{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:29:10Z","timestamp":1782865750505,"version":"3.54.5"},"reference-count":46,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,11,29]],"date-time":"2020-11-29T00:00:00Z","timestamp":1606608000000},"content-version":"am","delay-in-days":334,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T00:00:00Z","timestamp":1577750400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["K08NS094547"],"award-info":[{"award-number":["K08NS094547"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005831","name":"Foundation for Anesthesia Education and Research","doi-asserted-by":"publisher","award":["MRTG\u2010BS"],"award-info":[{"award-number":["MRTG\u2010BS"]}],"id":[{"id":"10.13039\/100005831","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS088339"],"award-info":[{"award-number":["R01NS088339"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01RX001222"],"award-info":[{"award-number":["I01RX001222"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Our tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma, including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fibre loss.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Delayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved pain<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Losartan, an angiotensin\u2010receptor blocker with anti\u2010fibrotic abilities, recapitulates the effect of exercise on post\u2010injury recovery and may provide an enhanced recovery option for those who are unable to exercise after injury<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Chronic pain and disability after limb injury are major public health problems. Early mobilization after injury improves functional outcomes for patients, although when and how to implement rehabilitation strategies remains a clinical challenge. Additionally, whether the beneficial effects of exercise can be reproduced using pharmacological tools remains unknown and may benefit patients who are unable to exercise as a result of immobilization. We developed a murine model of orthopaedic trauma combining tibia fracture and pin fixation with muscle damage. Behavioural measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microcomputed tomagraphic scanning, and muscle fibre size distribution and fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fibre size lasting up to 5\u00a0weeks from injury. We also observed that allowing \u2018late\u2019 (weeks 1\u20132) rather than \u2018early\u2019 (weeks 0\u20131) exercise after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was associated with reduced muscle fibrosis, earlier increase in muscle fibre diameter and a short\u2010term benefit in reducing callus volume. Providing the anti\u2010fibrotic angiotensin receptor blocker losartan to mice in drinking water reduced both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes and that losartan is a viable candidate for translational studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp278991","type":"journal-article","created":{"date-parts":[[2019,11,29]],"date-time":"2019-11-29T20:09:53Z","timestamp":1575058193000},"page":"317-329","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Angiotensin receptor blockade mimics the effect of exercise on recovery after orthopaedic trauma by decreasing pain and improving muscle regeneration"],"prefix":"10.1113","volume":"598","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4422-2014","authenticated-orcid":false,"given":"Vivianne L.","family":"Tawfik","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Perioperative and Pain Medicine Stanford University  Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9687-7397","authenticated-orcid":false,"given":"Marco","family":"Quarta","sequence":"additional","affiliation":[{"name":"Department of Neurology Stanford University School of Medicine  Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Paine","sequence":"additional","affiliation":[{"name":"Department of Neurology Stanford University School of Medicine  Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Forman","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Perioperative and Pain Medicine Stanford University  Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka","family":"Pajarinen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Stanford University School of Medicine  Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Takemura","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Perioperative and Pain Medicine Stanford University  Stanford CA USA"},{"name":"Department of Anesthesiology University of Toyama  Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart B.","family":"Goodman","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Stanford University School of Medicine  Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Rando","sequence":"additional","affiliation":[{"name":"Department of Neurology Stanford University School of Medicine  Stanford CA USA"},{"name":"Veterans Affairs Palo Alto Healthcare System  Palo Alto CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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