Annuaire
In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin.
Mol Ther Nucleic Acids, 4:e262.
Major physiological changes are governed by alternative splicing of RNA, and itsmisregulation 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 anddemonstrate the effects of the biguanide metformin, on alternative splicing. Themechanism 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. Thedrug 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.
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