201. The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: role of endogenous TLR ligands
- Author
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Kitipong, Uaesoontrachoon, Hee-Jae, Cha, Beryl, Ampong, Arpana, Sali, Jack, Vandermeulen, Benjamin, Wei, Brittany, Creeden, Tony, Huynh, James, Quinn, Kathleen, Tatem, Sree, Rayavarapu, Eric P, Hoffman, and Kanneboyina, Nagaraju
- Subjects
Male ,Mice, Knockout ,Primary Immunodeficiency Diseases ,Toll-Like Receptors ,Immunologic Deficiency Syndromes ,Membrane Proteins ,Enzyme-Linked Immunosorbent Assay ,Ligands ,Real-Time Polymerase Chain Reaction ,Immunohistochemistry ,Article ,Mice ,Phenotype ,Muscular Dystrophies, Limb-Girdle ,Myeloid Differentiation Factor 88 ,Disease Progression ,Animals ,Muscle, Skeletal ,Dysferlin - 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.
- Published
- 2013