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

• Published in: The Journal of clinical investigation Vol. 127; no. 2; pp. 549 - 563
• Main Authors: Brockhoff, Marielle, Rion, Nathalie, Chojnowska, Kathrin, Wiktorowicz, Tatiana, Eickhorst, Christopher, Erne, Beat, Frank, Stephan, Angelini, Corrado, Furling, Denis, Rüegg, Markus A, Sinnreich, Michael, Castets, Perrine
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-02-2017
• Subjects: Adult; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Biomedical research; Biopsy; Care and treatment; Cellular signal transduction; Colleges & universities; Development and progression; Disease; Disease Models, Animal; Female; Fibroblasts; Gene expression; Genes; Genetic aspects; Health aspects; Humans; Kinases; Life Sciences; Male; Mechanistic Target of Rapamycin Complex 1; Metabolism; Mice; Mice, Mutant Strains; Microscopy; Middle Aged; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Muscle Fibers, Skeletal - enzymology; Muscle Relaxation - drug effects; Muscle Relaxation - genetics; Musculoskeletal system; Myotonic dystrophy; Myotonic Dystrophy - drug therapy; Myotonic Dystrophy - enzymology; Myotonic Dystrophy - genetics; Myotonic Dystrophy - physiopathology; Myotonin-Protein Kinase - genetics; Myotonin-Protein Kinase - metabolism; Pathology; Phosphorylation; Protein kinases; Proteins; Ribonucleotides - pharmacology; Rodents; Signal Transduction - drug effects; Signal Transduction - genetics; Sirolimus - pharmacokinetics; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci89616

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.