β-烟酰胺单核苷酸对尘肺大鼠呼吸肌疲劳的改善作用及其线粒体相关机制

Effect ofβ-nicotinamide mononucleotide on respiratory muscle fatigue in pneumoconiosis rats and its mitochondrial mechanism

采用大鼠尘肺模型,探讨β-烟酰胺单核苷酸(NMN)对呼吸肌功能的改善作用及线粒体相关机制。通过气管注射石英粉尘建立大鼠慢性尘肺模型,造模3个月后,治疗组灌胃给予NMN 300,150 mg/kg,给药4周后进行各项指标检测。结果显示,尘肺模型大鼠出现明显的呼吸异常和通气障碍,表现为呼吸频率增加,呼吸幅度下降(P<0.01),血液pH、PaO_(2)和SaO_(2)均显著降低,而PaCO_(2)显著升高(P<0.01),NMN给药可以明显改善模型大鼠的呼吸功能,增加血氧饱和度。NMN可明显增强离体膈肌的收缩功能和ATP含量,改善肌肉疲劳状态(P<0.05,P<0.01)。尘肺大鼠膈肌线粒体膜电位显著降低(P<0.01),琥珀酸脱氢酶(SDH)活力显著下降(P<0.01),同时超氧化物歧化酶(SOD)活力下降、丙二醛(MDA)水平增加(P<0.05),表明膈肌线粒体氧化代谢障碍和氧化应激损害,NMN对这些膈肌线粒体功能相关改变具有明显的改善。NMN可以显著上调尘肺大鼠膈肌Sirt1、Pgc-1α、Nrf1和Tfam等线粒体生物发生相关基因的mRNA水平。结果表明,NMN灌胃给药可以调节尘肺模型大鼠膈肌线粒体功能,改善膈肌能量代谢,增强膈肌收缩功能,进而改善呼吸和通气状态,此作用可能是通过促进膈肌线粒体生物发生而介导的。

To explore the effect ofβ-nicotinamide mononucleotide(NMN)on respiratory muscle function and its mitochondrial related mechanism,the rat model of chronic pneumoconiosis was established by intratracheal injec‐tion of quartz dust.Three months after the model was established,the treatment group was given NMN 300 and 150 mg/kg by gavage.All indexes were detected 4 weeks after administration.The results showed that the pneu‐moconiosis model rats had obvious respiratory abnormalities and ventilation disorders,including the respiratory rate increase,the respiratory amplitude decrease(P<0.01),the significantly decreased blood pH value,PaO_(2)and SaO_(2),and significantly increased PaCO_(2)(P<0.01).NMN could significantly improve the respiratory func‐tion and increase the blood oxygen saturation of the model rats.It could significantly enhance the contractile func‐tion and ATP content of diaphragm and improve muscle fatigue(P<0.05,P<0.01).In model rats,the mitochon‐drial membrane potential of diaphragm and activity of SDH decreased significantly(P<0.01),while the activity of SOD decreased and the level of MDA increased(P<0.05),however,NMN could significantly improve oxida‐tive stress and mitochondrial function of diaphragm.NMN could significantly up-regulate the mRNA levels of mitochondrial biogenesis related genes such as Sirt1,Pgc-1α,Nrf1 and Tfam in the diaphragm.In conclusion,this experiment showed that NMN intragastric administration can regulate the function of diaphragm mitochon‐dria in pneumoconiosis model rats,improve diaphragm energy metabolism,enhance diaphragm contraction function,and then improve the state of respiration and ventilation,which may be mediated by promoting the biogenesis of diaphragm mitochondria.