title: Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I.
abstract: 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.
authors.forename: Marielle
authors.initials: M
authors.lastname: Brockhoff
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rion
authors.forename: Kathrin
authors.initials: K
authors.lastname: Chojnowska
authors.forename: Tatiana
authors.initials: T
authors.lastname: Wiktorowicz
authors.forename: Christopher
authors.initials: C
authors.lastname: Eickhorst
authors.forename: Beat
authors.initials: B
authors.lastname: Erne
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.forename: Michael
authors.initials: M
authors.lastname: Sinnreich
authors.forename: Perrine
authors.initials: P
authors.lastname: Castets
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000201:enzymology*; D009126:Muscle Relaxation / Q000187:drug effects / Q000235:genetics; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D065636:Myotonin-Protein Kinase / Q000235:genetics / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D020123:Sirolimus / Q000493:pharmacokinetics / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C585517:DMPK protein, human; C585516:DMPK protein, mouse; D046912:Multiprotein Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000076222:Mechanistic Target of Rapamycin Complex 1; D065636:Myotonin-Protein Kinase; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D020123:Sirolimus