Major Progress on Age Related Muscle Wastage

We seem to have a real lead here for tackling the problem of age related muscle loss. It appears to be related to the switching from dormancy to active for the stem cells involved. It also looks like that creative therapies are plausible and may become available fairly quickly.

More importantly, this knowledge will promote a deep search among alternative health types to locate a natural activator that is presently overlooked. I suspect that this could be discovered.

At least we now have a clear starting point and this should result in corrective therapies in several years. It is very good news as the loss of muscle strength directly brings on bone weakness and the whole range of unpleasant age related physical failures. Yet it is completely possible to remain active into the century mark. Strong matters a lot.

Scientists make old muscles young again in attempt to combat ageing

Posted on 27/09/2012

http://www.kcl.ac.uk/newsevents/news/newsrecords/2012/09-Sept/scientists-make-old-muscles-young-again-in-attempt-to-combat-ageing.aspx

Researchers at King’s College London, Harvard University and Massachusetts General Hospital have identified for the first time a key factor responsible for declining muscle repair during ageing, and discovered how to halt the process in mice with a common drug.

Although an early study, the finding provides clues as to how muscles lose mass with age, which can result in weakness that affects mobility and may cause falls.

Published today in the journal Nature, and funded by the Biotechnology, and Biological Sciences Research Council, Harvard Stem Cell Institute and National Institutes of Health (US), the study looked at stem cells found inside muscle - which are responsible for repairing injury - to find out why the ability of muscles to regenerate declines with age. A dormant reservoir of stem cells is present inside every muscle, ready to be activated by exercise and injury to repair any damage. When needed, these cells divide into hundreds of new muscle fibres that repair the muscle. At the end of the repairing process some of these cells also replenish the pool of dormant stem cells so that the muscle retains the ability to repair itself again and again.

The researchers carried out a study on old mice and found the number of dormant stem cells present in the pool reduces with age, which could explain the decline in the muscle’s ability to repair and regenerate as it gets older. When these old muscles were screened the team found high levels of FGF2, a protein that has the ability to stimulate cells to divide. While encouraging stem cells to divide and repair muscle is a normal and crucial process, they found that FGF2 could also awaken the dormant pool of stem cells even when they were not needed. The continued activation of dormant stem cells meant the pool was depleted over time, so when the muscle really needed stem cells to repair itself the muscle was unable to respond properly. 

Following this finding, the researchers attempted to inhibit FGF2 in old muscles to prevent the stem cell pool from being kick-started into action unnecessarily. By administering a common FGF2 inhibitor drug they were able to inhibit the decline in the number of muscle stem cells in the mice.

Dr Albert Basson, Senior Lecturer from the Department of Craniofacial Development and Stem Cell Biology at the King’s College London Dental Institute, said: ‘Preventing or reversing muscle wasting in old age in humans is still a way off, but this study has for the first time revealed a process which could be responsible for age-related muscle wasting, which is extremely exciting.

‘The finding opens up the possibility that one day we could develop treatments to make old muscles young again. If we could do this, we may be able to enable people to live more mobile, independent lives as they age.’

Dr Andrew Brack, senior and corresponding author of the study from Harvard University, said: ‘Analogous to the importance of recovery for athletes training for a sporting event, we now know that it is essential for adult stem cells to rest between bouts of expenditure. Preventing stem cell recuperation leads to their eventual demise.’

Kieran Jones, co-author of the study from King’s, added: ‘We do not yet know how or why levels of the protein FGF2 increase with age, triggering stem cells to be activated when they are not needed. This is something that needs to be explored.

‘The next step is to analyse old muscle in humans to see if the same mechanism could be responsible for stem cell depletion in human muscle fibres, leading to loss of mass and wastage.’

Notes to editors

For further information or to request a copy of the Nature paper, please contact Emma Reynolds, PR Manager (Health) at King’s College London, on  

HOPKINS RESEARCHERS SOLVE KEY PART OF OLD MYSTERY IN GENERATING MUSCLE MASS

http://www.hopkinsmedicine.org/news/media/releases/hopkins_researchers_solve_key_part_of_old_mystery_in_generating_muscle_massRelease

Date: 09/27/2012

Implications for treating muscular dystrophy and other muscle wasting diseases

Working with mice, Johns Hopkins researchers have solved a key part of a muscle regeneration mystery plaguing scientists for years, adding strong support to the theory that muscle mass can be built without a complete, fully functional supply of muscle stem cells.

