TY - JOUR AU - Brockhoff, Marielle AU - Rion, Nathalie AU - Chojnowska, Kathrin AU - Wiktorowicz, Tatiana AU - Eickhorst, Christopher AU - Erne, Beat AU - Frank, Stephan AU - Angelini, Corrado AU - Furling, Denis AU - Rüegg, Markus A. AU - Sinnreich, Michael AU - Castets, Perrine T1 - Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I PY - 2017/02/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI89616 VL - 127 IS - 2 UR - https://doi.org/10.1172/JCI89616 SP - 549 EP - 563 PB - The American Society for Clinical Investigation ER -