Grant: Pro. Gr. - PA: Inst. of Musculoskeletal Health and Arthritis: IMHA Mandate Areas

Skeletal muscle needs to be connected to peripheral nerves to stay healthy and contract to move limbs. If you cut a peripheral nerve the muscle is immediately paralyzed and begins to degrade. Peripheral nerves can regrow. If the nerve grows back to muscle quickly, the muscle can self-repair. However, muscles ability to self-repair is time limited and if the nerve is not reconnected to muscle soon enough the muscle dies. It is replaced by scar tissue and fat that can't contract, leaving the injured limb unable to move. These injuries happen in heavy industry and farming, sporting and motor vehicle accidents, leaving people with new found physical disability that compromises quality of life, and imparts significant costs to society because of increased use of health resources and lost productivity as people may not be able to continue to work. Fibroadipogenic progenitors (FAPs) are the cells in muscle that are responsible for laying down scar tissue and fat in long-term denervated muscle, destroying the muscle. How the cutting of a nerve to a muscle causes FAPs to cause irreversible muscle scarring is not well understood, and because of this there are no treatments to keep long term denervated muscle healthy until the nerve regrows and reconnects to the muscle. We used a rat model of nerve damage, that cuts a nerve in their hind limb, to determine how the FAPs are regulated by nerve injury. The rat model mimics human perfectly and causes little to no discomfort to the animal. In studies to date, we have found two factors called GDNF and PGE2 that appear to be critical regulators of FAPs. In this project we will determine exactly how GDNF and PGE control FAPs and use our rat model of nerve injury to test both GDNF and PGE2 to see if manipulating the 2 factors separately, or together, are able to keep denervated muscle intact, healthy and ready to receive the nerve when it grows back, ending physical disability from trauma.