Molecular, Physiological, and Motor Performance Defects in DMSXL Mice Carrying >1,000 CTG Repeats from the Human DM1 Locus

Abstract

Myotonic dystrophy type 1 (DM1) is caused by an unstable CTG repeat expansion in the 3′UTR of the DM protein kinase (DMPK) gene. DMPK transcripts carrying CUG expansions form nuclear foci and affect splicing regulation of various RNA transcripts. Furthermore, bidirectional transcription over the DMPK gene and non-conventional RNA translation of repeated transcripts have been described in DM1. It is clear now that this disease may involve multiple pathogenic pathways including changes in gene expression, RNA stability and splicing regulation, protein translation, and micro–RNA metabolism. We previously generated transgenic mice with 45-kb of the DM1 locus and >300 CTG repeats (DM300 mice). After successive breeding and a high level of CTG repeat instability, we obtained transgenic mice carrying >1,000 CTG (DMSXL mice). Here we described for the first time the expression pattern of the DMPK sense transcripts in DMSXL and human tissues. Interestingly, we also demonstrate that DMPK antisense transcripts are expressed in various DMSXL and human tissues, and that both sense and antisense transcripts accumulate in independent nuclear foci that do not co-localize together. Molecular features of DM1-associated RNA toxicity in DMSXL mice (such as foci accumulation and mild missplicing), were associated with high mortality, growth retardation, and muscle defects (abnormal histopathology, reduced muscle strength, and lower motor performances). We have found that lower levels of IGFBP-3 may contribute to DMSXL growth retardation, while increased proteasome activity may affect muscle function. These data demonstrate that the human DM1 locus carrying very large expansions induced a variety of molecular and physiological defects in transgenic mice, reflecting DM1 to a certain extent. As a result, DMSXL mice provide an animal tool to decipher various aspects of the disease mechanisms. In addition, these mice can be used to test the preclinical impact of systemic therapeutic strategies on molecular and physiological phenotypes.

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of Myotonic Dystrophy

“…In the present study, we have used DMSXL transgenic mice. These mice express the DMPK gene in a variety of tissues with a pattern similar to the patterns of the murine Dmpk gene in mice and the DMPK gene in human tissues (Huguet et al, 2012). To address whether the DMSXL transgenic mice animal model, which carry a long CTG repeat and display DM1 features (Gomes-Pereira et al, 2011), have respiratory problems, we tested and compared the breathing function in DMSXL and control mice.…”

“…Mild missplicing of target RNA is observed in muscles and heart tissues. These molecular features of DM1-associated RNA toxicity were associated with high mortality, growth retardation and muscle defects (abnormal histopathology, reduced muscle strength and lower motor performances) (Huguet et al, 2012). …”

Abnormal sodium current properties contribute to cardiac electrical and contractile dysfunction in a mouse model of myotonic dystrophy type 1

“…Thus, this is a precious model to study the time course of the disease with aging. It has been previously shown that DMSXL mice have reduced muscle strength, lower motor performances, peripheral neuropathy and respiratory impairments [13][14][15].…”

“…The originality of this model lies in the pattern of expression of the DMPK gene in DMSXL which is similar to DM1 patients including a high level of expression in the heart [13]. This model reproduces the main clinical characteristics observed in the human disease including reduced muscle strength, lower motor performances, peripheral neuropathy and respiratory impairments [13][14][15]. However, nothing is known about the cardiac phenotype of the DMSXL mouse.…”

RNA–protein interactions in unstable microsatellite diseases

“…DMSXL, derived from the DM300 line, is another transgenic model with >1000 CTG repeats due to intergenerational instability that led to ‘big jumps’ in CTG repeat number (Gomes-Pereira et al, 2007). These models exhibit different aspects of DM disease, such as muscle pathology, cardiac conduction problems, behavioral abnormalities accompanied by intranuclear RNA foci pathology and some tissue-specific splicing deficits (Gomes-Pereira et al, 2011; Hernandez-Hernandez et al, 2013; Huguet et al, 2012). Taken together, these mouse models serve as valuable tools to gain insight into DM disease mechanisms and for preclinical assessment of therapeutics targeting repeat expansion RNAs.…”