Oxidative stress causes muscle structural alterations via p38 MAPK signaling in COPD mouse model
Oxidative stress causes muscle structural alterations via p38 MAPK signaling in COPD mouse model
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DOI：
10.1007/s00774-022-01371-1
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发表时间：
2022-09
影响因子：
3.3
通讯作者：
Y. Mano;Manabu Tsukamoto;Ke-Yong Wang;Takayuki Nabeshima;Kenji Kosugi;Takafumi Tajima;Y. Yamanaka;Hitoshi Suzuki;M. Kawasaki;Eiichiro Nakamura;Qian Zhou;K. Azuma;T. Nakashima;Yuki Tamura;K. Kozaki;K. Nakazato;Yun-Shan Li;K. Kawai;K. Yatera;A. Sakai
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文献类型：
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作者：
Y. Mano;Manabu Tsukamoto;Ke-Yong Wang;Takayuki Nabeshima;Kenji Kosugi;Takafumi Tajima;Y. Yamanaka;Hitoshi Suzuki;M. Kawasaki;Eiichiro Nakamura;Qian Zhou;K. Azuma;T. Nakashima;Yuki Tamura;K. Kozaki;K. Nakazato;Yun-Shan Li;K. Kawai;K. Yatera;A. Sakai
肌肉减少症是慢性阻塞性肺疾病（COPD）的一种并发症，对体力活动和生活质量产生负面影响。然而，COPD影响骨骼肌的潜在机制仍有待阐明。因此，我们研究了弹性蛋白酶诱导的肺气肿mouse models.Materials和methods 10周龄雄性C57 BL/6 J小鼠的肌肉中的氧化应激和结构改变之间的关联进行治疗，无论是intraperitoneal猪胰弹性蛋白酶（PPE）溶解在盐水中，或盐水单独。给药12周后处死小鼠，取肺和肢体肌肉进行氧化应激、p38丝裂原活化蛋白激酶（p38 MAPK）信号通路和与氧化应激相关的肌肉萎缩信号通路的蛋白质分析。此外，C57 BL/6 J小鼠PPE或生理盐水治疗的影响进行了分析，口服给药的虾青素或p38 inhibitors.ResultsThe比目鱼肌的重量，I型肌纤维的比例，和肌纤维的横截面积在PPE组低于那些在对照组。PPE组骨骼肌中的氧化应激标志物水平升高。p38 MAPK信号通路在比目鱼肌中被激活，导致泛素-蛋白酶体系统的激活和自噬。虾青素和p38抑制剂减弱肌肉结构的改变，通过失活的p38 MAPK信号通路。ConclusionsThis研究提供了第一个证据，在COPD小鼠模型，氧化应激引发一系列肌肉结构的变化。我们的发现为COPD患者的肌肉减少症提供了一个新的治疗靶点。
IntroductionSarcopenia is a complication of Chronic Obstructive Pulmonary Disease (COPD) that negatively affects physical activity and quality of life. However, the underlying mechanism by which COPD affects skeletal muscles remains to be elucidated. Therefore, we investigated the association between oxidative stress and structural alterations in muscles in elastase-induced emphysema mouse models.Materials and methodsTwelve-week-old male C57BL/6J mice were treated with either intratracheal porcine pancreatic elastase (PPE) dissolved in saline, or saline alone. The mice were euthanized 12 weeks after treatment, and the lungs and limb muscles were used for protein analysis of oxidative stress, p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and muscle atrophy signaling pathway related with oxidative stress. Furthermore, C57BL/6J mice treated with PPE or saline were analyzed for the effects of oral administration of astaxanthin or p38 inhibitor.ResultsThe weight of the soleus muscle, proportion of type I muscle fibers, and cross-sectional areas of muscle fibers in the PPE group were lower than those in the control group. Oxidative stress marker levels in the PPE group were elevated in skeletal muscles. The p38 MAPK signaling pathway was activated in the soleus muscles, leading to the activation of the ubiquitin–proteasome system and autophagy. Astaxanthin and p38 inhibitors attenuated alterations in muscle structure through the deactivation of the p38 MAPK signaling pathway.ConclusionsThis study provides first evidence in COPD mouse model that oxidative stress trigger a series of muscle structural changes. Our findings suggest a novel target for sarcopenia in COPD.