{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T14:50:13Z","timestamp":1780325413419,"version":"3.54.1"},"reference-count":39,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T00:00:00Z","timestamp":1640304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague\u2013Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed.<\/jats:p>","DOI":"10.3390\/ijms23010169","type":"journal-article","created":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T08:38:46Z","timestamp":1640335126000},"page":"169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction"],"prefix":"10.3390","volume":"23","author":[{"given":"Lisa A.","family":"Walter","sequence":"first","affiliation":[{"name":"Department of Kinesiology, St. Ambrose University, Davenport, IA 52803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren P.","family":"Blake","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, St. Ambrose University, Davenport, IA 52803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4447-1448","authenticated-orcid":false,"given":"Yann S.","family":"Gallot","sequence":"additional","affiliation":[{"name":"LBEPS, Univ Evry, IRBA, Universit\u00e9 Paris Saclay, 91025 Evry, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles J.","family":"Arends","sequence":"additional","affiliation":[{"name":"Palmer Center for Chiropractic Research, Palmer College of Chiropractic, Davenport, IA 52803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9935-4292","authenticated-orcid":false,"given":"Randall S.","family":"Sozio","sequence":"additional","affiliation":[{"name":"Palmer Center for Chiropractic Research, Palmer College of Chiropractic, Davenport, IA 52803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M.","family":"Onifer","sequence":"additional","affiliation":[{"name":"Palmer Center for Chiropractic Research, Palmer College of Chiropractic, Davenport, IA 52803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle R.","family":"Bohnert","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, St. Ambrose University, Davenport, IA 52803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R892","DOI":"10.1016\/S0960-9822(07)00554-4","article-title":"Muscle development: Electrical control of gene expression","volume":"8","author":"Hughes","year":"1998","journal-title":"Curr. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1152\/jappl.2001.90.3.1119","article-title":"Historical Perspectives: Plasticity of mammalian skeletal muscle","volume":"90","author":"Pette","year":"2001","journal-title":"J. Appl. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.4081\/bam.2014.1.5","article-title":"The Biology of Long-Term Denervated Skeletal Muscle","volume":"24","author":"Carlson","year":"2014","journal-title":"Eur. J. Transl. Myol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jpeds.2012.05.067","article-title":"Pathophysiological insights derived by natural history and motor function of spinal muscular atrophy","volume":"162","author":"Farrar","year":"2013","journal-title":"J. Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1093\/brain\/118.3.707","article-title":"Natural history of amyotrophic lateral sclerosis in a database population Validation of a scoring system and a model for survival prediction","volume":"118","author":"Haverkamp","year":"1995","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1378\/chest.103.2.508","article-title":"Pulmonary function at diagnosis of amyotrophic lateral sclerosis. Rate of deterioration","volume":"103","author":"Schiffman","year":"1993","journal-title":"Chest"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S245","DOI":"10.1542\/peds.2008-2952K","article-title":"Special considerations in the respiratory management of spinal muscular atrophy","volume":"123","author":"Schroth","year":"2009","journal-title":"Pediatrics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nrm3270","article-title":"The unfolded protein response: Controlling cell fate decisions under ER stress and beyond","volume":"13","author":"Hetz","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/nrd2755","article-title":"Cell death and endoplasmic reticulum stress: Disease relevance and therapeutic opportunities","volume":"7","author":"Kim","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_10","first-page":"293","article-title":"The cellular response to protein misfolding in the endoplasmic reticulum","volume":"7","author":"Welihinda","year":"2018","journal-title":"Gene Expr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15388","DOI":"10.1128\/JVI.79.24.15388-15397.2005","article-title":"Production of infectious human cytomegalovirus virions is inhibited by drugs that disrupt calcium homeostasis in the endoplasmic reticulum","volume":"79","author":"Isler","year":"2005","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1158\/1535-7163.MCT-06-0629","article-title":"Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2,5-dimethyl-celecoxib, a non-coxib analogue of celecoxib","volume":"6","author":"Pyrko","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1084\/jem.81.3.233","article-title":"A study of tissue culture cells by electron microscopy: Methods and preliminary observations","volume":"81","author":"Porter","year":"1945","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1085\/jgp.201711889","article-title":"The relationship between form and function throughout the history of excitation\u2013contraction coupling","volume":"150","year":"2018","journal-title":"J. Gen. