Nester Gonzalez-Cadavid, Ph.D.; Charles R. Drew University of Medicine and Science, Peer Reviewed Medical Research Program Investigator Initiated Research Award

To understand the mechanisms of tissue fibrosis, the problem that we are facing in our grant is a very serious situation that most soldiers face not only in battle but also under heavy exercise and other military activities, which is experimenting heavy trauma and injury and then having an abnormal healing process.

So we want to get a correction for that problem and that is essentially the aim of the grant. When a soldier experiences injury in the muscle or any individual, there is a loss of the units that are called myofibers, and these are-it's normally replaced slowly so that at the end their full histology and function of the muscle can be recovered. However, in many cases, there is an abnormal process where the myofibers are not replaced completely or they are defective and there is a connective tissue invasion of the muscle that leads to what is called lypo-fibrotic degeneration. So what happens is that there are a series of fat-containing cells that infiltrate the tissue as well as an excessive deposit of protein that is the most important in the body-it is named collagen. But when it is excessive, then it gets disorganized and what happens is that the tissue would become rigid, would lose the function, and in this case muscle contraction; so this has to be avoided.

Our hypothesis is that by using muscle-derived stem cells together with a biological approach based on the inhibition of a protein that is called myostatin and that inhibits the muscle mass, we can then get a better replenishment of the myofibers and avoid fibrosis because myostatin is not only an inhibitor of muscle mass, but also is a profibrotic element.

The importance of this project is that it's not restricted only to muscle injury in soldiers, but it may apply also to genetically inherited diseases in general in young people that are called muscle dystrophies. We use a mouse model which is called the MDX mouse. That replicates one of these muscle dystrophies, Duchenne muscular dystrophy, so we try to isolate first the muscle-derived stem cells from the MDX mouse from the wild-type mouse that is a normal mouse which is a control and from what is called a myostatin knockout mouse because it's a hyper-muscular mouse. We study these cells in vitro and try to see what are their similarities and their differences in order to then be able by modulating myostatin to try to get the more effective treatment when we put in in vivo cells. But the second part is to take the muscle-derived stem cells from the myostatin knockout mouse and then compare the healing or muscle regeneration efficacy of these cells with the normal muscle-derived stem cells. And we also try to block in the mouse the production of myostatin. This is essentially what we are doing and so far this is a work in progress in terms of the experiments that we have conducted in culture. We have reached several conclusions; perhaps the most important one is that counterintuitively the muscle-derived stem cells obtained from this big mouse that lacks myostatin cannot form myofibers. So this is very intriguing; we are trying to find out why this happens. We are doing a series of quantitations and we'll complete that with measuring muscle function as well and then we will be able to answer this fundamental question.