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Publication : GSK3β mediates muscle pathology in myotonic dystrophy.

First Author  Jones K Year  2012
Journal  J Clin Invest Volume  122
Issue  12 Pages  4461-72
PubMed ID  23160194 Mgi Jnum  J:193973
Mgi Id  MGI:5469998 Doi  10.1172/JCI64081
Citation  Jones K, et al. (2012) GSK3beta mediates muscle pathology in myotonic dystrophy. J Clin Invest 122(12):4461-72
abstractText  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 3beta (GSK3beta). Using a mouse model of DM1 (HSA(LR)), we found that CUG repeats in the 3' untranslated region (UTR) of human skeletal actin increase active GSK3beta in skeletal muscle of mice, prior to the development of skeletal muscle weakness. Inhibition of GSK3beta 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 GSK3beta activity might be beneficial for improvement of muscle function in patients with DM1.
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