二甲双胍缓解小鼠肌肉衰老的代谢组学研究

田嵩浩, 赵慧婷, 杨小峰, 蒋丛林, 冯微, 姜玉锁

中国药学杂志 ›› 2023, Vol. 58 ›› Issue (13) : 1178-1185.

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中国药学杂志
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中国药学杂志 ›› 2023, Vol. 58 ›› Issue (13) : 1178-1185. DOI: 10.11669/cpj.2023.13.003
论著

二甲双胍缓解小鼠肌肉衰老的代谢组学研究

  • 田嵩浩1,2, 赵慧婷3, 杨小峰4, 蒋丛林1, 冯微1, 姜玉锁1*
作者信息 +

A Metabolomic Study of Metformin in Alleviating Muscle Aging in Mice

  • TIAN Song-hao1,2, ZHAO Hui-ting3, YANG Xiao-feng4, JIANG Cong-lin1, FENG Wei1, JIANG Yu-suo1*
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摘要

目的 探究二甲双胍缓解小鼠肌肉衰老的机制。方法 2月龄雄性BALB/c 小鼠随机分成对照组、衰老模型组和二甲双胍组,每组10只。用125 mg·kg-1 D-半乳糖(D-galactose,D-gal)皮下注射8周诱导衰老小鼠模型。比色法测定小鼠血清和肌肉上清中过氧化氢酶(catalase,CAT)、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)、总超氧化物歧化酶(superoxide dismutase,SOD)和丙二醛(malondialdehyde,MDA)的含量。高效液相色谱串联电喷雾质谱(LC-ESI-MS/MS)广靶代谢组学方法研究二甲双胍对衰老小鼠腓肠肌代谢物的影响。结果 二甲双胍对衰老小鼠的体质量和采食量没有影响。四肢悬垂试验显示二甲双胍显著增加了衰老小鼠肌肉力量(P<0.01)。二甲双胍显著增加了血清和肌肉上清中的SOD和GSH-Px水平(P<0.01),显著降低了血清和肌肉上清中的MDA含量(P<0.01)。通过代谢组学测定发现,衰老小鼠腓肠肌中5种差异代谢物丙氨酸-异亮氨酸(Ala-Ile)、异亮氨酸-谷氨酸(Ile-Glu)、亮氨酸-脯氨酸-酪氨酸(Leu-Pro-Tyr)、吡啶-3,4-二羧酸(pyridine-3,4-dicarboxylic acid)和15(R)-前列腺素E1[15(R)-prostaglandin E1]在二甲双胍的作用下恢复到与对照组相同的水平。结论 二甲双胍可能通过调节肌肉小肽和前列腺素水平、发挥抗氧化和抗炎特性缓解小鼠肌肉衰老。

Abstract

OBJECTIVE To investigate the mechanism of metformin to alleviate muscle aging in mice. METHODS Two-month-old male BALB/c mice were randomly divided into control group, senescence model group and metformin group, with 10 mice in each group. The aging mouse model was induced by subcutaneous injection of 125 mg·kg-1 D-galactose (D-gal) for 8 weeks. The levels of CAT, GSH-Px, SOD and MDA in serum and muscle supernatant were measured colorimetrically. LC-ESI-MS/MS broad-target metabolomics was used to study the effects of metformin on metabolites in the gastrocnemius muscle of aging mice. RESULTS Metformin had no effect on body weight and food intake of aging mice. The limb draping test showed that metformin significantly increased muscle strength in aging mice (P<0.01). Metformin significantly increased SOD and GSH-Px levels in serum and muscle supernatants (P<0.01) and significantly decreased MDA levels in serum and muscle supernatants (P<0.01). Five differential metabolites, Ala-Ile, Ile-Glu and Leu-Pro-Tyr, pyridine-3,4-dicarboxylic acid and 15(R)-prostaglandin E1 were found to be restored to the same levels as controls in the gastrocnemius muscle of aging mice by metabolomic analysis. CONCLUSION Metformin may alleviate muscle aging in mice by modulating muscle small peptide and prostaglandin levels and exerting antioxidant and anti-inflammatory properties.

