title: NKX2-5, a modifier of skeletal muscle pathology due to RNA toxicity.
abstract: RNA toxicity is implicated in a number of disorders; especially those associated with expanded repeat sequences, such as myotonic dystrophy (DM1). Previously, we have shown increased NKX2-5 expression in RNA toxicity associated with DM1. Here, we investigate the relationship between NKX2-5 expression and muscle pathology due to RNA toxicity. In skeletal muscle from mice with RNA toxicity and individuals with DM1, expression of Nkx2-5 or NKX2-5 and its downstream targets are significantly correlated with severity of histopathology. Using C2C12 myoblasts, we show that over-expression of NKX2-5 or mutant DMPK 3'UTR results in myogenic differentiation defects, which can be rescued by knockdown of Nkx2-5, despite continued toxic RNA expression. Furthermore, in a mouse model of NKX2-5 over-expression, we find defects in muscle regeneration after induced damage, similar to those seen in mice with RNA toxicity. Using mouse models of Nkx2-5 over-expression and depletion, we find that NKX2-5 levels modify disease phenotypes in mice with RNA toxicity.
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Gladman
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Ramesh S
authors.initials: RS
authors.lastname: Yadava
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Mahua
authors.initials: M
authors.lastname: Mandal
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Yun K
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA mahadevan@virginia.edu.
authors.forename: Mani S
authors.initials: MS
authors.lastname: Mahadevan
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D060045:Genes, Modifier; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D065636:Myotonin-Protein Kinase / Q000235:genetics; D012313:RNA / Q000633:toxicity*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D012313:RNA; D065636:Myotonin-Protein Kinase