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

    loading  Checking for direct PDF access through Ovid

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 vitroscreening 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/regenerationin vivoinmdxmouse muscle. Also, knockout of the central TLR adaptor protein, myd88 inmdxmice significantly improved skeletal and cardiac muscle function. Likewise, proof-of-concept experiments showed that treating youngmdxmice 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.

Related Topics

    loading  Loading Related Articles