Why Aging Muscles Heal Poorly
August 15, 2007
Science Daily — Communication is critical. Garbled in, garbled out,
so to (mis-)speak. Workers who get incomplete instructions produce an
incomplete product, and that's exactly what happens with the stem
cells in our aging muscles, according to researchers from the
Stanford University School of Medicine.
Their study found that, as we age, the lines of communication to the
stem cells of our muscles deteriorate and, without the full
instructions, it takes longer for injured muscles to heal. Even then,
the repairs aren't as good. But now that the researchers have
uncovered the conduit that conveys the work orders to muscle stem
cells, that knowledge could open the door to new therapies for
injuries in a host of different tissues.
The key to the whole process is Wnt, a protein traditionally thought
to help promote maintenance and proliferation of stem cells in many
tissues. But in this instance, Wnt appears to block proper
communication.
"That was a total surprise," said Thomas Rando, MD, PhD, associate
professor of neurology and neurological sciences. "We had no idea
that the Wnt signaling pathway would have a negative effect on stem
cell function." Rando, who also does research and clinical work at
the Veterans Affairs Palo Alto Health Care System, is senior author
of the research that will be published in the Aug. 10 issue of
Science.
Rando said many drugs can block Wnt signaling. "Theoretically, given
the number of ways to block Wnt and Wnt signaling, one could envision
this becoming a therapeutic,
the healing of aged tissues by reducing this effect of Wnt signaling
on the resident stem cells."
In addition to helping the elderly heal faster and better from muscle
injuries, Rando said, the potential benefits could include tissues
such as skin, gut and bone marrow, or for that matter, potentially
any tissue, such as liver and brain, in which stem cells contribute
to normal cellular turnover.
Rando and his colleagues made the discovery while studying the effect
of environment on muscle stem cell activity in mice. Rando had
already discovered that old muscle stem cells, if placed in a
youthful environment, had just as great a capacity for repairing
acutely damaged tissue as do young cells.
It was while the researchers were testing the opposite situation -
how the repair capabilities of young muscle stem cells were affected
by being placed in an aged environment - that the Wnt pathway came to
light. The work was done with live mice whose circulatory systems
were joined, and in lab dishes with young cells immersed in serum
from old blood.
As expected, the young muscle stem cells were influenced negatively
by the aged environment, repairing damaged muscle tissue just as
slowly and poorly as old stem cells in the same surroundings. This
confirmed their earlier research showing that the ability of muscle
stem cells to regenerate tissue depends on the age of the cells'
environment (including the age of the blood supplying the tissue),
not the age of the stem cell.
Although Rando's research focused on the repair of acute trauma to
muscles, he suspects that the same sort of problem arises on a lesser
scale in repairing damage that results from the normal wear and tear
of aging.
Rando also found that the misdirected stem cells - the ones that
failed to generate new muscle cells in the old environment - were
instead differentiating into scar-tissue-
fibroblasts. The stem cells weren't just failing to respond to the
garbled instructions, they were actually giving rise to daughter
cells that turned into the wrong thing. The consequence of muscle
stem cells producing fewer muscle cells (myoblasts) and more
fibroblasts is that the healing muscle had more scar tissue, also
known as fibrosis.
"That says something about how cells decide who they're going to be.
Even if they start off knowing they're supposed to be a muscle cell,
they can change," said Rando. "If you're exposed to the wrong
environment, it will change your fate."
Rando said the type of fibrosis that occurs in the aging muscle
tissue is the same type seen in muscular dystrophy. He is already
exploring how inhibiting Wnt signaling might help provide therapy for
that disease.
Wnt has also popped up unexpectedly in work by researchers at the
National Institutes of Health, published in the same issue of
Science, who were studying the effects of a deficiency of a hormone
called klotho. Klotho deficiency causes a syndrome that resembles
extremely rapid aging in mice, which end up dying very young compared
with normal mice. In seeking to understand why that happens, the NIH
researchers discovered that klotho inhibits Wnt activity. The
hypothesis is that klotho production declines with age, and thus its
effectiveness against Wnt decreases, allowing Wnt activity to pick up
and disrupt the normal signaling to the stem cells in a variety of
tissues studied.
Rando said that, although the work of his team and the NIH
researchers is different in terms of the techniques used and the
questions being studied, "what's surprising is how supportive of each
other the fundamental conclusions (of the two papers) are about Wnt
signaling and aging."
Rando's Stanford co-authors are Andrew Brack, PhD, postdoctoral
scholar; Michael Conboy, PhD, postdoctoral scholar; Sudeep Roy,
research assistant; Mark Lee, MD, PhD, postdoctoral scholar; and
Calvin Kuo, MD, PhD, assistant professor of hematology. The research
was funded by the NIH, the Department of Veterans Affairs, the
Ellison Medical Foundation and an NIH Director's Pioneer Award to
Rando.
Note: This story has been adapted from a news release issued by
Stanford University Medical Center.
http://www.scienced
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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