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; Amy Chan; Abigail Liebow; Makiko Yasuda; Lin Gan; Tim Racie; Martin Maier; Satya Kuchimanchi; Don Foster; Stuart Milstein; Klaus Charisse; Alfica Sehgal; Muthiah Manoharan; Rachel Meyers; Kevin Fitzgerald; Amy Simon; Robert J. Desnick; William Querbes

doi:10.1038/mtna.2015.36

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

Amy Chan, Abigail Liebow, Makiko Yasuda, Lin Gan, Tim Racie, Martin Maier, Satya Kuchimanchi, Don Foster, Stuart Milstein, Klaus Charisse, Alfica Sehgal, Muthiah Manoharan, Rachel Meyers, Kevin Fitzgerald, Amy Simon, Robert J. Desnick, William Querbes

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

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.

Original language	English
Article number	e263
Journal	Molecular Therapy Nucleic Acids
Volume	4
DOIs	https://doi.org/10.1038/mtna.2015.36
State	Published - 3 Nov 2015
Externally published	Yes

Keywords

AMPK
Metformin
RBM3
alternative splicing
myotonic dystrophy type 1

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10.1038/mtna.2015.36

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Laustriat, D., Gide, J., Barrault, L., Chautard, E., Benoit, C., Auboeuf, D., Boland, A., Battail, C., Artiguenave, F., Deleuze, J. F., Bénit, P., Rustin, P., Franc, S., Charpentier, G., Furling, D., Bassez, G., Nissan, X., Martinat, C., Peschanski, M., ... Querbes, W. (2015). In Vitro and in Vivo Modulation of Alternative Splicing by the Biguanide Metformin. Molecular Therapy Nucleic Acids, 4, Article e263. https://doi.org/10.1038/mtna.2015.36

@article{9e4f25a8daf34555a737867d3f96acc1,

title = "In Vitro and in Vivo Modulation of Alternative Splicing by the Biguanide Metformin",

abstract = "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 = "AMPK, Metformin, RBM3, alternative splicing, myotonic dystrophy type 1",

author = "Delphine Laustriat and Jacqueline Gide and Laetitia Barrault and Emilie Chautard and Clara Benoit and Didier Auboeuf and Anne Boland and Christophe Battail and Fran{\c c}ois Artiguenave and Deleuze, \{Jean Fran{\c c}ois\} and Paule B{\'e}nit and Pierre Rustin and Sylvia Franc and Guillaume Charpentier and Denis Furling and Guillaume Bassez and Xavier Nissan and C{\'e}cile Martinat and Marc Peschanski and Sandrine Baghdoyan and Amy Chan and Abigail Liebow and Makiko Yasuda and Lin Gan and Tim Racie and Martin Maier and Satya Kuchimanchi and Don Foster and Stuart Milstein and Klaus Charisse and Alfica Sehgal and Muthiah Manoharan and Rachel Meyers and Kevin Fitzgerald and Amy Simon and Desnick, \{Robert J.\} and William Querbes",

note = "Funding Information: We thank Laetitia Aubry (INSERM/UEVE UMR 861, Evry, France) for discussions. The authors also thank Karen Sermon (Department of Embryology and Genetics, Vrije Universiteit Brussel, Brussels, Belgium) for providing embryonic stem cell lines, Thomas Andy Cooper (Baylor College of Medicine, Houston, TX) for cTNT minigenes, Odile Jouy and Marie-H{\'e}l{\`e}ne Petit for organizing the Metforgene clinical trial on diabetic patients (NCT 01349387) and collection of blood samples, Morgane Gauthier for the purification of primary human myoblasts, Safa Saker (Genethon, Evry, France), and the Genethon DNA and Cell Bank for processing patients{\textquoteright} blood samples. I-Stem is part of the Biotherapies Institute for Rare Diseases (BIRD) supported by the Association Fran{\c c}aise contre les Myopathies (AFM-T{\'e}l{\'e}thon). This work was supported in part by INSERM, AFM-T{\'e}l{\'e}thon (Association Fran{\c c}aise des Myopathes), and additional grants from the European Commission (STEM-HD, FP6), the Labex REVIVE, and DIM Stem P{\^o}le. P.B. and P.R. were supported by AMMi and ANR. The authors declare that there are no competing financial interests in relation to the work described.",

