Numerous research teams are interested in finding ways to enhance muscle regeneration, and below find the publicity materials for a couple of different lines of research along these lines – researchers in search of specific mechanisms that might be amenable to change, and thus the potential foundation for a drug discovery program and therapies in the clinic. Enhanced muscle regeneration encompasses more than just faster and more comprehensive recovery from injury, as much the same set of mechanisms are also involved in the normal maintenance and growth of muscles. As I’m sure the audience here is well aware, muscle tissue weakens and diminishes with age, a condition known as sarcopenia. Researchers hope that enhancements to the processes of muscle repair will be able to at least partially compensate for the losses of age, or delay those losses somewhat, even though they fail to directly address the underlying reasons for this form of age-related decline.
There is considerable debate over the causes of sarcopenia, and as for most aspects of aging, it is not yet possible to draw a consensus line of cause and effect from the sort of root cause forms of cellular damage outlined in the SENS rejuvenation research proposals all the way to well known age-related diseases, passing through the better explored metabolic changes observed in aging along the way. There is a great deal of data for sarcopenia, however: it is a puzzle in which at least some of the pieces are already joined together, even if it isn’t quite settled as how these little islands of knowledge relate to one another in the bigger picture.
Changes in processing of amino acids appear important, as does the decline in diet and exercise in later life. Cellular senescence is implicated, as is becoming the case in many parts of the field now that more attention is being given to removal of senescent cells. Loss of mitochondrial function is also thought important, and there are related views involving loss of capillaries and nutrient supply in older tissue. Of late, there has been a fairly compelling argument to point to loss of stem cell activity as the primary lynchpin issue, though everything else just mentioned may well contribute to that loss. Everything is connected to everything else in cellular metabolism, and there are many angles from which the wise men can approach this elephant.
Muscle stem cells usually nestle quietly along the muscle fibers. They spring into action when a muscle is damaged by trauma or overuse, dividing rapidly to generate enough muscle cells to repair the injury. But it’s not entirely clear what signals present in inflammation activate the stem cells. Prostaglandin E2, or PGE2, is a metabolite produced by immune cells that infiltrate the muscle fiber as well by the muscle tissue itself in response to injury. Anti-inflammatory treatments have been shown to adversely affect muscle recovery, but because they affect many different pathways, it’s been tough to identify who the real players are in muscle regeneration.
Researchers discovered a role for PGE2 in muscle repair by noting that its receptor was expressed at higher levels on stem cells shortly after injury. They found that muscle stem cells that had undergone injury displayed an increase in the expression of a gene encoding for a receptor called EP4, which binds to PGE2. Furthermore, they showed that the levels of PGE2 in the muscle tissue increased dramatically within a three-day period after injury, indicating it is a transient, naturally occurring immune modulator. “This transient pulse of PGE2 is a natural response to injury. When we tested the effect of a one-day exposure to PGE2 on muscle stem cells growing in culture, we saw a profound effect on the proliferation of the cells. One week after a single one-day exposure, the number of cells had increased sixfold compared with controls.”
After seeing what happened in laboratory-grown cells, researchers tested the effect of a single injection of PGE2 into the legs of the mice after injury. “When we gave mice a single shot of PGE2 directly to the muscle, it robustly affected muscle regeneration and even increased strength. Conversely, if we inhibited the ability of the muscle stem cells to respond to naturally produced PGE2 by blocking the expression of EP4 or by giving them a single dose of a nonsteroidal anti-inflammatory drug to suppress PGE2 production, the acquisition of strength was impeded.” The researchers next plan to test the effect of PGE2 on human muscle stem cells in the laboratory, and to study whether and how aging affects the stem cells’ response. Because PGE2 is approved by the Food and Drug Administration for use in the induction of labor, a path to the clinic could be relatively speedy.
Earlier this year, researchers published findings showing that a nuclear receptor called REV-ERB is involved in lowering LDL cholesterol. They previously studied REV-ERB’s role in regulating mammals’ internal clocks. Now the researchers are uncovering REV-ERB’s role in muscle regeneration. Skeletal muscle comprises 40 to 50 percent of our total body mass and is essential for postural support, locomotion and breathing. With a high capacity for regeneration, skeletal muscle normally maintains muscle mass and function in response to minor injuries and normal wear and tear without much trouble. When injuries are severe – with more than 20 percent loss of muscle mass – normal muscle regeneration often cannot keep pace with the regenerative demands. In this scenario, the loss of skeletal muscle mass can trigger widespread fibrosis and loss of muscle function.
“Identifying new means of accelerating muscle regeneration has proved a daunting challenge. Therefore understanding the underlying mechanisms that regulate muscle cell regeneration and coordinate regenerative repair could provide future therapeutic options for stymieing the loss of muscle function in the traumatically injured.” A simplified version of muscle cells’ life-cycle looks like this: muscle stem cells produce myoblasts that will either reproduce (proliferate) or form muscle tissue (differentiate). Successful regeneration of skeletal muscle after traumatic injury depends on the replenishment of muscle fibers through elevated myoblast proliferation and differentiation.
The research team identified a mechanism through which REV-ERB may regulate gene expression pre and post muscle differentiation. “We demonstrate that REV-ERB can stimulate muscle regeneration upon acute muscle injury in an animal model. Our findings reveal that REV-ERB may be a potent therapeutic target for the treatment of a myriad of muscular disorders.”