June 1, 2010 Dr. Kanneboyina Nagaraju and colleagues at the Children's National Medical Center, Washington, DC demonstrate that affected muscle may directly contribute to inflammation in muscular dystrophy.
Their report can be found in the June 2010 issue of The American Journal of Pathology.
Muscular dystrophy is a group of genetic diseases that result in progressive weakening of the human body, leading to muscle wasting and even the inability to walk. Many patients with muscular dystrophy shown signs of inflammation; however, the mechanisms governing this inflammation in disease pathogenesis remain unexplored.
To investigate the role of the inflammasome, which is responsible for activation of inflammatory processes, in muscular dystrophy, Rawat et al examined the inflammasome platform in mouse and human tissues that develop limb girdle muscular dystrophy type 2B (LGMD2B). They found that components of the inflammasome pathway were upregulated and activated in diseased muscle as compared with control muscle and that primary skeletal muscle cells can secrete inflammatory mediators, directly participating in inflammasome formation. Moreover, diseased muscle cells expressed innate immune molecules, suggesting that affected muscle may directly contribute to inflammation in muscular dystrophy and providing a new therapeutic target for LGMD2B.
Dr. Nagarju's group concludes that "it is likely that age-related physiological changes in the skeletal muscle, together with environmental insults, can initiate the disease process in LGMD2B. … [They] propose that the increase in vesicular trafficking and plasma membrane repair defects associated with LGMD2B results in the release of ATP and other endogenous danger/alarm signals (e.g, HMGB1, S100 proteins). These molecules, in turn, bind to their cellular receptors (toll-like receptors, P2X7 receptors) and activate the inflammasome pathway. … Downstream processes [may then] activate not only inflammation and fibrosis but also lead to significant muscle fiber damage and dysfunction."
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- Rawat R, Cohen TV, Ampong B, Francia D, Pons A, Hoffman EP, Nagaraju K. Inflammasome Up-Regulation and Activation in Dysferlin-Deficient Skeletal Muscle. American Journal Of Pathology, 2010; DOI: 10.2353/ajpath.2010.090058
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