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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adult
-
Animals
-
CHO Cells
-
Cricetinae
-
Cyclin D3 / metabolism
-
Enzyme Stability
-
Female
-
Gene Expression Regulation, Enzymologic
-
Glycogen Synthase Kinase 3 / antagonists & inhibitors
-
Glycogen Synthase Kinase 3 / genetics
-
Glycogen Synthase Kinase 3 / metabolism*
-
Glycogen Synthase Kinase 3 beta
-
Humans
-
Lithium / pharmacology
-
Lithium / therapeutic use
-
Male
-
Mice
-
Middle Aged
-
Muscle Fibers, Skeletal / enzymology
-
Muscle Fibers, Skeletal / pathology
-
Muscle Strength / drug effects
-
Muscle, Skeletal / enzymology*
-
Muscle, Skeletal / pathology
-
Myotonic Dystrophy / drug therapy
-
Myotonic Dystrophy / enzymology*
-
Myotonic Dystrophy / pathology
-
Phosphorylation
-
Protein Processing, Post-Translational
-
Thiadiazoles / pharmacology
-
Thiadiazoles / therapeutic use
Substances
-
4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
-
CCND3 protein, human
-
Cyclin D3
-
Thiadiazoles
-
Lithium
-
GSK3B protein, human
-
Glycogen Synthase Kinase 3 beta
-
Gsk3b protein, mouse
-
Glycogen Synthase Kinase 3