Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury.
Animals
Peripheral Nerve Injuries
/ metabolism
Muscle, Skeletal
/ innervation
Mice
Neuromuscular Junction
/ metabolism
Nanog Homeobox Protein
/ metabolism
Nerve Regeneration
/ physiology
Cellular Reprogramming
/ genetics
Receptors, Cholinergic
/ metabolism
Disease Models, Animal
Sciatic Nerve
/ injuries
Muscle Development
/ genetics
Mice, Inbred C57BL
Male
Female
PAX7 Transcription Factor
/ metabolism
Neurogenesis
/ genetics
Synaptic Vesicles
/ metabolism
Mice, Transgenic
Doxycycline
/ pharmacology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 Oct 2024
25 Oct 2024
Historique:
received:
17
11
2023
accepted:
03
10
2024
medline:
26
10
2024
pubmed:
26
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39455585
doi: 10.1038/s41467-024-53276-4
pii: 10.1038/s41467-024-53276-4
doi:
Substances chimiques
Nanog Homeobox Protein
0
Nanog protein, mouse
0
Receptors, Cholinergic
0
PAX7 Transcription Factor
0
Doxycycline
N12000U13O
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9218Subventions
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : R01AG068250
Informations de copyright
© 2024. The Author(s).
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