title: TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy.
abstract: Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults, is characterized by progressive muscle wasting and multi-systemic complications. DM1 is the prototype for disorders caused by RNA toxicity. Currently, no therapies exist. Here, we identify that fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor super-family, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and in tissues from DM1 patients, and that its expression correlates with severity of muscle pathology. This is associated with downstream signaling through the NF-κB pathways. In mice with RNA toxicity, genetic deletion of Fn14 results in reduced muscle pathology and better function. Importantly, blocking TWEAK/Fn14 signaling with an anti-TWEAK antibody likewise improves muscle histopathology and functional outcomes in affected mice. These results reveal new avenues for therapeutic development and provide proof of concept for a novel therapeutic target for which clinically available therapy exists to potentially treat muscular dystrophy in DM1.
authors.affiliation: Department of Pathology and.
authors.forename: Ramesh S
authors.initials: RS
authors.lastname: Yadava
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Erin P
authors.initials: EP
authors.lastname: Foff
authors.affiliation: Department of Pathology and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Pathology and.
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Gladman
authors.affiliation: Department of Pathology and.
authors.forename: Yun K
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Department of Neurology, University of Rochester, Rochester, NY 14642, USA and.
authors.forename: Kirti S
authors.initials: KS
authors.lastname: Bhatt
authors.affiliation: Department of Neurology, University of Rochester, Rochester, NY 14642, USA and.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
authors.affiliation: Department of Immunology, Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Zheng
authors.affiliation: Department of Pathology and mahadevan@virginia.edu.
authors.forename: Mani S
authors.initials: MS
authors.lastname: Mahadevan
mesh_terms: D000328:Adult; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009223:Myotonic Dystrophy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000074049:Cytokine TWEAK; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors