Virginia Research Day 2025

Faculty Research Biomedical

01 NANOG induces skeletal muscle reprogramming and enhances reinnervation after peripheral nerve injury

Pihu Mehrotra; James Jablonski; John Toftegaard; Yali Zhang; Shahryar Shahini; Jianmin Wang; Carey W. Hung; Reilly Ellis; Gabriella Kayal; Nika Rajabian; Song Liu; Susan B. Udin; Stelios T. Andreadis; Kirkwood E. Personius; Kelly C. S. Roballo Corresponding author: kroballo@vcom.edu

Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact the quality of life by causing long-term disability. PNI is characterized by nerve degeneration distal to the site of nerve injury resulting in long periods of skeletal muscle denervation. During this period, muscle fibers atrophy and frequently become incapable of “accepting” innervation because of the slow speed of axon regeneration post-injury. We hypothesize that reprogramming the skeletal muscle to an embryonic like state may preserve its reinnervation capability University at Buffalo Roswell Park Comprehensive Cancer Center Edward Via College of Osteopathic Medicine Virginia-Maryland College of Veterinary Medicine, Virginia Tech Center of Excellence in Bioinformatics and Life Sciences Center for Cell, Gene and Tissue Engineering (CGTE)

following PNI. To this end, we generate a mouse model in which NANOG, a pluripotency-associated transcription factor is expressed locally upon delivery of doxycycline (Dox) in a polymeric vehicle. NANOG expression in the muscle upregulates the percentage of Pax7+ nuclei and expression of eMYHC along with other genes that are involved in muscle development. In a sciatic nerve transection model, NANOG expression leads to upregulation of key genes associated with myogenesis, neurogenesis, and neuromuscular junction (NMJ) formation.

Further, NANOG mice demonstrate extensive overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs) indicating restored innervation. Indeed, NANOG mice show greater improvement in motor function as compared to wild-type (WT) animals, as evidenced by improved toe-spread reflex, EMG responses, and isometric force production. In conclusion, we demonstrate that reprogramming muscle can be an effective strategy to improve reinnervation and functional outcomes after PNI.

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