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

GSK3β mediates muscle pathology in myotonic dystrophy

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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 7

Inhibition of GSK3β corrects levels of cyclin D3 and translational activity of CUGBP1 in skeletal muscle of HSALR mice.

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Inhibition of GSK3β corrects levels of cyclin D3 and translational activ...
Western blot analysis of GSK3β and cyclin D3 in skeletal muscle (gastroc) of 6-month-old WT and HSALR mice before and after treatment with lithium (A) and TDZD-8 (B). β-Actin shows protein loading. (C) Lithium reduces amounts of the translation repressor complexes CUGBP1–p-S51–eIF2α in skeletal muscle of HSALR mice. Top panel: CUGBP1 was precipitated with anti-CUGBP1 from skeletal muscle of 6-month-old WT and HSALR mice, treated and untreated with lithium, and the IPs were probed with antibodies to p-S51–eIF2α. Heavy chain IgGs signals are also shown. Bottom panels (input): Western blotting with antibodies to the total eIF2α. The membrane was reprobed with β-actin.
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