Abstract
Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1−/−; Mbnl2−/− double knockouts (DKOs) are embryonic lethal, Mbnl1−/−; Mbnl2+/− mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1−/− knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease.
Highlights
Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease characterized by a multi‐systemic phenotype, including skeletal muscle myotonia and progressive weakness/ wasting, cardiac arrhythmias, ocular ‘dust‐like’ cataracts, insulin insensitivity, hypogammaglobulinemia, hypersomnia and cerebral atrophy (Ranum & Cooper, 2006; Udd & Krahe, 2012)
Our results demonstrate that the major symptoms of cardiac and skeletal muscle disease in DM can be recapitulated in Mbnl compound knockout models and that sequestration of both Mbnl1 and Mbnl2 by C(C)UGexp RNAs is an important pathogenic feature of DM
We noted that Mbnl2 protein levels increased strikingly in Mbnl1 KOs, in skeletal muscle (Fig 1A), in agreement with a recent study that reported Mbnl2 protein upregulation following shRNA‐mediated knockdown of Mbnl1 in C2C12 myoblasts (Wang et al, 2012)
Summary
Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease characterized by a multi‐systemic phenotype, including skeletal muscle myotonia and progressive weakness/ wasting, cardiac arrhythmias, ocular ‘dust‐like’ cataracts, insulin insensitivity, hypogammaglobulinemia, hypersomnia and cerebral atrophy (Ranum & Cooper, 2006; Udd & Krahe, 2012). DM is caused by expansions of either CTG trinucleotide repeats in the 30 untranslated region (30 UTR) of the DMPK gene on chromosome 19 (DM type 1, DM1) or CCTG repeats in the first intron of the CNBP gene on chromosome 3 (DM type 2, DM2) (Ranum & Cooper, 2006; Udd & Krahe, 2012) These non‐ coding C(C)TG expansion, or C(C)TGexp, mutations generate pathogenic C(C)UGexp RNAs that are toxic because they perturb the normal cellular activities of several RNA binding factors, including the muscleblind‐like (MBNL), CUGBP1 and ETR3‐like (CELF), hnRNP H and STAU1 proteins (Ho et al, 2004; Kanadia et al, 2003; Miller et al, 2000; Paul et al, 2006; Philips et al, 1998; Ravel‐Chapuis et al, 2012; Timchenko et al, 1996).
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