| First Author | Henriques-Pons A | Year | 2014 |
| Journal | Hum Mol Genet | Volume | 23 |
| Issue | 10 | Pages | 2604-17 |
| PubMed ID | 24368419 | Mgi Jnum | J:209059 |
| Mgi Id | MGI:5565621 | Doi | 10.1093/hmg/ddt656 |
| Citation | Henriques-Pons A, et al. (2014) Role of Toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle. Hum Mol Genet 23(10):2604-17 |
| abstractText | 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. |
