Molecular Therapy: Nucleic Acids (Jan 2015)

In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin

  • Delphine Laustriat,
  • Jacqueline Gide,
  • Laetitia Barrault,
  • Emilie Chautard,
  • Clara Benoit,
  • Didier Auboeuf,
  • Anne Boland,
  • Christophe Battail,
  • François Artiguenave,
  • Jean-François Deleuze,
  • Paule Bénit,
  • Pierre Rustin,
  • Sylvia Franc,
  • Guillaume Charpentier,
  • Denis Furling,
  • Guillaume Bassez,
  • Xavier Nissan,
  • Cécile Martinat,
  • Marc Peschanski,
  • Sandrine Baghdoyan

DOI
https://doi.org/10.1038/mtna.2015.35
Journal volume & issue
Vol. 4, no. C

Abstract

Read online

Major physiological changes are governed by alternative splicing of RNA, and its misregulation may lead to specific diseases. With the use of a genome-wide approach, we show here that this splicing step can be modified by medication and demonstrate the effects of the biguanide metformin, on alternative splicing. The mechanism of action involves AMPK activation and downregulation of the RBM3 RNA-binding protein. The effects of metformin treatment were tested on myotonic dystrophy type I (DM1), a multisystemic disease considered to be a spliceopathy. We show that this drug promotes a corrective effect on several splicing defects associated with DM1 in derivatives of human embryonic stem cells carrying the causal mutation of DM1 as well as in primary myoblasts derived from patients. The biological effects of metformin were shown to be compatible with typical therapeutic dosages in a clinical investigation involving diabetic patients. The drug appears to act as a modifier of alternative splicing of a subset of genes and may therefore have novel therapeutic potential for many more diseases besides those directly linked to defective alternative splicing.

Keywords