Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury
Abstract Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact 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 peri...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-10-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53276-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850204254912905216 |
|---|---|
| author | Pihu Mehrotra James Jablonski John Toftegaard Yali Zhang Shahryar Shahini Jianmin Wang Carey W. Hung Reilly Ellis Gabriella Kayal Nika Rajabian Song Liu Kelly C. S. Roballo Susan B. Udin Stelios T. Andreadis Kirkwood E. Personius |
| author_facet | Pihu Mehrotra James Jablonski John Toftegaard Yali Zhang Shahryar Shahini Jianmin Wang Carey W. Hung Reilly Ellis Gabriella Kayal Nika Rajabian Song Liu Kelly C. S. Roballo Susan B. Udin Stelios T. Andreadis Kirkwood E. Personius |
| author_sort | Pihu Mehrotra |
| collection | DOAJ |
| description | Abstract Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact 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 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. |
| format | Article |
| id | doaj-art-b6d34f0cfb5e4f448addffc2432a0236 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b6d34f0cfb5e4f448addffc2432a02362025-08-20T02:11:18ZengNature PortfolioNature Communications2041-17232024-10-0115111910.1038/s41467-024-53276-4Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injuryPihu Mehrotra0James Jablonski1John Toftegaard2Yali Zhang3Shahryar Shahini4Jianmin Wang5Carey W. Hung6Reilly Ellis7Gabriella Kayal8Nika Rajabian9Song Liu10Kelly C. S. Roballo11Susan B. Udin12Stelios T. Andreadis13Kirkwood E. Personius14Department of Chemical and Biological Engineering, University at BuffaloDepartment of Department of Rehabilitation Science, University at BuffaloDepartment of Biomedical Engineering, University at Buffalo, NYDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDepartment of Chemical and Biological Engineering, University at BuffaloDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterBiomedical Affairs and Research, Edward Via College of Osteopathic MedicineBiomedical Affairs and Research, Edward Via College of Osteopathic MedicineBiomedical Affairs and Research, Edward Via College of Osteopathic MedicineDepartment of Chemical and Biological Engineering, University at BuffaloDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterBiomedical Affairs and Research, Edward Via College of Osteopathic MedicineDepartment of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at BuffaloDepartment of Chemical and Biological Engineering, University at BuffaloDepartment of Department of Rehabilitation Science, University at BuffaloAbstract Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact 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 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.https://doi.org/10.1038/s41467-024-53276-4 |
| spellingShingle | Pihu Mehrotra James Jablonski John Toftegaard Yali Zhang Shahryar Shahini Jianmin Wang Carey W. Hung Reilly Ellis Gabriella Kayal Nika Rajabian Song Liu Kelly C. S. Roballo Susan B. Udin Stelios T. Andreadis Kirkwood E. Personius Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury Nature Communications |
| title | Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury |
| title_full | Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury |
| title_fullStr | Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury |
| title_full_unstemmed | Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury |
| title_short | Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury |
| title_sort | skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury |
| url | https://doi.org/10.1038/s41467-024-53276-4 |
| work_keys_str_mv | AT pihumehrotra skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT jamesjablonski skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT johntoftegaard skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT yalizhang skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT shahryarshahini skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT jianminwang skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT careywhung skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT reillyellis skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT gabriellakayal skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT nikarajabian skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT songliu skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT kellycsroballo skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT susanbudin skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT steliostandreadis skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury AT kirkwoodepersonius skeletalmusclereprogrammingenhancesreinnervationafterperipheralnerveinjury |