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Hum Mol Genet ; 24(7): 2035-48, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25504044

RESUMO

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.


Assuntos
Distrofia Miotônica/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Fatores de Necrose Tumoral/metabolismo , Adulto , Animais , Anticorpos/administração & dosagem , Citocina TWEAK , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Distrofia Miotônica/tratamento farmacológico , Distrofia Miotônica/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Receptores do Fator de Necrose Tumoral/genética , Transdução de Sinais/efeitos dos fármacos , Receptor de TWEAK , Inibidores do Fator de Necrose Tumoral , Fatores de Necrose Tumoral/genética
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