GSK3β mediates muscle pathology in myotonic dystrophy
Karlie Jones, … , Nikolai A. Timchenko, Lubov T. Timchenko
Karlie Jones, … , Nikolai A. Timchenko, Lubov T. Timchenko
Published December 3, 2012; First published November 19, 2012
Citation Information: J Clin Invest. 2012;122(12):4461-4472. https://doi.org/10.1172/JCI64081.
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Categories: Research Article Muscle biology

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 (HSALR), 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

Karlie Jones, Christina Wei, Polina Iakova, Enrico Bugiardini, Christiane Schneider-Gold, Giovanni Meola, James Woodgett, James Killian, Nikolai A. Timchenko, Lubov T. Timchenko

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Figure 2

The expansion of CUG repeats increases GSK3β protein in skeletal muscle from HSALR mice.

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The expansion of CUG repeats increases GSK3β protein in skeletal muscle ...
(A) Levels of total GSK3α, GSK3β, cyclin D3, and actin were determined by Western blot analyses of total protein extracts from skeletal muscle (soleus) of HSALR mice (at 6 months of age) and extracts from matching WT mice. CRM, cross-reactive material. (B) Ratios of signals of GSK3β and cyclin D3, as presented in A, to actin. The standard deviations for 3 experiments are shown. (C) GSK3β is increased in skeletal muscle of 1-month-old HSALR mice. Protein extracts from skeletal muscle (gastroc) of 1-month-old WT and HSALR mice were analyzed by Western blot with antibodies to total GSK3β and re-probed with antibodies to actin. Shown are ratios of GSK3β signals, as presented in C, to actin. The standard deviations shown are based on 3 repeats. (D) CUGBP1 is increased in muscle of HSALR mice. Protein extracts from skeletal muscle (soleus) of age-matched HSALR and WT mice were analyzed by Western blot assay. The membrane was re-probed with antibodies to actin and stained with Coomassie blue to verify protein loading and integrity. (E) Ratios of CUGBP1 signals presented in D (as an average of 4 mutant and 2 WT mice) to actin signals. The standard deviations are shown for 3 experiments.