Gene named for mythical Irish land could aid muscle function after traumatic nerve injuries

BUFFALO, N.Y. — The key to recovering from traumatic nerve injuries, like those sustained in motor vehicle accidents or gunshot wounds, may be a gene named for the land of everlasting youth in Irish folklore.

In a study published Oct. 25 in Nature Communications, a University at Buffalo-led research team describes how the gene, called NANOG, can improve the regrowth of damaged nerves and re-establish innervation (the process of nerves growing and connecting with organs or tissues) after traumatic severing of peripheral nerves.

The gene’s name is derived from Tír na nÓg, which is a mythical land associated with youth, beauty and joy.

“In human biology, NANOG is an incredibly powerful gene that we have previously shown is capable of reversing aging in adult stem cells and skeletal muscle by a process of cellular reprogramming,” says co-corresponding author Stelios Andreadis, PhD, a SUNY Distinguished Professor in the Department of Chemical and Biological Engineering. “Here, we examined whether reprogramming the muscle would make it amenable to accept new nerves as well, since muscle innervates readily during development but not so easily later in life.”

For the study, the researchers generated a mouse model with sciatic nerve damage. They then used a special delivery system – called a polymeric vehicle – to deliver a common antibiotic (doxycycline) directly to the damaged muscle and nerve tissue.

Doxycycline acts as a switch, turning on (also known as expressing) NANOG. Once activated, NANOG increased the number of muscle stem cells (Pax7+) and induced expression of embryonic myosin heavy chain (eMYHC), a key gene that is normally found in skeletal muscle during embryonic development, to be expressed in the adult tissue.

Compared to mice who did not receive doxycycline, the mice with NANOG expression showed an increase in muscle development, nerve development, and the synaptic connections between muscles and nerves. The mice also showed improved motor function as measured by isometric force production, electromyography response and toe-spread reflex.

“Ultimately, we demonstrated that NANOG can reprogram skeletal muscle cells to an embryonic-like state, and repair damaged parts of the neuromuscular system after nerve injury,” says co-corresponding author Kirkwood Personius, PT, PhD, a clinical associate professor in the Department of Rehabilitation Science. “This is significant because it has potential to help mitigate long-term disability for people with debilitating nerve injuries.”

The study was supported by funding from the National Institutes of Health, the State University of New York Research Seed Grant Program, and the UB Clinical and Translational Science Institute. Researchers utilized equipment at the UB Center of Excellence in Bioinformatics and Life Sciences for RNA sequencing.

Study co-authors at UB represent the Center for Cell, Gene and Tissues Engineering; the Department of Biomedical Engineering, which is a program of the School of Engineering and Applied Sciences and the Jacobs School of Medicine and Biomedical Sciences; and the Department of Physiology and Biophysics.

Additional co-authors represent Roswell Park Comprehensive Cancer Center, the Edward Via College of Osteopathic Medicine, and Virginia Tech.