CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Academic Article uri icon

abstract

  • The neuromuscular disease myotonic dystrophy type I (DM1) affects multiple organ systems with the major symptoms being severe muscle weakness, progressive muscle wasting and myotonia. The causative mutation in DM1 is a CTG repeat expansion in the 3'-untranslated region of the DM protein kinase (DMPK) gene. RNA transcribed from the expanded allele contains the expanded CUG repeats and leads to the nuclear depletion of Muscleblind-like 1 (MBNL1) and to the increased steady-state levels of CUG-binding protein 1 (CUGBP1). The pathogenic effects of MBNL1 depletion have previously been tested by the generation of MBNL1 knockout mice, but the consequence of CUGBP1 overexpression in adult muscle is not known. In a DM1 mouse model expressing RNA containing 960 CUG repeats in skeletal muscle, CUGBP1 up-regulation is temporally correlated with severe muscle wasting. In this study, we generated transgenic mice with doxycycline-inducible and skeletal muscle-specific expression of CUGBP1. Adult mouse skeletal muscle overexpressing CUGBP1 reproduces molecular and physiological defects of DM1 tissue. The results from this study strongly suggest that CUGBP1 has a major role in DM1 skeletal muscle pathogenesis.

published proceedings

  • Hum Mol Genet

author list (cited authors)

  • Ward, A. J., Rimer, M., Killian, J. M., Dowling, J. J., & Cooper, T. A.

citation count

  • 114

complete list of authors

  • Ward, Amanda J||Rimer, Mendell||Killian, James M||Dowling, James J||Cooper, Thomas A

publication date

  • September 2010