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 6

Muscle weakness in adult HSALR mice is accompanied by a reduction of activated myogenic satellite cells.

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Muscle weakness in adult HSALR mice is accompanied by a reduction of act...
(A) A reduction of muscle strength in HSALR mice. Grip strength in WT and HSALR mice of different ages (1, 3, and 6 months). *P < 0.05, **P < 0.005. (B) Increase in myofiber number in young (1 month old) and reduction of myofiber number in adult (6 months old) HSALR mice. Total number of fibers per field (×20) in maximal cross section areas of TA and gastroc from matched WT and HSALR mice. *P < 0.05, **P < 0.005, ***P < 0.0005. (C) Myofiber area is reduced in young (1 month old) HSALR mice but increased in adult (6 months old) HSALR mice. The y axis shows average fiber area (in pixels). *P < 0.05, ***P < 0.0005. (D) The number of nuclei beneath the basal lamina varies in young and adult HSALR mice. The y axis shows the number of nuclei beneath the basal lamina in TA and gastroc from young and adult HSALR mice per field (×20). *P < 0.05, **P < 0.005. (E) The number of activated Pax-7–positive cells is increased in young (2 months old) but reduced in adult (7 months old) HSALR mice. The y axis shows total number of activated Pax-7–positive cells isolated from whole gastroc of matched WT and HSALR mice. *P < 0.036, ***P < 0.0004. (F) Levels of Pax-7 protein are increased in 1-month-old and reduced in adult HSALR mice. Muscle samples from soleus of age- and sex-matched WT and HSALR mice were examined by Western blot assay with antibodies to Pax-7 and β-actin, as a control for protein loading. (G) Increase in internal nuclei in myofibers of HSALR mice. The average number of internal nuclei per field (×20) in 1-month- and 6-month-old WT and HSALR mice, based on the analyses of 200–300 fibers, is shown. *P < 0.05, **P < 0.005. SEM is shown.