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/jcp.25852","article-title":"Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease","volume":"233","author":"Bohnert","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, K., and Kaufman, R. (2006). Protein folding in the endoplasmic reticulum and the unfolded protein response. Handbook of Experimental Pharmacology, Springer.","DOI":"10.1007\/3-540-29717-0_3"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nrc3800","article-title":"The impact of the endoplasmic reticulum protein-folding environment on cancer development","volume":"14","author":"Wang","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/sj.cdd.4401840","article-title":"From acute ER stress to physiological roles of the Unfolded Protein Response","volume":"13","author":"Wu","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/16729","article-title":"Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase","volume":"397","author":"Harding","year":"1999","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/S0022-2836(02)00234-6","article-title":"Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response","volume":"318","author":"Ma","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nrm2199","article-title":"Signal integration in the endoplasmic reticulum unfolded protein response","volume":"8","author":"Ron","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.tem.2012.06.003","article-title":"New insights into ER stress-induced insulin resistance","volume":"23","author":"Flamment","year":"2012","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1101\/gad.12.12.1812","article-title":"A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase\/endoribonuclease (Ire1p) in mammalian cells","volume":"12","author":"Tirasophon","year":"1998","journal-title":"Genes Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3787","DOI":"10.1091\/mbc.10.11.3787","article-title":"Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress","volume":"10","author":"Haze","year":"1999","journal-title":"Mol. Biol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yu, Z., Wang, A.M., Adachi, H., Katsuno, M., Sobue, G., Yue, Z., Robins, D.M., and Lieberman, A.P. (2011). Macroautophagy is regulated by the UPR\u2013mediator CHOP and accentuates the phenotype of SBMA mice. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002321"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1096\/fj.201600250RR","article-title":"Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia","volume":"30","author":"Bohnert","year":"2016","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e00184-19","DOI":"10.1128\/MCB.00184-19","article-title":"The Toll-Like Receptor\/MyD88\/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia","volume":"39","author":"Bohnert","year":"2019","journal-title":"Mol. Cell. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1096\/fj.201800683RR","article-title":"PERK regulates skeletal muscle mass and contractile function in adult mice","volume":"33","author":"Gallot","year":"2019","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e21821","DOI":"10.1096\/fj.202100777RR","article-title":"MyD88-mediated signaling intercedes in neurogenic muscle atrophy through multiple mechanisms","volume":"35","author":"Parveen","year":"2021","journal-title":"FASEB J."},{"key":"ref_30","first-page":"170","article-title":"Activation of the endoplasmic reticulum stress response in skeletal muscle of G93A*SOD1 amyotrophic lateral sclerosis mice","volume":"9","author":"Echen","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gallot, Y., and Bohnert, K. (2021). Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052567"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1101\/gad.1830709","article-title":"XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy","volume":"23","author":"Hetz","year":"2009","journal-title":"Genes Dev."},{"key":"ref_33","first-page":"E907","article-title":"Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4","volume":"305","author":"Bongers","year":"2013","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1097\/01.mlg.0000177076.33294.89","article-title":"Effects of denervation on neuromuscular junctions in the thyroarytenoid muscle","volume":"115","author":"Kumai","year":"2005","journal-title":"Laryngoscope"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.orthres.2004.08.027","article-title":"Gene expression of nAChR, SNAP-25 and GAP-43 in skeletal muscles following botulinum toxin A injection: A study in rats","volume":"23","author":"Ma","year":"2005","journal-title":"J. Orthop. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4499","DOI":"10.1113\/JP271212","article-title":"The ageing neuromuscular system and sarcopenia: A mitochondrial perspective","volume":"594","author":"Rygiel","year":"2016","journal-title":"J. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1097\/WNR.0000000000000949","article-title":"Spinal manipulative therapy reduces peripheral neuropathic pain in the rat","volume":"29","author":"Onifer","year":"2018","journal-title":"Neuroreport"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.jneumeth.2012.05.013","article-title":"Cutaneous and electrically evoked glutamate signaling in the adult rat somatosensory system","volume":"208","author":"Onifer","year":"2012","journal-title":"J Neurosci Methods."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.neuropharm.2013.01.020","article-title":"PPAR\u03b3 activation blocks development and reduces established neuropathic pain in rats","volume":"70","author":"Morgenweck","year":"2013","journal-title":"Neuropharmacology"}],"updated-by":[{"DOI":"10.3390\/ijms27114768","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T00:00:00Z","timestamp":1640304000000}}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/169\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T16:14:16Z","timestamp":1779898456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,24]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23010169"],"URL":"https:\/\/doi.org\/10.3390\/ijms23010169","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,24]]}}}