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From: NIH news releases and news items [mailto:[log in to unmask]] On
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Sent: Thursday, October 14, 2010 4:48 PM
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Subject: CELL-SIGNALING LINK BETWEEN MUSCLE INFLAMMATION AND REGENERATION
IDENTIFIED

U.S. Department of Health and Human Services 
NATIONAL INSTITUTES OF HEALTH NIH News 
National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS) <http://www.niams.nih.gov/>
For Immediate Release: Thursday, October 14, 2010

CONTACT: Trish Reynolds, 301-496-8190, <e-mail:[log in to unmask]>

MEDIA AVAILABILITY 
CELL-SIGNALING LINK BETWEEN MUSCLE INFLAMMATION AND REGENERATION IDENTIFIED

WHAT

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.

WHO

Vittorio Sartorelli, M.D., is the senior investigator in the NIAMS
Intramural Research Program's Laboratory of Muscle Stem Cells and Gene
Regulation. His lab's role in this study was to explore and define the role
of the p38 MAP kinase in promoting EzH2 phosphorylation. Some of the
Sanford-Burnham Institute's research was also funded, in part, by NIAMS. Dr.
Sartorelli and his NIAMS colleagues have been collaborating with the Italian
and U.S. muscle researchers who conducted this study for more than a decade.
Dr. Sartorelli is available to discuss the study findings upon request.

CONTACT

To schedule interviews, please contact Trish Reynolds, 301-496-8190,
<e-mail:[log in to unmask]>.

The mission of the National Institute of Arthritis and Musculoskeletal and
Skin Diseases, a part of the U.S. Department of Health and Human Services'
National Institutes of Health, is to support research into the causes,
treatment, and prevention of arthritis and musculoskeletal and skin
diseases; the training of basic and clinical scientists to carry out this
research; and the dissemination of information on research progress in these
diseases. For more information about NIAMS, call the information
clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the
NIAMS Web site at <http://www.niams.nih.gov>.

The National Institutes of Health (NIH) -- The Nation's Medical Research
Agency -- includes 27 Institutes and Centers and is a component of the U.S.
Department of Health and Human Services. It is the primary federal agency
for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.

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