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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)4461-4472
Number of pages12
JournalJournal of Clinical Investigation
Volume122
Issue number12
DOIs
Publication statusPublished - Dec 3 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Jones, K., Wei, C., Iakova, P., Bugiardini, E., Schneider-Gold, C., Meola, G., Woodgett, J., Killian, J., Timchenko, N. A., & Timchenko, L. T. (2012). GSK3β mediates muscle pathology in myotonic dystrophy. Journal of Clinical Investigation, 122(12), 4461-4472. https://doi.org/10.1172/JCI64081