"This is good news for those with muscular dystrophy and other muscle wasting disorders that involve diminished stem cell function," says Se-Jin Lee, M.D., Ph.D., lead author of a report on the research in the August issue of the Proceedings of the National Academy of Sciences and professor ofmolecular biology and genetics at the Johns Hopkins University School of Medicine.

Muscle stem cells, known as satellite cells, reside next to muscle fibers and are usually dormant in adult mammals, including humans. 

After exercise or injury, they are stimulated to divide and fuse, either with themselves or with nearby muscle fibers, to increase or replace muscle mass. In muscle wasting disorders, like muscular dystrophy, muscle degeneration initially activates satellite cells to regenerate lost tissue, but eventually the renewal cycle is exhausted and the balance tips in favor of degeneration, the researchers explain.

Muscle maintenance and growth under healthy, non-injury conditions have been more of a mystery, including the role of myostatin, a protein secreted from muscle cells to stop muscle growth. Blocking myostatin function in normal mice causes them to bulk up by 25 to 50 percent. What is not known is which cells receive and react to the myostatin signal. Current suspects include satellite cells and muscle cells themselves.

In this latest study, researchers used three approaches to figure out whether satellite cells are required for myostatin activity. They first looked at specially bred mice with severe defects in either satellite cell function or number. When they used drugs or genetic engineering to block myostatin function in both types of mice, muscle mass still increased significantly compared to that seen in mice with normal satellite cell function, suggesting that myostatin is able to act, at least partially, without full satellite cell function.

Second, the researchers guessed that if myostatin directly inhibits the growth of satellite cells, their numbers should increase in the absence of myostatin. The researchers marked the satellite cells with a permanent dye and then blocked myostatin activity with a drug.

 
Mouse muscle mass increased significantly as expected, but the satellite cells did not increase in number, nor were they found fusing with muscle fibers at a higher rate. According to Lee, these results strongly suggest that myostatin does not suppress satellite cell proliferation.

Third, to further confirm their theory that myostatin acts primarily through muscle cells and not satellite cells, the team engineered mice with muscle cells lacking a protein receptor that binds to myostatin. If satellite cells harbor most of the myostatin receptors, removal of receptors in muscle cells should not alter myostatin activity and should result in muscles of normal girth. Instead, what the researchers saw was a moderate, but statistically significant, increase in muscle mass. The evidence once again, they said, suggested that muscle cells are themselves important receivers of myostatin signals.

Lee notes that, since the results give no evidence that satellite cells are of primary importance to the myostatin pathway, even patients with low muscle mass due to compromised satellite cell function may be able to rebuild some of their muscle tone through drug therapy that blocks myostatin activity.

"Everybody loses muscle mass as they age, and the most popular explanation is that this occurs as a result of satellite cell loss. If you block the myostatin pathway, can you increase muscle mass, mobility and independence for our aging population?" asks Lee. "Our results in mice suggest that, indeed, this strategy may be a way to get around the satellite cell problem."

Authors on the paper include Se-Jin Lee, Thanh Huynh, Yun-Sil Lee and Suzanne Sebald from The Johns Hopkins University, Sarah Wilcox-Adelman of Boston Biomedical Research Institute, Naoki Iwamori and Martin Matzuk of Baylor College of Medicine, and Christoph Lepper and Chen-Ming Fan from the Carnegie Institution for Science.

This work was supported by grants from the NIH Office of the Director (DP5OD009208), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR059685, R01AR060636, R01AR060042), the National Institute of Neurological Disorders and Stroke (P01NS0720027), the National Institute of Child Health and Human Development (R01HD032067) and the Jain Foundation.

Disclosure: Under a licensing agreement between Pfizer Inc. and The Johns Hopkins University, Lee is entitled to a share of royalty received by the university on sales of products related to myostatin. The terms of this arrangement are being managed by the university in accordance with its conflict of interest policies.