{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T21:56:29Z","timestamp":1788299789049,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOV-408234"],"award-info":[{"award-number":["MOV-408234"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Peripheral nerve injury denervates muscle, resulting in muscle paralysis and atrophy. This is reversible if timely muscle reinnervation occurs. With delayed reinnervation, the muscle\u2019s reparative ability declines, and muscle-resident fibro-adipogenic progenitor cells (FAPs) proliferate and differentiate, inducing fibro-fatty muscle degradation and thereby physical disability. The mechanisms by which the peripheral nerve regulates FAPs expansion and differentiation are incompletely understood. Using the rat tibial neve transection model, we demonstrated an increased FAPs content and a changing FAPs phenotype, with an increased capacity for adipocyte and fibroblast differentiation, in gastrocnemius muscle post-denervation. The FAPs response was inhibited by immediate tibial nerve repair with muscle reinnervation via neuromuscular junctions (NMJs) and sensory organs (e.g., muscle spindles) or the sensory protection of muscle (where a pure sensory nerve is sutured to the distal tibial nerve stump) with reinnervation by muscle spindles alone. We found that both procedures reduced denervation-mediated increases in glial-cell-line-derived neurotrophic factor (GDNF) in muscle and that GDNF promoted FAPs adipogenic and fibrogenic differentiation in vitro. These results suggest that the peripheral nerve controls FAPs recruitment and differentiation via the modulation of muscle GDNF expression through NMJs and muscle spindles. GDNF can serve as a therapeutic target in the management of denervation-induced muscle injury.<\/jats:p>","DOI":"10.3390\/ijms25031847","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T05:22:44Z","timestamp":1707110564000},"page":"1847","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Utilization of the Rat Tibial Nerve Transection Model to Evaluate Cellular and Molecular Mechanisms Underpinning Denervation-Mediated Muscle Injury"],"prefix":"10.3390","volume":"25","author":[{"given":"Christina","family":"Doherty","sequence":"first","affiliation":[{"name":"Keenan Research Center for Biomedical Science, St. Michael\u2019s Hospital, Unity Health Toronto, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Lodyga","sequence":"additional","affiliation":[{"name":"Keenan Research Center for Biomedical Science, St. Michael\u2019s Hospital, Unity Health Toronto, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6380-6856","authenticated-orcid":false,"given":"Judy","family":"Correa","sequence":"additional","affiliation":[{"name":"Keenan Research Center for Biomedical Science, St. Michael\u2019s Hospital, Unity Health Toronto, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Di Ciano-Oliveira","sequence":"additional","affiliation":[{"name":"Keenan Research Center for Biomedical Science, St. Michael\u2019s Hospital, Unity Health Toronto, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J.","family":"Plant","sequence":"additional","affiliation":[{"name":"Keenan Research Center for Biomedical Science, St. Michael\u2019s Hospital, Unity Health Toronto, Toronto, ON M5B 1T8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1367-348X","authenticated-orcid":false,"given":"James R.","family":"Bain","sequence":"additional","affiliation":[{"name":"Division of Plastic Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Batt","sequence":"additional","affiliation":[{"name":"Keenan Research Center for Biomedical Science, St. Michael\u2019s Hospital, Unity Health Toronto, Toronto, ON M5B 1T8, Canada"},{"name":"Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bergmeister, K.D., Gro\u00dfe-Hartlage, L., Daeschler, S.C., Rhodius, P., Bocker, A., Beyersdorff, M., Kern, A.O., Kneser, U., and Harhaus, L. 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