title: Role of Toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle.
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 and immune cells and activate downstream processes that facilitate degeneration and regeneration in dystrophic skeletal muscle. Here, we demonstrate that dystrophin-deficient mouse muscle 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 dystrophin-deficient 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.
authors.affiliation: Center for Genetic Medicine Research.
authors.forename: Andrea
authors.initials: A
authors.lastname: Henriques-Pons
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Sree
authors.initials: S
authors.lastname: Rayavarapu
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Cohen
authors.forename: Beryl
authors.initials: B
authors.lastname: Ampong
authors.forename: Hee Jae
authors.initials: HJ
authors.lastname: Cha
authors.forename: Vanessa
authors.initials: V
authors.lastname: Jahnke
authors.forename: Jack
authors.initials: J
authors.lastname: Van der Meulen
authors.forename: Daqing
authors.initials: D
authors.lastname: Wang
authors.forename: Weiwen
authors.initials: W
authors.lastname: Jiang
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.forename: Sudhir
authors.initials: S
authors.lastname: Agrawal
authors.forename: Chistopher F
authors.initials: CF
authors.lastname: Spurney
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D016189:Dystrophin / Q000172:deficiency; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000276:immunology / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016189:Dystrophin; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9