{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T18:07:08Z","timestamp":1789063628109,"version":"build-2803163510"},"reference-count":63,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP256f0137011"],"award-info":[{"award-number":["JP256f0137011"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Proper use of fingers and limbs is crucial for people to carry out normal activities of daily living. Therefore, when fingers or limbs are severed accidentally, replantation is attempted whenever possible. However, even when replantation is successful and fingers or limbs are preserved, functional limitations often arise due to contractures in reattached fingers or limbs, although mechanisms underlying contractures or countermeasures to ameliorate them are not well understood. Here, using a rat femoral artery ischemia-reperfusion (I\/R) model, we show that oxidative stress caused by accumulation of oxidative DNA damage occurs in gastrocnemius and soleus muscles after I\/R induces muscle cell apoptosis. Moreover, we demonstrate that administration of the antioxidant N-acetyl cysteine (NAC) significantly suppresses oxidative stress accumulation and apoptosis induction in both muscles. We observed that collagen fibers accumulate in the gastrocnemius and soleus muscles after I\/R in our model, and that collagen fiber accumulation was significantly suppressed by NAC administration. We demonstrate that adding hydrogen peroxide (H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ), a reactive oxygen species (ROS), to an\n                    <jats:italic>in vitro<\/jats:italic>\n                    C2C12 myoblast culture system significantly increased expression of the apoptosis-inducing factors Bcl-2-associated X protein (BAX) and Caspase 3, while co-treatment with NAC significantly counteracted this increase and increased expression of the anti-apoptotic factor B-cell lymphoma 2 (Bcl2). Also using the C2C12 myoblast culture system, we show that H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    significantly increased expression of Cellular Communication Network Factor 2 (CCN2), which induces fibrosis, while co-addition of NAC with H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    significantly suppressed CCN2 induction. Our findings shed light on mechanisms underlying I\/R injury in limbs and suggest countermeasures.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0357829","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T17:23:35Z","timestamp":1789061015000},"page":"e0357829","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["N-acetylcysteine attenuates oxidative-stress-associated apoptosis and collagen deposition after rat hindlimb ischemia-reperfusion injury"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7133-7691","authenticated-orcid":true,"given":"Hideto","family":"Matsunaga","sequence":"first","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuji","family":"Yonemitsu","sequence":"additional","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0460-2087","authenticated-orcid":true,"given":"Katsumasa","family":"Ideo","sequence":"additional","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junnosuke","family":"Ide","sequence":"additional","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life 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Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Hisanaga","sequence":"additional","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Tanoue","sequence":"additional","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life 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Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Tokunaga","sequence":"additional","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuki","family":"Karasugi","sequence":"additional","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8658-9546","authenticated-orcid":true,"given":"Takeshi","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Kumamoto University","place":["Kumamoto, Japan"],"department":["Department of Orthopedic Surgery, Faculty of Life 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de Oliveira","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"pone.0357829.ref029","doi-asserted-by":"crossref","first-page":"217","DOI":"10.3109\/2000656X.2012.709726","article-title":"Effect of prolonged ischaemic time on muscular atrophy and regenerating nerve fibres in transplantation of the rat hind limb","volume":"46","author":"N Tsuji","year":"2012","journal-title":"J Plast Surg Hand Surg"},{"issue":"1","key":"pone.0357829.ref030","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1002\/micr.1920120105","article-title":"Improved survival in a replantation model containing ischemic muscle","volume":"12","author":"MJ Concannon","year":"1991","journal-title":"Microsurgery"},{"key":"pone.0357829.ref031","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/978-4-431-67865-6_6","article-title":"Limb Replantation in the Rat.","volume-title":"Experimental and Clinical Reconstructive Microsurgery","author":"A Minami","year":"2003"},{"issue":"3","key":"pone.0357829.ref032","doi-asserted-by":"crossref","DOI":"10.1177\/2309499019874470","article-title":"Inhibitory effect of edaravone on systemic inflammation and local damage in skeletal muscles following long-term ischemia to murine hind limb","volume":"27","author":"H Yokoyama","year":"2019","journal-title":"J Orthop Surg (Hong Kong)"},{"key":"pone.0357829.ref033","doi-asserted-by":"crossref","first-page":"453748","DOI":"10.1155\/2015\/453748","article-title":"The effect of iloprost and N-acetylcysteine on skeletal muscle injury in an acute aortic ischemia-reperfusion model: an experimental study","volume":"2015","author":"O Tiryakioglu","year":"2015","journal-title":"Biomed Res Int"},{"issue":"5","key":"pone.0357829.ref034","first-page":"2255","article-title":"Quantitative photoacoustic imaging for early detection of muscle ischemia injury","volume":"9","author":"L Chen","year":"2017","journal-title":"Am J Transl 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Today"},{"issue":"9","key":"pone.0357829.ref038","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.3390\/biomedicines12092079","article-title":"Comparison of different animal models in hindlimb functional recovery after acute limb ischemia-reperfusion injury","volume":"12","author":"NN Zheleznova","year":"2024","journal-title":"Biomedicines"},{"key":"pone.0357829.ref039","doi-asserted-by":"crossref","first-page":"116544","DOI":"10.1016\/j.lfs.2019.116544","article-title":"N-acetyl-l-cysteine exacerbates kidney dysfunction caused by a chronic high-sodium diet in renal ischemia and reperfusion rats","volume":"231","author":"CM Rom\u00e3o","year":"2019","journal-title":"Life Sci"},{"issue":"3","key":"pone.0357829.ref040","doi-asserted-by":"crossref","first-page":"359","DOI":"10.3109\/17453679408995472","article-title":"Upper limb replantation. 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