Myotonic Dystrophy type 1 (DM1) is a complex neuromuscular disease characterized by skeletal muscle wasting, weakness, myotonia and insulin resistance. DM1 is caused by the expanded RNA CUG repeats that misregulate RNA homeostasis through RNA-binding proteins, CUGBP1 and MBNL1. Therapeutic approaches for DM1 reducing toxicity of the mutant CUG repeats are actively developing;however, there is still no cure for DM1. Here we propose to examine the hypothesis that the genetic inhibition of Glycogen Synthase kinase 3b (GSK3b) improves skeletal muscle pathology in the DM1 mouse model. We found that the mutant CUG repeats increase enzymatic activity and the levels of GSK3b in skeletal muscle biopsies from patients with DM1 and in skeletal muscle of the DM1 mouse model, HSALR mice. We showed that the treatments of HSALR mice with lithium (Li), a known inhibitor of GSK3b, or with the potent inhibitor of GSK3b, TDZD-8, reduce the number of fibers with internal nuclei, increase grip strength and reduce myotonia. Such improvement of muscle pathology in the HSALR mice was accompanied by the normalization of GSK3b activity and by correction of expression of one of the GSK3b substrates, cyclin D3. The correction of cyclin D3 by the inhibition of GSK3b leads to the reduction of the suppressive form of CUGBP1, which causes skeletal muscle atrophy and weakness. Since these GSK3 inhibitors reduce both GSK3b and GSK3a, Specific Aim 1 of this proposal will examine if a genetic reduction of GSK3b in HSALR mice will lead to the reduction of DM1 muscle pathology. To achieve the genetic reduction of GSK3b, muscle specific GSK3b knock out (SbKO) mice are crossed with HSALR mice, producing HSALR/SbKO mice. Improvement of muscle pathology in HSALR/SbKO mice will provide a background for the development of therapy for DM1 patients which will be based on the inhibitors of GSK3. Since Li is approved by FDA to treat mood diseases and because potent inhibitors of GSK3b are used in the pre-clinical studies for other diseases, the application of these inhibitors might accelerate the development of DM1 therapy using GSK3b inhibitors. The increase of GSK3b in DM1 muscle suggests that other substrates of GSK3b might be also altered in DM1. Patients with DM1 have a predisposition to Type 2 Diabetes (T2D). It is known, that GSK3b is increased in skeletal muscle of patients with T2D. The increase of GSK3b in T2D causes a reduction of the activity of glycogen synthase that leads to the reduction of the glycogen synthesis and alteration of glucose metabolism. We hypothesize that the increase of GSK3b in skeletal muscle of HSALR mice causes glucose and insulin insensitivity and predisposition to T2D. This hypothesis will be tested in the Aim 2. In summary, our study will show if the genetic inhibition of GSK3b might improve muscle pathology and enhance insulin and glucose sensitivity in the DM1 mouse model. The knowledge, obtained in mouse model of DM1, will be translated to the clinical therapy of DM1.
Myotonic Dystrophy type 1 is a multisystem disease without cure. We propose to apply basic science expertise to determine the role of the genetic inhibition of GSK3b kinase in the improvement of muscle dysfunction in DM1. The knowledge, obtained in the mouse model of DM1, will be translated to the development of the therapeutic interventions in DM1.
|Wei, Christina; Stock, Lauren; Schneider-Gold, Christiane et al. (2018) Reduction of Cellular Nucleic Acid Binding Protein Encoded by a Myotonic Dystrophy Type 2 Gene Causes Muscle Atrophy. Mol Cell Biol 38:|
|Wei, Christina; Stock, Lauren; Valanejad, Leila et al. (2018) Correction of GSK3? at young age prevents muscle pathology in mice with myotonic dystrophy type 1. FASEB J 32:2073-2085|
|Lewis, Kyle; Valanejad, Leila; Cast, Ashley et al. (2017) RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner. Mol Cell Biol 37:|
|Jin, Jingling; Valanejad, Leila; Nguyen, Thuy Phuong et al. (2016) Activation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease. Cell Rep 16:744-56|
|Jones, Karlie; Wei, Christina; Schoser, Benedikt et al. (2015) Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5. Proc Natl Acad Sci U S A 112:8041-5|
|Breaux, Meghan; Lewis, Kyle; Valanejad, Leila et al. (2015) p300 Regulates Liver Functions by Controlling p53 and C/EBP Family Proteins through Multiple Signaling Pathways. Mol Cell Biol 35:3005-16|