GSK3β mediates muscle pathology in myotonic dystrophy
Karlie Jones, Christina Wei, Polina Iakova, Enrico Bugiardini, Christiane Schneider-Gold, Giovanni Meola, James Woodgett, James Killian, Nikolai A. Timchenko, Lubov T. Timchenko
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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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 3

Misregulation of GSK3β expression in DM1 myogenesis.

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Misregulation of GSK3β expression in DM1 myogenesis. Western blot analys...
Western blot analysis of cytoplasmic (Cyto) and nuclear proteins from normal (A) and DM1 myoblasts (B) at different stages of differentiation (1, 3, and 5 days in the fusion medium) with antibodies to total GSK3β, total cyclin D3, and β-actin as control. To verify the separation of nuclear and cytoplasmic proteins, the protein extracts were probed with antibodies to a nuclear protein, Rb, and to a preferentially cytoplasmic protein, HSP70. Curves show the quantification of GSK3β (C and D) and cyclin D3 (E and F) signals (adjusted to β-actin) as percentage of signals for these proteins at each time point relative to 0 time point in cytoplasm (C and E) and in nuclei (D and F) of normal and DM1 myoblasts. Intensities of GSK3β and cyclin D3 signal in myoblasts (0 time point of differentiation) were counted as 100%. The x axis shows number of days in the differentiation medium. The standard deviations represent values for 3 experiments.