Manipulating TWEAK and CD163 to Spur Muscle Regeneration

The immune cells known as macrophages are involved in the regulation of regeneration, mostly in a beneficial sense, though here researchers identify an activity that suppresses excessive regeneration in muscle tissue. Sometimes excessive regeneration is exactly what is desired for medical purposes, however:

By removing the protein CD163 from mice, scientists have boosted muscle repair and recovery of blood flow after ischemic injury (damage caused by restriction of blood flow). The findings point to a target for potential treatments aimed at enhancing muscle regeneration. CD163 was known to scientists, mostly as a molecule involved in scavenging excess hemoglobin from the body, but its role in regulating muscle repair was not. Mice lacking CD163 showed increased blood flow and muscle repair, compared with controls, after an injury coming from a restriction of blood flow in one leg. Examining the mice lacking CD163, researchers were surprised to find that blood vessels and muscle fibers also grew substantially (roughly 10 percent) in their uninjured legs. "We were astonished. Why would something we did, which caused an injury to one leg, help tissue in the other leg regenerate when it wasn't injured in the first place?"

Potentially, researchers could try to achieve the effect of removing CD163 in humans by giving patients an antibody against CD163, but more research is needed to know how this might work. CD163 levels have been found to increase in aging humans in multiple studies. Macrophages, which are a type of white blood cell, appear to release a soluble form of CD163 in response to injury. In the blood, CD163 soaks up and counteracts another protein called TWEAK, which stimulates muscle cells to multiply. In CD163's absence, TWEAK can have a greater effect, and can apparently stimulate muscle growth distant from the site of injury. When infused into normal mice, TWEAK does not have any effect on muscle growth, possibly because of circulating CD163.

Scientists that study muscle cells have been interested in TWEAK for several years, but some studies have suggested that TWEAK negatively regulates muscle regeneration - the opposite of what this team observed. To prove that TWEAK was needed for the extra repair seen in mice lacking CD163, the researchers showed that if they injected an antibody against TWEAK, thus removing it from the blood, it eliminated the extra repair activity. "I think our results show a specific mechanism by which muscle regeneration takes place. TWEAK can be a pro-regenerative factor, but its effects have to be transient and limited."



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