<i>β</i>-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

刘薇; 何君; 侯玲; 王涛; 季方

doi:10.11665/j.issn.1000-5048.20220510

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

刘薇¹,
何君¹,
侯玲¹,
王涛²,
季方¹

1.
南京市职业病防治院药剂科，南京 210042
2.
中国药科大学药物科学研究院新药筛选中心，南京 210009

基金项目: 南京市卫生科技发展资助项目（No.YKK21188）

计量
- 文章访问数: 194
- HTML全文浏览量: 7
- PDF下载量: 387
出版历程
- 收稿日期: 2022-04-02
- 修回日期: 2022-06-26
- 刊出日期: 2022-10-24

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

1.
Department of Pharmaceutics, Nanjing Prevention and Treatment Center for Occupational Diseases, Nanjing 210042
2.
Center for New Drug Screening, Institute of Pharmaceutical Research, China Pharmaceutical University, Nanjing 210009, China

Funds: This study was supported by the Project of Nanjing Health Science and Technology Development (No.YKK21188)

摘要

摘要: 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、PaO₂和SaO₂均显著降低，而PaCO₂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。
- β-烟酰胺单核苷酸 /
- 尘肺 /
- 呼吸肌疲劳 /
- 线粒体
Abstract: To explore the effect of β-nicotinamide mononucleotide (NMN) on respiratory muscle function and its mitochondrial related mechanism, the rat model of chronic pneumoconiosis was established by intratracheal injection 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 pneumoconiosis 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, PaO₂ and SaO₂, and significantly increased PaCO₂ (P < 0.01).NMN could significantly improve the respiratory function and increase the blood oxygen saturation of the model rats.It could significantly enhance the contractile function and ATP content of diaphragm and improve muscle fatigue (P < 0.05, P < 0.01).In model rats,the mitochondrial 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 oxidative 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 mitochondria 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.
- β-nicotinamide mononucleotide /
- pneumoconiosis /
- respiratory muscle fatigue /
- mitochondrion

HTML全文

参考文献(23)

[1]	.J Environ Occup Med（环境与职业医学），2018，35（8）：677-689.
[2]	Yan P，Ye LB，Chen WQ. Progress in therapeutic targets and development of drugs against chronic obstructive pulmonary disease［J］. J China Pharm Univ（中国药科大学学报），2021，52（2）：144-155.
[3]	Langer D，Charususin N，Jácome C，et al. Efficacy of a novel method for inspiratory muscle training in people with chronic obstructive pulmonary disease［J］. Phys Ther，2015，95（9）：1264-1273.
[4]	Yin PY，Chen FQ. Research progress of TCM treatment of ventilator fatigue in acute phase of chronic obstructive pulmonary disease［J］. Mod J Integr Tradit Chin West Med（现代中西医结合杂志），2021，30（35）：3987-3990.
[5]	Romani M，Sorrentino V，Oh CM，et al. NADPLA⁺ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle［J］. Cell Rep，2021，34（3）：108660.
[6]	She J，Sheng R，Qin ZH. Pharmacology and potential implications of nicotinamide adenine dinucleotide precursors［J］. Aging Dis，2021，12（8）：1879-1897.
[7]	Liu W，Jiang SF，Tu L，et al. Mechanism of JinShuiBao capsule in ameliorating rat pneumoconiosis model［J］. J China Pharm Univ（中国药科大学学报），2018，49（4）：476-482.
[8]	Jiao GY，Li CF，Tan ST，et al. Effect of end-expiratory positive pressure on contractile function and ultrastructure of diaphragm［J］. Med J Chin PLA（解放军医学杂志），2008，33（6）：676-679.
[9]	Wang J，Jiang SF，Hu WY，et al. Pharmacodynamic study on Jinshuibao Capsules on rat pneumoconiosis model［J］. Occup Health（职业与健康），2018，34（13）：1772-1776.
[10]	Uddin GM，Youngson NA，Sinclair DA，et al. Head to head comparison of short-term treatment with the NAD（+） precursor nicotinamide mononucleotide （NMN） and 6 weeks of exercise in obese female mice［J］. Front Pharmacol，2016，7：258.
[11]	Hu T，Zhou XY，Xue D，et al. Protective effect of modified sijunzi decoction against diaphragmatic mitochondria injury of mice with chronic obstructive pulmonary disease［J］. J Guangzhou Univ Tradit Chin Med（广州中医药大学学报），2020，37（3）：523-527.
[12]	Ye B，Li FX. Clinical studies on the functions of mitochondrial function of intercostal muscles in patients with chronic obstruction pulmonary disease［J］. Chin J Lung Dis Electron Ed（中华肺部疾病杂志电子版），2018，11（5）：544-550.
[13]	Puente-Maestu L，Pérez-Parra J，Godoy R，et al. Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients［J］. Eur Respir J，2009，33（5）：1045-1052.
[14]	Davila A，Liu L，Chellappa K，et al. Nicotinamide adenine dinucleotide is transported into mammalian mitochondria［J］. eLife，2018，7：e33246.
[15]	Fletcher RS，Ratajczak J，Doig CL，et al. Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells［J］. Mol Metab，2017，6（8）：819-832.
[16]	Xue CL，Zhuge YL，Zeng JX. Improved effect of curcumin on mitochondrial dysfunction induced by high glucose in L6 cells［J］. J China Pharm Univ（中国药科大学学报），2016，47（3）：342-347.
[17]	Taylor DF，Bishop DJ. Transcription factor movement and exercise-induced mitochondrial biogenesis in human skeletal muscle：current knowledge and future perspectives［J］. Int J Mol Sci，2022，23（3）：1517.
[18]	Sligar J，DeBruin DA，Saner NJ，et al. The importance of mitochondrial quality control for maintaining skeletal muscle function across health span［J］. Am J Physiol Cell Physiol，2022，322（3）：C461-C467.
[19]	Huang RX，Tao J. Nicotinamide mononucleotide attenuates glucocorticoid-induced osteogenic inhibition by regulating the SIRT1/PGC-1α signaling pathway［J］. Mol Med Rep，2020，22（1）：145-154.
[20]	Rajabi M，Vafaee MS，Hosseini L，et al. Pretreatment with nicotinamide mononucleotide increases the effect of ischaemic postconditioning on cardioprotection and mitochondrial function following ex vivo myocardial reperfusion injury in aged rats［J］. Clin Exp Pharmacol Physiol，2022，49（4）：474-482.
[21]	Parry HA，Roberts MD，Kavazis AN. Human skeletal muscle mitochondrial adaptations following resistance exercise training［J］. Int J Sports Med，2020，41（6）：349-359.
[22]	Philp AM，Saner NJ，Lazarou M，et al. The influence of aerobic exercise on mitochondrial quality control in skeletal muscle［J］. J Physiol，2021，599（14）：3463-3476.
[23]	Wahwah N，Kras KA，Roust LR，et al. Subpopulation-specific differences in skeletal muscle mitochondria in humans with obesity：insights from studies employing acute nutritional and exercise stimuli［J］. Am J Physiol Endocrinol Metab，2020，318（4）：E538-E553.