CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1.
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.
Ward
Amanda J
AJ
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Rimer
Mendell
M
Killian
James M
JM
Dowling
James J
JJ
Cooper
Thomas A
TA
D017398:Alternative Splicing; D000818:Animals; D000067879:CELF1 Protein; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D000067879:CELF1 Protein; C102843:CELF1 protein, human; D016601:RNA-Binding Proteins