N-acetylcysteine attenuates oxidative-stress-associated apoptosis and collagen deposition after rat hindlimb ischemia-reperfusion injury
- 1Department of Orthopedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
Abstract
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 (H2O2), a reactive oxygen species (ROS), to an in vitro 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 H2O2 significantly increased expression of Cellular Communication Network Factor 2 (CCN2), which induces fibrosis, while co-addition of NAC with H2O2 significantly suppressed CCN2 induction. Our findings shed light on mechanisms underlying I/R injury in limbs and suggest countermeasures.
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BibTeX
@article{matsunaga2026nacetylcysteine,
title = {{N-acetylcysteine attenuates oxidative-stress-associated apoptosis and collagen deposition after rat hindlimb ischemia-reperfusion injury}},
author = {Hideto Matsunaga and Ryuji Yonemitsu and Katsumasa Ideo and Junnosuke Ide and Masaki Shimada and Makoto Tateyama and Xiao Tian and Shu Takata and Kosei Takata and Shuntaro Tanimura and Yuto Shibata and Naoto Yoshimura and Kazuya Maeda and Junki Kawakami and Takahiro Arima and Yuki Kai and Soichiro Karata and Hikaru Goshogawa and Satoshi Hisanaga and Kazuki Sugimoto and Hironori Tanoue and Masaki Yugami and Takayuki Nakamura and Yusuke Uehara and Tetsuro Masuda and Takuya Tokunaga and Tatsuki Karasugi and Takeshi Miyamoto},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0357829},
url = {https://doi.org/10.1371/journal.pone.0357829},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - N-acetylcysteine attenuates oxidative-stress-associated apoptosis and collagen deposition after rat hindlimb ischemia-reperfusion injury
AU - Hideto Matsunaga
AU - Ryuji Yonemitsu
AU - Katsumasa Ideo
AU - Junnosuke Ide
AU - Masaki Shimada
AU - Makoto Tateyama
AU - Xiao Tian
AU - Shu Takata
AU - Kosei Takata
AU - Shuntaro Tanimura
AU - Yuto Shibata
AU - Naoto Yoshimura
AU - Kazuya Maeda
AU - Junki Kawakami
AU - Takahiro Arima
AU - Yuki Kai
AU - Soichiro Karata
AU - Hikaru Goshogawa
AU - Satoshi Hisanaga
AU - Kazuki Sugimoto
AU - Hironori Tanoue
AU - Masaki Yugami
AU - Takayuki Nakamura
AU - Yusuke Uehara
AU - Tetsuro Masuda
AU - Takuya Tokunaga
AU - Tatsuki Karasugi
AU - Takeshi Miyamoto
PY - 2026
DA - 2026/09/10
JO - PLOS One
DO - 10.1371/journal.pone.0357829
UR - https://doi.org/10.1371/journal.pone.0357829
AB - 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 (H2O2), a reactive oxygen species (ROS), to an in vitro 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 H2O2 significantly increased expression of Cellular Communication Network Factor 2 (CCN2), which induces fibrosis, while co-addition of NAC with H2O2 significantly suppressed CCN2 induction. Our findings shed light on mechanisms underlying I/R injury in limbs and suggest countermeasures.
SN - 1932-6203
ER -