关键词

代谢组学 / 二甲双胍 / 衰老 / 肌肉 / 差异代谢物

Key words

metabolomics / metformin / aging / muscle / differential metabolite

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田嵩浩, 赵慧婷, 杨小峰, 蒋丛林, 冯微, 姜玉锁. 二甲双胍缓解小鼠肌肉衰老的代谢组学研究[J]. 中国药学杂志, 2023, 58(13): 1178-1185 https://doi.org/10.11669/cpj.2023.13.003
TIAN Song-hao, ZHAO Hui-ting, YANG Xiao-feng, JIANG Cong-lin, FENG Wei, JIANG Yu-suo. A Metabolomic Study of Metformin in Alleviating Muscle Aging in Mice[J]. Chinese Pharmaceutical Journal, 2023, 58(13): 1178-1185 https://doi.org/10.11669/cpj.2023.13.003
中图分类号： R966   

参考文献

[1] FAN J, KOU X, JIA S, et al. Autophagy as a potential target for sarcopenia [J]. J Cell Physiol, 2016, 231(7): 1450-1459.
[2] LARSSON L, DEGENS H, LI M, et al. Sarcopenia: aging-related loss of muscle mass and function [J]. Physiol Rev, 2019, 99(1): 427-511.
[3] WALTZ T B, FIVENSON E M, MOREVATI M, et al. Sarcopenia, aging and prospective interventional strategies [J]. Curr Med Chem, 2018, 25(40): 5588-5596.
[4] AZMAN K F, ZAKARIA R. D-Galactose-induced accelerated aging model: an overview [J]. Biogerontology, 2019, 20(6): 763-782.
[5] ULLAH F, ALI T, ULLAH N, et al. Caffeine prevents D-galactose-induced cognitive deficits, oxidative stress, neuroinflammation and neurodegeneration in the adult rat brain [J]. Neurochem Int, 2015, 90(11):114-124.
[6] NI Y, WU T, YANG L, et al. Protective effects of astaxanthin on a combination of D-galactose and jet lag-induced aging model in mice [J]. Endocr J, 2018, 65(5): 569-578.
[7] KOU X, LI J, LIU X, et al. Ampelopsin attenuates the atrophy of skeletal muscle from d-gal-induced aging rats through activating AMPK/SIRT1/PGC-1α signaling cascade [J]. Biomed Pharmacother, 2017, 90(6):311-320.
[8] YANG Y F, YANG W, LIAO Z Y, et al. MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging [J]. Cell Death Dis, 2021, 12(12): 1-13.
[9] FATEMI I, KHALUOI A, KAEIDI A, et al. Protective effect of metformin on D-galactose-induced aging model in mice [J]. Iran J Basic Med Sci, 2018, 21(1): 19-25.
[10] BARZILAI N, CRANDALL J P, KRITCHEVSKY S B, et al. Metformin as a tool to target aging [J]. Cell Metab, 2016, 23(6): 1060-1065.
[11] AMIN S N, HUSSEIN U K, YASSA H D, et al. Synergistic actions of vitamin D and metformin on skeletal muscles and insulin resistance of type 2 diabetic rats [J]. J Cell Physiol, 2018, 233(8): 5768-5779.
[12] HASAN M M, SHALABY S M, EL-GENDY J, et al. Beneficial effects of metformin on muscle atrophy induced by obesity in rats [J]. J Cell Biochem, 2019, 120(4): 5677-5686.
[13] YANG Y, LIAO Z, XIAO Q. Metformin ameliorates skeletal muscle atrophy in Grx1 KO mice by regulating intramuscular lipid accumulation and glucose utilization [J]. Biochem Biophys Res Commun, 2020, 533(4): 1226-1232.
[14] YOUSUF Y, DATU A, BARNES B, et al. Metformin alleviates muscle wasting post-thermal injury by increasing Pax7-positive muscle progenitor cells [J]. Stem Cell Res Ther, 2020, 11(1): 1-14.
[15] SENESI P, MONTESANO A, LUZI L, et al. Metformin treatment prevents sedentariness related damages in mice [J]. J Diabetes Res, 2016, 2016: 8274685. Doi: 10.1155/2016/8274689.
[16] JOHNSON C H, IVANISEVIC J, SIUZDAK G. Metabolomics: beyond biomarkers and towards mechanisms [J]. Nat Rev Mol Cell Bio, 2016, 17(7): 451-459.
