Role of toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle

dc.creatorPons, Andrea Henriques
dc.creatorYu, Qing
dc.creatorRayavarapu, Sree
dc.creatorCohen, Tatiana V
dc.creatorAmpong, Beryl
dc.creatorCha, Hee Jae
dc.creatorJahnke, Vanessa
dc.creatorVan der Meulen, Jack
dc.creatorWang, Daqing
dc.creatorJiang, Weiwen
dc.creatorKandimalla, Ekambar R
dc.creatorAgrawal, Sudhir
dc.creatorSpurney, Christopher F
dc.creatorNagaraju, Kanneboyina
dc.date2015-06-01T19:34:24Z
dc.date2015-06-01T19:34:24Z
dc.date2014
dc.date.accessioned2023-09-26T22:38:27Z
dc.date.available2023-09-26T22:38:27Z
dc.identifierPONS, Andrea Henriques et al. Role of toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle. Human Molecular Genetics, v.23, n.10, p. 2604-2607, 2014.
dc.identifier1460-2083
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/10615
dc.identifier10.1093/hmg/ddt656
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8881367
dc.descriptionAlthough the cause of Duchenne muscular dystrophy (DMD) is known, the specific factors that initiate and perpetuate disease progression are not well understood.We hypothesized that leaky dystrophin-deficient skeletal muscle releases endogenous danger signals (TLR ligands), which bind to Toll-like receptors (TLRs) on muscle andimmunecellsand activate downstreamprocesses that facilitate degeneration andregeneration in dystrophic skeletal muscle. Here, we demonstrate that dystrophin-deficient mousemuscle cells show increased expression of several cell-surface and endosomal TLRs. In vitro screening identified ssRNA as a relevant endogenous TLR7 ligand. TLR7 activation led to myd88-dependent production of pro-inflammatory cytokines in dystrophindeficient muscle cells, and cause significant degeneration/regeneration in vivo in mdx mouse muscle. Also, knockout of the central TLR adaptor protein, myd88 in mdx mice significantly improved skeletal and cardiac muscle function. Likewise, proof-of-concept experiments showed that treating young mdx mice with a TLR7/9 antagonist significantly reduced skeletal muscle inflammation and increased muscle force, suggesting that blocking this pathway may have therapeutic potential for DMD.
dc.formatapplication/pdf
dc.languageeng
dc.publisherOxford University Press
dc.rightsopen access
dc.subjectHeart muscle
dc.subjectDystrophin-deficient skeletal
dc.subjectDuchenne muscular dystrophy (DMD)
dc.subjectToll-like receptors (TLRs)
dc.titleRole of toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle
dc.typeArticle


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