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Scientists discover clues to what makes human muscle age

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Scientists discover clues to what makes human muscle age

http://www.eurekalert.org/pub_releases/2009-09/uoc--sdc092809.php

A study led by researchers at the University of California, Berkeley, has

identified critical biochemical pathways linked to the aging of human muscle. By

manipulating these pathways, the researchers were able to turn back the clock on

old human muscle, restoring its ability to repair and rebuild itself.

The findings will be reported in the Sept. 30 issue of the journal EMBO

Molecular Medicine, a peer-reviewed, scientific publication of the European

Molecular Biology Organization.

" Our study shows that the ability of old human muscle to be maintained and

repaired by muscle stem cells can be restored to youthful vigor given the right

mix of biochemical signals, " said Professor Irina Conboy, a faculty member in

the graduate bioengineering program that is run jointly by UC Berkeley and UC

San Francisco, and head of the research team conducting the study. " This

provides promising new targets for forestalling the debilitating muscle atrophy

that accompanies aging, and perhaps other tissue degenerative disorders as

well. "

Previous research in animal models led by Conboy, who is also an investigator at

the Berkeley Stem Cell Center and at the California Institute for Quantitative

Biosciences (QB3), revealed that the ability of adult stem cells to do their job

of repairing and replacing damaged tissue is governed by the molecular signals

they get from surrounding muscle tissue, and that those signals change with age

in ways that preclude productive tissue repair.

Those studies have also shown that the regenerative function in old stem cells

can be revived given the appropriate biochemical signals. What was not clear

until this new study was whether similar rules applied for humans. Unlike

humans, laboratory animals are bred to have identical genes and are raised in

similar environments, noted Conboy, who received a New Faculty Award from the

California Institute of Regenerative Medicine (CIRM) that helped fund this

research. Moreover, the typical human lifespan lasts seven to eight decades,

while lab mice are reaching the end of their lives by age 2.

Working in collaboration with Dr. Kjaer and his research group at the

Institute of Sports Medicine and Centre of Healthy Aging at the University of

Copenhagen in Denmark, the UC Berkeley researchers compared samples of muscle

tissue from nearly 30 healthy men who participated in an exercise physiology

study. The young subjects ranged from age 21 to 24 and averaged 22.6 years of

age, while the old study participants averaged 71.3 years, with a span of 68 to

74 years of age.

In experiments conducted by Dr. Charlotte Suetta, a post-doctoral researcher in

Kjaer's lab, muscle biopsies were taken from the quadriceps of all the subjects

at the beginning of the study. The men then had the leg from which the muscle

tissue was taken immobilized in a cast for two weeks to simulate muscle atrophy.

After the cast was removed, the study participants exercised with weights to

regain muscle mass in their newly freed legs. Additional samples of muscle

tissue for each subject were taken at three days and again at four weeks after

cast removal, and then sent to UC Berkeley for analysis.

Carlson and Conboy, researchers at UC Berkeley, found that before

the legs were immobilized, the adult stem cells responsible for muscle repair

and regeneration were only half as numerous in the old muscle as they were in

young tissue. That difference increased even more during the exercise phase,

with younger tissue having four times more regenerative cells that were actively

repairing worn tissue compared with the old muscle, in which muscle stem cells

remained inactive. The researchers also observed that old muscle showed signs of

inflammatory response and scar formation during immobility and again four weeks

after the cast was removed.

" Two weeks of immobilization only mildly affected young muscle, in terms of

tissue maintenance and functionality, whereas old muscle began to atrophy and

manifest signs of rapid tissue deterioration, " said Carlson, the study's first

author and a UC Berkeley post-doctoral scholar funded in part by CIRM. " The old

muscle also didn't recover as well with exercise. This emphasizes the importance

of older populations staying active because the evidence is that for their

muscle, long periods of disuse may irrevocably worsen the stem cells'

regenerative environment. "

At the same time, the researchers warned that in the elderly, too rigorous an

exercise program after immobility may also cause replacement of functional

muscle by scarring and inflammation. " It's like a Catch-22, " said Conboy.

The researchers further examined the response of the human muscle to biochemical

signals. They learned from previous studies that adult muscle stem cells have a

receptor called Notch, which triggers growth when activated. Those stem cells

also have a receptor for the protein TGF-beta that, when excessively activated,

sets off a chain reaction that ultimately inhibits a cell's ability to divide.

The researchers said that aging in mice is associated in part with the

progressive decline of Notch and increased levels of TGF-beta, ultimately

blocking the stem cells' capacity to effectively rebuild the body.

This study revealed that the same pathways are at play in human muscle, but also

showed for the first time that mitogen-activated protein (MAP) kinase was an

important positive regulator of Notch activity essential for human muscle

repair, and that it was rendered inactive in old tissue. MAP kinase (MAPK) is

familiar to developmental biologists since it is an important enzyme for organ

formation in such diverse species as nematodes, fruit flies and mice.

For old human muscle, MAPK levels are low, so the Notch pathway is not activated

and the stem cells no longer perform their muscle regeneration jobs properly,

the researchers said.

When levels of MAPK were experimentally inhibited, young human muscle was no

longer able to regenerate. The reverse was true when the researchers cultured

old human muscle in a solution where activation of MAPK had been forced. In that

case, the regenerative ability of the old muscle was significantly enhanced.

" The fact that this MAPK pathway has been conserved throughout evolution, from

worms to flies to humans, shows that it is important, " said Conboy. " Now we know

that it plays a key role in regulation and aging of human tissue regeneration.

In practical terms, we now know that to enhance regeneration of old human muscle

and restore tissue health, we can either target the MAPK or the Notch pathways.

The ultimate goal, of course, is to move this research toward clinical trials. "

###

Other co-authors of the EMBO Molecular Medicine paper include Abigail Mackey at

the University of Copenhagen in Denmark, and Per Aagaard at the University of

Southern Denmark.

The National Institutes of Health, the California Institute of

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