[17] KIM H W. Metabolomic approaches to investigate the effect of metformin: an overview [J]. Int J Mol Sci, 2021, 22(19): 10275. Doi: https://doi.org/10.3390/ijms221910275.
[18] WEI H, GAO Z, ZHENG L, et al. Protective effects of fucoidan on Aβ25–35 and d-Gal-induced neurotoxicity in PC12 cells and d-Gal-induced cognitive dysfunction in mice [J]. Mar Drugs, 2017, 15(3): 77. Doi: 10.3390/md15030077.
[19] LIU H, ZHANG X, XIAO J, et al. Astaxanthin attenuates D-galactose-induced brain aging in rats by ameliorating oxidative stress, mitochondrial dysfunction, and regulating metabolic markers [J]. Food Funct, 2020, 11(5): 4103-4113.
[20] CHEN L, HUANG S, HUANG K, et al. Lactobacillus paracasei PS23 decelerated age-related muscle loss by ensuring mitochondrial function in SAMP8 mice [J]. Aging (Albany N Y), 2019, 11(2): 756-770.
[21] KANG M J, MOON J W, LEE J O, et al. Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a [J]. J Cachexia Sarcopeni, 2022, 13(1): 605-620.
[22] HAN X, TAO Y L, DENG Y P, et al. Metformin ameliorates insulitis in STZ-induced diabetic mice [J]. Peer J, 2017, 5: e3155. Doi: 10.7717/peerj.3155.
[23] ANISIMOV V N, BERSTEIN L M, EGORMIN P A, et al. Metformin slows down aging and extends life span of female SHR mice [J]. Cell Cycle, 2008, 7(17): 2769-2773.
[24] BOENGLER K, KOSIOL M, MAYR M, et al. Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue [J]. J Cachexia Sarcopenia Muscle, 2017, 8(3): 349-369.
[25] HU D, XIE F, XIAO Y, et al. Metformin: a potential candidate for targeting aging mechanisms [J]. Aging Dis, 2021, 12(2): 480-493.
[26] HERNÁNDEZ-ARCIGA U, HERNÁNDEZ-ÁLVAREZ D, LÓPEZ-CERVANTES S P, et al. Effect of long-term moderate-exercise combined with metformin-treatment on antioxidant enzymes activity and expression in the gastrocnemius of old female Wistar rats [J]. Biogerontology, 2020, 21(6): 787-805.
[27] CHURCHWARD-VENNE T A, BREEN L, PHILLIPS S M. Alterations in human muscle protein metabolism with aging: protein and exercise as countermeasures to offset sarcopenia [J]. Bio Factors, 2014, 40(2): 199-205.
[28] BROOKS E L, MUTENGWA V S, ABDALLA A, et al. Determination of tryptophan metabolism from biological tissues and fluids using high performance liquid chromatography with simultaneous dual electrochemical detection [J]. Analyst, 2019, 144(20): 6011-6018.
[29] WANG D, YANG Y, ZOU X, et al. Antioxidant apigenin relieves age-related muscle atrophy by inhibiting oxidative stress and hyperactive mitophagy and apoptosis in skeletal muscle of mice [J]. J Gerontol A Biol Sci Med Sci, 2020, 75(11): 2081-2088.
[30] LIANG X, YAN Z, MA W, et al. Peroxiredoxin 4 protects against ovarian ageing by ameliorating D-galactose-induced oxidative damage in mice [J]. Cell Death Dis, 2020, 11(12): 1-10.
[31] PRISK V, HUARD J. Muscle injuries and repair: the role of prostaglandins and inflammation [J]. Histol Histopathol, 2003, 18(4): 1243-1256.
[32] KRISTÓFI R, ERIKSSON J W. Metformin as an anti-inflammatory agent: A short review [J]. J Endocrinol, 2021, 251(2): R11-R22.

基金

山西省高等教育振兴计划“1331工程”资助(J201811301)
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