RESUMO
Myotonic dystrophy type 1 (DM1) is caused by an expanded (CTG)n tract in the 3'UTR of the DM protein kinase (DMPK) gene. The RNA transcripts produced from the expanded allele sequester or alter the function of RNA-binding proteins (MBNL1, CUGBP1, etc.). The sequestration of MBNL1 results in RNA-splicing defects that contribute to disease. Overexpression of MBNL1 in skeletal muscle has been shown to rescue some of the DM1 features in a mouse model and has been proposed as a therapeutic strategy for DM1. Here, we sought to confirm if overexpression of MBNL1 rescues the phenotypes in a different mouse model of RNA toxicity. Using an inducible mouse model of RNA toxicity in which expression of the mutant DMPK 3'UTR results in RNA foci formation, MBNL1 sequestration, splicing defects, myotonia and cardiac conduction defects, we find that MBNL1 overexpression did not rescue skeletal muscle function nor beneficially affect cardiac conduction. Surprisingly, MBNL1 overexpression also did not rescue myotonia, though variable rescue of Clcn1 splicing and other splicing defects was seen. Additionally, contrary to the previous study, we found evidence for increased muscle histopathology with MBNL1 overexpression. Overall, we did not find evidence for beneficial effects from overexpression of MBNL1 as a means to correct RNA toxicity mediated by mRNAs containing an expanded DMPK 3'UTR.
Assuntos
Músculo Esquelético/metabolismo , Distrofia Miotônica/genética , Proteínas de Ligação a RNA/genética , Regiões 3' não Traduzidas , Processamento Alternativo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Músculo Esquelético/citologia , Distrofia Miotônica/metabolismo , Miotonina Proteína Quinase/genética , Fenótipo , Splicing de RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
A patient with recurrent pulmonary emboli collected heart rate data during exercise, which provided important premorbid clues to changes in cardiopulmonary exercise tolerance coincident with accrual of thrombus in the central circulation. On both occasions, chronotropic incompetence (CI) preceded the pulmonary emboli events. When patients with programmed exercise goals notice CI, they should seek professional guidance.
Assuntos
Frequência Cardíaca/fisiologia , Monitorização Ambulatorial/métodos , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/fisiopatologia , Humanos , MasculinoRESUMO
Myotonic dystrophy type 1(DM1) is the prototype for diseases caused by RNA toxicity. RNAs from the mutant allele contain an expanded (CUG)n tract within the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The toxic RNAs affect the function of RNA binding proteins leading to sequestration of muscleblind-like (MBNL) proteins and increased levels of CELF1 (CUGBP, Elav-like family member 1). The mechanism for increased CELF1 is not very clear. One favored proposition is hyper-phosphorylation of CELF1 by Protein Kinase C alpha (PKCα) leading to increased CELF1 stability. However, most of the evidence supporting a role for PKC-α relies on pharmacological inhibition of PKC. To further investigate the role of PKCs in the pathogenesis of RNA toxicity, we generated transgenic mice with RNA toxicity that lacked both the PKCα and PKCß isoforms. We find that these mice show similar disease progression as mice wildtype for the PKC isoforms. Additionally, the expression of CELF1 is also not affected by deficiency of PKCα and PKCß in these RNA toxicity mice. These data suggest that disease phenotypes of these RNA toxicity mice are independent of PKCα and PKCß.