Journal Article

Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury

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

2024

Overview

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. Peripheral nerves slowly regrow after injury, but often fail to form functional synapses. Here, authors use NANOG, a pluripotency factor, to induce denervated muscle to a pro-regenerative state improving muscle reinnervation after nerve transection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/107 / 13/51 / 14/19 / 14/63 / 38/90 / 631/443/7 / 64/60 / 692/308/575 / 692/617/375/430 / Animals / Antibiotics / Atrophy / Cellular Reprogramming - genetics / Degeneration / Denervation / Disease Models, Animal / Doxycycline / Doxycycline - pharmacology / Embryogenesis / Female / Genes / Humanities and Social Sciences / Injuries / Innervation / Male / Mice / Mice, Inbred C57BL / Mice, Transgenic / multidisciplinary / Muscle contraction / Muscle Development - genetics / Muscle, Skeletal - innervation / Muscle, Skeletal - metabolism / Muscles / Musculoskeletal system / Myogenesis / Nanog Homeobox Protein - genetics / Nanog Homeobox Protein - metabolism / Nerve Regeneration - physiology / Neurogenesis / Neurogenesis - genetics / Neuromuscular Junction - metabolism / Neuromuscular junctions / PAX7 Transcription Factor - genetics / PAX7 Transcription Factor - metabolism / Peripheral Nerve Injuries - genetics / Peripheral Nerve Injuries - metabolism / Peripheral Nerve Injuries - physiopathology / Peripheral nerves / Pluripotency / Quality of life / Receptor mechanisms / Receptors, Cholinergic - genetics / Receptors, Cholinergic - metabolism / Regeneration / Reinnervation / Sciatic nerve / Sciatic Nerve - injuries / Science / Science (multidisciplinary) / Skeletal muscle / Synapses / Synaptic vesicles / Synaptic Vesicles - metabolism / Synaptogenesis