Expanded CTG repeats within the DMPK 3' UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy.

Abstract

Severe skeletal muscle wasting is the most debilitating symptom experienced by individuals with myotonic dystrophy type 1 (DM1). We present a DM1 mouse model with inducible and skeletal muscle-specific expression of large tracts of CTG repeats in the context of DMPK exon 15. These mice recapitulate many findings associated with DM1 skeletal muscle, such as CUG RNA foci with Muscleblind-like 1 (MBNL1) protein colocalization, misregulation of developmentally regulated alternative splicing events, myotonia, characteristic histological abnormalities, and increased CUGBP1 protein levels. Importantly, this DM1 mouse model recapitulates severe muscle wasting, which has not been reported in models in which depletion of MBNL1 is the main feature. Using these mice, we discovered previously undescribed alternative splicing events that are responsive to CUGBP1 and not MBNL, and these events were found to be misregulated in individuals with DM1. Our results indicate that increased CUGBP1 protein levels are associated with DMPK-CUG RNA expression, suggesting a role for CUGBP1-specific splicing or cytoplasmic functions in muscle wasting.

• Authors: James P Orengo, Pierre Chambon, Daniel Metzger, Dennis R Mosier, G Jackson Snipes, Thomas A Cooper
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 7 Pg. 2646-51 (Feb 19 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18272483 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 3' Untranslated Regions
• CELF1 Protein
• CELF1 protein, mouse
• DMPK protein, mouse
• RNA-Binding Proteins
• Myotonin-Protein Kinase
• Protein Serine-Threonine Kinases

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Base Sequence
• CELF1 Protein
• Disease Models, Animal
• Disease Progression
• Gene Expression Regulation, Enzymologic
• Mice
• Muscle, Skeletal (enzymology)
• Myotonic Dystrophy (enzymology, genetics, pathology)
• Myotonin-Protein Kinase
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA Splicing (genetics)
• RNA-Binding Proteins (metabolism)
• Sensitivity and Specificity