title: The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: role of endogenous TLR ligands.
abstract: An absence of dysferlin leads to activation of innate immune receptors such as Toll-like receptors (TLRs) and skeletal muscle inflammation. Myeloid differentiation primary response gene 88 (MyD88) is a key mediator of TLR-dependent innate immune signalling. We hypothesized that endogenous TLR ligands released from the leaking dysferlin-deficient muscle fibres engage TLRs on muscle and immune cells and contribute to disease progression. To test this hypothesis, we generated and characterized dysferlin and MyD88 double-deficient mice. Double-deficient mice exhibited improved body weight, grip strength, and maximum muscle contractile force at 6-8 months of age when compared to MyD88-sufficient, dysferlin-deficient A/J mice. Double-deficient mice also showed a decrease in total fibre number, which contributed to the observed increase in the number of central nuclei/fibres. These results indicate that there was less regeneration in the double-deficient mice. We next tested the hypothesis that endogenous ligands, such as single-stranded ribonucleic acids (ssRNAs), released from damaged muscle cells bind to TLR-7/8 and perpetuate the disease progression. We found that injection of ssRNA into the skeletal muscle of pre-symptomatic mice (2 months old) resulted in a significant increase in degenerative fibres, inflammation, and regenerating fibres in A/J mice. In contrast, characteristic histological features were significantly decreased in double-deficient mice. These data point to a clear role for the TLR pathway in the pathogenesis of dysferlin deficiency and suggest that TLR-7/8 antagonists may have therapeutic value in this disease.
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
authors.forename: Kitipong
authors.initials: K
authors.lastname: Uaesoontrachoon
authors.forename: Hee-Jae
authors.initials: HJ
authors.lastname: Cha
authors.forename: Beryl
authors.initials: B
authors.lastname: Ampong
authors.forename: Arpana
authors.initials: A
authors.lastname: Sali
authors.forename: Jack
authors.initials: J
authors.lastname: Vandermeulen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wei
authors.forename: Brittany
authors.initials: B
authors.lastname: Creeden
authors.forename: Tony
authors.initials: T
authors.lastname: Huynh
authors.forename: James
authors.initials: J
authors.lastname: Quinn
authors.forename: Kathleen
authors.initials: K
authors.lastname: Tatem
authors.forename: Sree
authors.initials: S
authors.lastname: Rayavarapu
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000818:Animals; D018450:Disease Progression; D000073939:Dysferlin; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism; D010641:Phenotype; D000081207:Primary Immunodeficiency Diseases; D060888:Real-Time Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: C497505:Dysf protein, mouse; D000073939:Dysferlin; D008024:Ligands; C507779:MYD88 protein, human; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors
keywords: Toll-like receptor; degeneration; dysferlin; inflammation; osteopontin; regeneration; single-stranded RNA