Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

Brockhoff, Marielle and Rion, Nathalie and Chojnowska, Kathrin and Wiktorowicz, Tatiana and Eickhorst, Christopher and Erne, Beat and Frank, Stephan and Angelini, Corrado and Furling, Denis and Rüegg, Markus A. and Sinnreich, Michael and Castets, Perrine. (2017) Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I. Journal of Clinical Investigation, 127 (2). pp. 549-563.

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Official URL: http://edoc.unibas.ch/54179/

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Myotonic dystrophy type I (DM1) is a disabling multisystemic disease that predominantly affects skeletal muscle. It is caused by expanded CTG repeats in the 3'-UTR of the dystrophia myotonica protein kinase (DMPK) gene. RNA hairpins formed by elongated DMPK transcripts sequester RNA-binding proteins, leading to mis-splicing of numerous pre-mRNAs. Here, we have investigated whether DM1-associated muscle pathology is related to deregulation of central metabolic pathways, which may identify potential therapeutic targets for the disease. In a well-characterized mouse model for DM1 (HSALR mice), activation of AMPK signaling in muscle was impaired under starved conditions, while mTORC1 signaling remained active. In parallel, autophagic flux was perturbed in HSALR muscle and in cultured human DM1 myotubes. Pharmacological approaches targeting AMPK/mTORC1 signaling greatly ameliorated muscle function in HSALR mice. AICAR, an AMPK activator, led to a strong reduction of myotonia, which was accompanied by partial correction of misregulated alternative splicing. Rapamycin, an mTORC1 inhibitor, improved muscle relaxation and increased muscle force in HSALR mice without affecting splicing. These findings highlight the involvement of AMPK/mTORC1 deregulation in DM1 muscle pathophysiology and may open potential avenues for the treatment of this disease.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A. and Castets, Perrine and Sinnreich, Michael
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Clinical Investigation
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:15 Nov 2017 13:33
Deposited On:16 Oct 2017 09:34

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