Interesting article on using decorin and igf to heal sports injuries
02-01-2006 11:59 AM
Interesting article on using decorin and igf to heal sports injuries
Using decorin, an anti-fibrosis agent, to improve muscle recovery after injury
Muscle lacerations - injuries to muscles in which there is tearing of muscle fibres - are common sports injuries. They occur in every sport and can be the result of external forces (for example, when a football player's quadriceps muscles are struck by another player's foot or leg) or internal duress (for example, when hamstring fibres are torn during a sudden acceleration).
When a muscle is lacerated, it undergoes a very systematic and unvarying process of repair, sometimes described as 'degeneration and regeneration'. First to occur are the 'necrotic changes' to the lacerated muscle, during which damaged muscle fibres are actively removed by white blood cells.
On stage next are the 'satellite cells', which may sound like protoplasm from outer space but are actually strange, almost embryonic cells. Satellite cells are natural components of muscle tissue; in response to an injury they first become somewhat unusual, tube-like cells and then begin to develop the characteristics of full-blown muscle fibres. All muscles possess a connective-tissue 'scaffolding' which supports the overall muscle, and within this scaffolding - at or near the site of the laceration - these 'baby' muscle cells (the satellite cells) do their growing-up. The process is a slow one, requiring many weeks - and does not always lead to full functional recovery of the muscle, especially if the laceration is severe.
We should point out that this muscular-regeneration process tends to be spurred on by a chemical called insulin-like growth factor-1 (IGF-1). The amount of IGF-1 in a tissue appears to be directly related to the extent to which regeneration occurs; levels of IGF-1 are increased within the body when extra amounts of human growth hormone are released by the pituitary gland. It is interesting to note that human subjects who are given human growth hormone tend to increase their concentrations of IGF-1 and lose less muscle mass in response to ageing. Laboratory mice treated with IGF-1 age at slower rates (from a muscular-system standpoint) than untreated mice.
As regeneration of a lacerated muscle is occurring, there is another, simultaneous process at work which actually tends to inhibit full muscular recovery. This process is called fibrosis - the filling in of muscle-tissue space with connective-tissue fibres. Fibrosis usually becomes apparent during the second week after a laceration or other serious muscle injury, and the extent of fibrosis tends to increase thereafter, as the healing process continues.
In one sense, fibrosis is a good thing. After all, it fills in empty space in a muscle and knits muscle tissue together, providing a permanent connecting point between various previously disconnected, ripped-up sections of muscle tissue. However, a negative aspect of fibrosis is that connective-tissue fibres can in effect take up space in a muscle which would otherwise be occupied by muscle cells. This makes it difficult for a muscle to regain its normal strength, since the density of muscle cells decreases (bear in mind that connective-tissue fibres can not contract).
Another negative aspect of fibrosis is that connective-tissue fibres tend to be stiffer and less resilient than muscle cells. It is more difficult to elongate a thick knot of connective tissue, compared with a group of muscle cells, and connective tissue also tends to be less rubber-band-like - and thus less able to use elastic energy to exert force and produce motion. As a result, muscles with significant fibrosis have less strength and flexibility and operate with less efficiency, compared to normal muscles. Unfortunately, IGF-1 does absolutely nothing to arrest fibrosis.
Fortunately, researchers at the University of Pittsburgh have been working hard to develop ways to control fibrosis. The Pittsburgh scientists realised that fibrosis is stimulated by the overproduction of a chemical called transforming growth factor-beta (TGF-beta). TGF-beta is produced by tissues in response to injury and disease and is the major cause of fibrosis in humans and other animals.
The Pittsburgh researchers also knew that decorin - a proteoglycan (a protein with sugar attached) naturally found in the human body - has the ability to de-activate TGF-beta. Decorin has been shown to inhibit fibrosis in the kidney, liver, and lung, so why - the Pennsylvania scientists reasoned - would it not also stop fibres from taking over muscle tissue?
In recent research, the Pittsburgh medical team has in fact been able to show that decorin is a powerful anti-fibrotic agent in muscle tissue - and thus that decorin administration has the potential to be an outstandingly effective treatment for muscle injury (Kazumasa, F. et al., 'The Use of An Antifibrosis Agent to Improve Muscle Recovery after Laceration,' The American Journal of Sports Medicine, Vol. 29 (4), pp. 394-402, 2001). In their benchmark study, the Pittsburgh scientists first surgically lacerated the gastrocnemius muscles in both hind legs of 16 laboratory mice. The mice were then divided into four groups with different time points for decorin injections (0, five, 10, and 15 days after laceration). At each time point, four different concentrations of human-recombinant decorin were utilised (0, five, 25, and 50 micrograms in 20 microlitres of saline solution). All animals were sacrificed for evaluation of healing and regeneration two weeks after injections were given. In a separate part of the investigation, 12 mice had their gastrocs similarly lacerated and were given decorin 15 days after the laceration - in the various doses of 0 (control), five, 25, and 50. These mice were checked for fibrosis two weeks after the injections.
Mouse myofibroblasts (connective-tissue cells which grow in muscle and can produce fibrosis) were also incubated in vitro with decorin added to the growth media, with TGF-beta added, with both decorin and TGF-beta mixed with the cells, and without either compound. This tissue-culture work revealed that TGF-beta indeed spurred connective-tissue growth, that decorin significantly inhibited it, and that when the two compounds were mixed together decorin had the ability to dramatically reduce TGF-beta's fibrotic powers.
Further good news
In the living mouse muscles, direct injection of the human-recombinant decorin not only reduced the extent of fibrosis - but also enhanced regeneration of real-live muscle cells. Higher doses of decorin seemed to be best: according to the researchers, using 25 to 50 micrograms resulted in better prevention of fibrosis, compared with five micrograms or control, and the use of 50 micrograms increased the number of regenerating muscle cells in the mouse gastrocs and also broadened the diameters of those regenerating cells, compared with the use of all lower doses.
In a unique aspect of the research designed to test the ability of decorin to spur on a lacerated muscle's return to full functionality, mouse gastroc muscles were lacerated, injected with 50 micrograms of decorin or a placebo two weeks later, and then tested for strength two weeks after that. Basically, the researchers were able to demonstrate that the placebo muscles were about 50% as strong as normal mouse gastrocs, whereas the decorin-treated muscles had returned to full strength.
Decorin appears to be a powerhouse - with beneficial effects on both muscle regeneration and fibrosis control in muscles which have suffered lacerations. This is exciting news, because muscle damage accounts for a huge proportion of both professional and recreational sports injuries, and yet the standard treatments for muscle damage are obviously inadequate. Rest, for example, promotes regeneration but does nothing to stop fibrosis. Likewise, the standard treatments of ice, heat, whirlpool therapy, compression, elevation, immobilisation, and drugs have various effects on muscle-damage symptoms and muscular inflammation, but it is clear that they are not optimally anti-fibrotic, and they do not maximally enhance regeneration. The treatment of lacerations with decorin - along with the utilisation of an outstanding post-injury muscle-strengthening programme- may prove to be the best-possible way of returning athletes to full activity - and full muscular function - in the shortest-possible time. For their outstanding efforts, the University of Pittsburgh researchers were awarded the prestigious Cabaud Award, given each year by the American Orthopaedic Society for Sports Medicine.
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