Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury.

Autor: Mehrotra P; Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA., Jablonski J; Department of Department of Rehabilitation Science, University at Buffalo, Buffalo, NY 14214, USA., Toftegard J; Department of Biomedical Engineering, University at Buffalo, NY, Buffalo, NY 14260, USA., Zhang Y; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA., Shahini S; Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA., Wang J; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA., Hung CW; Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA., Ellis R; Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA., Kayal G; Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA., Rajabian N; Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA., Liu S; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA., Roballo K; Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA.; Department of Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA., Udin SB; Department of Physiology and Biophysics, University at Buffalo, Amherst, NY 14203, USA., Andreadis ST; Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA.; Department of Biomedical Engineering, University at Buffalo, NY, Buffalo, NY 14260, USA.; Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA.; Center for Cell, Gene and Tissue Engineering (CGTE), University at Buffalo, Buffalo, NY 14260, USA., Personius KE; Department of Department of Rehabilitation Science, University at Buffalo, Buffalo, NY 14214, USA.; Center for Cell, Gene and Tissue Engineering (CGTE), University at Buffalo, Buffalo, NY 14260, USA.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2024 Jan 05. Date of Electronic Publication: 2024 Jan 05.
DOI: 10.21203/rs.3.rs-3463557/v1
Abstrakt: Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact quality of life by causing long-term disability. The onset of PNI is characterized by nerve degeneration distal to the 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 following PNI. To this end, we generated a mouse model in which NANOG, a pluripotency-associated transcription factor can be expressed locally upon delivery of doxycycline (Dox) in a polymeric vehicle. NANOG expression in the muscle upregulated 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 led to upregulation of key genes associated with myogenesis, neurogenesis and neuromuscular junction (NMJ) formation, and downregulation of key muscle atrophy genes. Further, NANOG mice demonstrated extensive overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs) indicating restored innervation. Indeed, NANOG mice showed 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 the muscle can be an effective strategy to improve reinnervation and functional outcomes after PNI.
Databáze: MEDLINE
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