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

Children’s National Medical Center. Center for Genetic Medicine Research. Washington, DC,USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inovações em Terapias, Ensino e Bioprodutos. Rio de Janeiro, RJ, Brasil.
Children´s Hospital. Children’s National Medical Center.Center for Genetic Medicine Research. Division of Cardiology. Washington, DC,USA
Children’s National Medical Center. Center for Genetic Medicine Research. Washington, DC,USA / The George Washington University. Department of Integrative Systems Biology. Washington, DC, USA.
Children’s National Medical Center. Center for Genetic Medicine Research. Washington, DC,USA.
Children’s National Medical Center. Center for Genetic Medicine Research. Washington, DC,USA
Children’s National Medical Center. Center for Genetic Medicine Research. Washington, DC,USA
Children’s National Medical Center. Center for Genetic Medicine Research. Washington, DC,USA
Children’s National Medical Center. Center for Genetic Medicine Research. Washington, DC,USA
Idera Pharmaceuticals, Inc.. Cambridge, MA, USA.
Idera Pharmaceuticals, Inc., Cambridge, MA, USA.
Idera Pharmaceuticals, Inc., Cambridge, MA, USA.
Idera Pharmaceuticals, Inc., Cambridge, MA, USA.
Children´s Hospital. Children’s National Medical Center.Center for Genetic Medicine Research. Division of Cardiology. Washington, DC,USA
Children´s Hospital. Children’s National Medical Center.Center for Genetic Medicine Research. Division of Cardiology. Washington, DC,USA

Abstract

Although 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.

Keywords

Heart muscle
Dystrophin-deficient skeletal
Duchenne muscular dystrophy (DMD)
Toll-like receptors (TLRs)

Publisher

Oxford University Press

Citation

PONS, 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.

DOI

10.1093/hmg/ddt656

ISSN

1460-2083

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/10615

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Open access

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