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Cell-Signaling Link Between Muscle Inflammation And Regeneration Identified
October 14th, 2010
An international team of scientists from Italy’s Dulbecco Telethon Institute, California’s Sanford-Burnham Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a component of the National Institutes of Health, has identified and described, for the first time, a cell-signaling pathway in mice that directs adult muscle stem cells to repair damaged muscle tissue.
Their findings, which appear in the October issue of Cell Stem Cell, could advance research into therapeutic targets for muscle atrophy, like that seen in the muscular dystrophies and advanced aging.
Scientists have understood for some time that muscle regeneration relies on the activation of muscle stem cells, called satellite cells, by protein molecules produced during inflammation. More recently, they discovered that a key protein in this process, Pax7, activates satellite cells after injury, cueing them to multiply, and, later, that Pax7 must be repressed so the cells can stop proliferating and develop into mature muscle cells that fuse with and repair damaged muscle fibers. What muscle researchers had not understood well was how the body turns Pax7 on and off.
Prior research by their team and others encouraged the Italian and NIAMS researchers to examine how Pax7 regulation was affected when a protein called tumor necrosis factor-alpha (TNFa), one of the key products of inflammation, is blocked with infliximab (Remicade). Infliximab binds up TNFa so it cannot effectively signal other molecules. The team found that when TNFa was rendered inactive, the satellite cells kept proliferating. In other words, TNFa is needed to “turn off” Pax7.
Taking their research a step further, the team set out to identify other proteins that might interact in the signaling chain between TNFa and Pax7. They found several key links: First, TNFa activates a protein called p38MAP kinase, which, in turn, activates a protein called EzH2, which engages another protein called YY1. Together, EzH2 and YY1 interact with the DNA of the satellite cells to repress the production of Pax7.
Because the failure of satellite cells to function correctly results in muscle atrophy, the researchers hope their findings, by adding to our understanding of how inflammation signals muscle to repair itself, will suggest new avenues of research on how and where to intervene in the signaling process to improve muscle repair capability.
Reference: Palacios D, Mozzetta C, Consalvi S, Caretti G, Saccone V, Proserpio V, Marquez VE, Valente S, Mai A, Forcales SV, Sartorelli V, Puri PL. TNF/p38a/Polycomb Signaling to Pax7 Locus in Satellite Cells Links Inflammation to the Epigenetic Control of Muscle Regeneration. Cell Stem Cell. 2010 Oct 8;7(4):455-69.
SOURCE: National Institutes of Health
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