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 9

TDZD-8 treatment improves skeletal muscle strength in HSALR mice.

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TDZD-8 treatment improves skeletal muscle strength in HSALR mice. (A) ...
(A) Improvement of grip strength in HSALR mice treated with TDZD-8. Grip strength in the 3-month-old HSALR mice before and after treatment with TDZD-8. SEM is shown. **P < 0.009880, ***P < 0.00006. (B) Treatment of HSALR mice with TDZD-8 normalizes levels of Pax-7. Western blot analysis of protein extracts from matching muscles (gastroc) from 3-month-old WT mice, untreated HSALR mice, and HSALR mice treated with TDZD-8 was performed with antibodies to Pax-7. β-Actin shows protein loading. (C) TDZD-8 treatment increases the number of activated Pax-7–positive cells. The y axis shows total number of Pax-7–positive cells isolated from gastroc of 4-month-old WT and HSALR mice, untreated (*P < 0.010838, untreated HSALR mice vs. matching WT mice) and treated with TDZD-8 (*P < 0.02952, treated HSALR mice vs. untreated HSALR mice) (see Methods).