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TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity

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 RN...

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Autores principales: Yadava, Ramesh S., Foff, Erin P., Yu, Qing, Gladman, Jordan T., Zheng, Timothy S., Mahadevan, Mani S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762946/
https://www.ncbi.nlm.nih.gov/pubmed/26901467
http://dx.doi.org/10.1371/journal.pone.0150192
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author Yadava, Ramesh S.
Foff, Erin P.
Yu, Qing
Gladman, Jordan T.
Zheng, Timothy S.
Mahadevan, Mani S.
author_facet Yadava, Ramesh S.
Foff, Erin P.
Yu, Qing
Gladman, Jordan T.
Zheng, Timothy S.
Mahadevan, Mani S.
author_sort Yadava, Ramesh S.
collection PubMed
description 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.
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spelling pubmed-47629462016-03-07 TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity Yadava, Ramesh S. Foff, Erin P. Yu, Qing Gladman, Jordan T. Zheng, Timothy S. Mahadevan, Mani S. PLoS One Research Article 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. Public Library of Science 2016-02-22 /pmc/articles/PMC4762946/ /pubmed/26901467 http://dx.doi.org/10.1371/journal.pone.0150192 Text en © 2016 Yadava et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Yadava, Ramesh S.
Foff, Erin P.
Yu, Qing
Gladman, Jordan T.
Zheng, Timothy S.
Mahadevan, Mani S.
TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity
title TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity
title_full TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity
title_fullStr TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity
title_full_unstemmed TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity
title_short TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity
title_sort tweak regulates muscle functions in a mouse model of rna toxicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762946/
https://www.ncbi.nlm.nih.gov/pubmed/26901467
http://dx.doi.org/10.1371/journal.pone.0150192
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