title: TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity.
abstract: Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, is caused by toxic RNAs produced from the mutant DM protein kinase (DMPK) gene. DM1 is characterized by progressive muscle wasting and weakness. Therapeutic strategies have mainly focused on targeting the toxic RNA. Previously, we found that fibroblast growth factor-inducible 14 (Fn14), the receptor for TWEAK, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and that blocking TWEAK/Fn14 signaling improves muscle function and histology. Here, we studied the effect of Tweak deficiency in a RNA toxicity mouse model. The genetic deletion of Tweak in these mice significantly reduced muscle damage and improved muscle function. In contrast, administration of TWEAK in the RNA toxicity mice impaired functional outcomes and worsened muscle histopathology. These studies show that signaling via TWEAK is deleterious to muscle in RNA toxicity and support the demonstrated utility of anti-TWEAK therapeutics.
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Ramesh S
authors.initials: RS
authors.lastname: Yadava
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Erin P
authors.initials: EP
authors.lastname: Foff
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Gladman
authors.affiliation: Department of Immunology, Biogen Idec, Cambridge, MA, United States of America.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Zheng
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Mani S
authors.initials: MS
authors.lastname: Mahadevan
mesh_terms: D000818:Animals; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology*; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors