title: GSK3β mediates muscle pathology in myotonic dystrophy.
abstract: Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease characterized by skeletal muscle wasting, weakness, and myotonia. DM1 is caused by the accumulation of CUG repeats, which alter the biological activities of RNA-binding proteins, including CUG-binding protein 1 (CUGBP1). CUGBP1 is an important skeletal muscle translational regulator that is activated by cyclin D3-dependent kinase 4 (CDK4). Here we show that mutant CUG repeats suppress Cdk4 signaling by increasing the stability and activity of glycogen synthase kinase 3β (GSK3β). Using a mouse model of DM1 (HSA(LR)), we found that CUG repeats in the 3' untranslated region (UTR) of human skeletal actin increase active GSK3β in skeletal muscle of mice, prior to the development of skeletal muscle weakness. Inhibition of GSK3β in both DM1 cell culture and mouse models corrected cyclin D3 levels and reduced muscle weakness and myotonia in DM1 mice. Our data predict that compounds normalizing GSK3β activity might be beneficial for improvement of muscle function in patients with DM1.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Karlie
authors.initials: K
authors.lastname: Jones
authors.forename: Christina
authors.initials: C
authors.lastname: Wei
authors.forename: Polina
authors.initials: P
authors.lastname: Iakova
authors.forename: Enrico
authors.initials: E
authors.lastname: Bugiardini
authors.forename: Christiane
authors.initials: C
authors.lastname: Schneider-Gold
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meola
authors.forename: James
authors.initials: J
authors.lastname: Woodgett
authors.forename: James
authors.initials: J
authors.lastname: Killian
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Timchenko
authors.forename: Lubov T
authors.initials: LT
authors.lastname: Timchenko
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D056743:Cyclin D3 / Q000378:metabolism; D004795:Enzyme Stability; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D009223:Myotonic Dystrophy / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013830:Thiadiazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; C534696:CCND3 protein, human; D056743:Cyclin D3; D013830:Thiadiazoles; D008094:Lithium; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3