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Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type i
- Source :
- Journal of Clinical Investigation, Vol. 127, No 2 (2017) pp. 549-563
- Publication Year :
- 2017
- Publisher :
- American Society for Clinical Investigation, 2017.
-
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.
- Subjects :
- 0301 basic medicine
Adult
Male
musculoskeletal diseases
congenital, hereditary, and neonatal diseases and abnormalities
Muscle Relaxation
Muscle Fibers, Skeletal
mTORC1
Biology
AMP-Activated Protein Kinases
Mechanistic Target of Rapamycin Complex 1
Myotonic dystrophy
Myotonin-Protein Kinase
03 medical and health sciences
Mice
medicine
Animals
Humans
Myotonic Dystrophy
Sirolimus
Myogenesis
TOR Serine-Threonine Kinases
Autophagy
Alternative splicing
AMPK
Skeletal muscle
General Medicine
Middle Aged
Ribonucleotides
medicine.disease
Aminoimidazole Carboxamide
Mice, Mutant Strains
Cell biology
Disease Models, Animal
030104 developmental biology
Muscle relaxation
medicine.anatomical_structure
Multiprotein Complexes
Female
Research Article
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation, Vol. 127, No 2 (2017) pp. 549-563
- Accession number :
- edsair.doi.dedup.....05cdd9515f9e8e5f3a5309734a034960