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Considering the accumulating evidence on the similarity of some beneficial effects, irisin can be a proposed effector of exercise; however, the mechanism underlying these effects remains largely unknown. More evidence on the mechanism of action might reveal its potential as a treatment strategy to substitute exercise recovery protocols for nerve injuries in physically disabled patients. To evaluate the underlying mechanism of irisin involvement in nerve adaptation and exerting beneficial effects, we studied the proteome profile alteration of mouse sciatic nerve after irisin administration. We also compared it with two 8\u2010week protocols of resistance exercise and endurance exercise. The results indicate that irisin contributes to the regulation of nerve metabolism via overexpression of Ckm and ATP5j2 proteins. Irisin administration may improve sciatic nerve function by maintaining the architecture, enhancing axonal transport, and promoting synapse plasticity through increased structural and regulatory proteins and NO production. We also showed that irisin has the potential to induce neurotrophic support on the sciatic nerve by maintaining cell redox homeostasis, and responses to oxidative stress via the upregulation of disulfide\u2010isomerase and superoxide dismutase enzymes. Comparing with exercise groups, these effects are somewhat exercise\u2010like responses. These data suggest that irisin can be a promising therapeutic candidate for specific targeting of defects in peripheral neuropathies and nerve injuries as an alternative for physical therapy.<\/jats:p>","DOI":"10.1111\/ejn.15202","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T03:48:03Z","timestamp":1616557683000},"page":"3262-3277","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Comparative proteome analyses highlight several exercise\u2010like responses of mouse sciatic nerve after IP injection of irisin"],"prefix":"10.1111","volume":"53","author":[{"given":"Sedigheh","family":"Momenzadeh","sequence":"first","affiliation":[{"name":"Department of Medical Biotechnology School of Advanced Technologies Shahrekord University of Medical Sciences Shahrekord Iran"},{"name":"Cellular and Molecular Research Center Basic Health Sciences Institute Shahrekord University of Medical 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