abstract

OBJECTIVE Factors governing microRNA expressions in response to changes of cellular environment are still largely unknown. Our aim was to determine whether insulin, the major hormone controlling whole-body energy homeostasis, is involved in the regulation of microRNA expressions in human skeletal muscle.

RESEARCH DESIGN AND METHODS We carried out comparative microRNA (miRNA) expression profiles in human skeletal muscle biopsies before and after a 3-h euglycemic-hyperinsulinemic clamp, with TaqMan low-density arrays. Then, using DNA microarrays, we determined the response to insulin of the miRNA putative target genes in order to determine their role in the transcriptional action of insulin. We further characterized the mechanism of action of insulin on two representative miRNAs, miR-1 and miR-133a, in human muscle cells.

RESULTS Insulin downregulated the expressions of 39 distinct miRNAs in human skeletal muscle. Their potential target mRNAs coded for proteins that were mainly involved in insulin signaling and ubiquitination-mediated proteolysis. Bioinformatic analysis suggested that combinations of different downregulated miRNAs worked in concert to regulate gene expressions in response to insulin. We further demonstrated that sterol regulatory element–binding protein (SREBP)-1c and myocyte enhancer factor 2C were involved in the effect of insulin on miR-1 and miR-133a expression. Interestingly, we found an impaired regulation of miRNAs by insulin in the skeletal muscle of type 2 diabetic patients, likely as consequences of altered SREBP-1c activation.

CONCLUSIONS This work demonstrates a new role of insulin in the regulation of miRNAs in human skeletal muscle and suggests a possible implication of these new modulators in insulin resistance.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received February 5, 2009.
    • Accepted August 5, 2009.
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  1. Diabetes vol. 58 no. 11 2555-2564
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