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 8

Lithium reduces skeletal muscle weakness in HSALR mice.

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Lithium reduces skeletal muscle weakness in HSALR mice. (A) Improvemen...
(A) Improvement of grip strength in the HSALR mice treated with lithium. Grip strength in 3-month-old HSALR mice before and after treatment with lithium is shown. ***P < 0.0001 (treated HSALR mice vs. untreated HSALR mice). SEM is shown. (B) H&E staining. Representative images of transverse cross-sections stained with H&E from TA of 6-month-old WT and HSALR mice before and after treatment with lithium. Arrowheads indicate internal nuclei in TA of HSALR mice before treatment with lithium. Scale bars: 75 μm. (C) Lithium reduces the number of internal nuclei in TA muscle from HSALR mice. The y axis shows the number of internal nuclei, determined by H&E staining, based on analysis of 200–300 fibers in a maximal region of the transverse sections of TA of 6-month-old HSALR mice before and after treatment with lithium. As a normal control, internal nuclei were counted in 200–300 fibers in matching muscle of 6-month-old WT mice. *P < 0.01172 (treated HSALR mice vs. untreated HSALR mice). SEM is shown.