year = "2015",

month = nov,

day = "3",

doi = "10.1038/mtna.2015.36",

language = "English",

volume = "4",

journal = "Molecular Therapy Nucleic Acids",

issn = "2162-2531",

publisher = "Cell Press",

}

Laustriat, D, Gide, J, Barrault, L, Chautard, E, Benoit, C, Auboeuf, D, Boland, A, Battail, C, Artiguenave, F, Deleuze, JF, Bénit, P, Rustin, P, Franc, S, Charpentier, G, Furling, D, Bassez, G, Nissan, X, Martinat, C, Peschanski, M, Baghdoyan, S, Chan, A, Liebow, A, Yasuda, M, Gan, L, Racie, T, Maier, M, Kuchimanchi, S, Foster, D, Milstein, S, Charisse, K, Sehgal, A, Manoharan, M, Meyers, R, Fitzgerald, K, Simon, A, Desnick, RJ & Querbes, W 2015, 'In Vitro and in Vivo Modulation of Alternative Splicing by the Biguanide Metformin', Molecular Therapy Nucleic Acids, vol. 4, e263. https://doi.org/10.1038/mtna.2015.36

TY - JOUR

T1 - In Vitro and in Vivo Modulation of Alternative Splicing by the Biguanide Metformin

AU - Laustriat, Delphine

AU - Gide, Jacqueline

AU - Barrault, Laetitia

AU - Chautard, Emilie

AU - Benoit, Clara

AU - Auboeuf, Didier

AU - Boland, Anne

AU - Battail, Christophe

AU - Artiguenave, François

AU - Deleuze, Jean François

AU - Bénit, Paule

AU - Rustin, Pierre

AU - Franc, Sylvia

AU - Charpentier, Guillaume

AU - Furling, Denis

AU - Bassez, Guillaume

AU - Nissan, Xavier

AU - Martinat, Cécile

AU - Peschanski, Marc

AU - Baghdoyan, Sandrine

AU - Chan, Amy

AU - Liebow, Abigail

AU - Yasuda, Makiko

AU - Gan, Lin

AU - Racie, Tim

AU - Maier, Martin

AU - Kuchimanchi, Satya

AU - Foster, Don

AU - Milstein, Stuart

AU - Charisse, Klaus

AU - Sehgal, Alfica

AU - Manoharan, Muthiah

AU - Meyers, Rachel

AU - Fitzgerald, Kevin

AU - Simon, Amy

AU - Desnick, Robert J.

AU - Querbes, William

N1 - Funding Information: We thank Laetitia Aubry (INSERM/UEVE UMR 861, Evry, France) for discussions. The authors also thank Karen Sermon (Department of Embryology and Genetics, Vrije Universiteit Brussel, Brussels, Belgium) for providing embryonic stem cell lines, Thomas Andy Cooper (Baylor College of Medicine, Houston, TX) for cTNT minigenes, Odile Jouy and Marie-Hélène Petit for organizing the Metforgene clinical trial on diabetic patients (NCT 01349387) and collection of blood samples, Morgane Gauthier for the purification of primary human myoblasts, Safa Saker (Genethon, Evry, France), and the Genethon DNA and Cell Bank for processing patients’ blood samples. I-Stem is part of the Biotherapies Institute for Rare Diseases (BIRD) supported by the Association Française contre les Myopathies (AFM-Téléthon). This work was supported in part by INSERM, AFM-Téléthon (Association Française des Myopathes), and additional grants from the European Commission (STEM-HD, FP6), the Labex REVIVE, and DIM Stem Pôle. P.B. and P.R. were supported by AMMi and ANR. The authors declare that there are no competing financial interests in relation to the work described.

PY - 2015/11/3

Y1 - 2015/11/3

N2 - 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.

AB - 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.

KW - AMPK

KW - Metformin

KW - RBM3

KW - alternative splicing

KW - myotonic dystrophy type 1

UR - https://www.scopus.com/pages/publications/84946197868

U2 - 10.1038/mtna.2015.36

DO - 10.1038/mtna.2015.36

M3 - Article

AN - SCOPUS:84946197868

SN - 2162-2531

VL - 4

JO - Molecular Therapy Nucleic Acids

JF - Molecular Therapy Nucleic Acids

M1 - e263

ER -

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

Abstract

Keywords

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