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SIRT1/SIRT3信号轴基因表达的影响

2014-09-24李方晖肖琳覃飞刘承宜

体育学刊 2014年4期
关键词:运动训练骨骼肌

李方晖+肖琳+覃飞+刘承宜

摘要:观察8周中等强度低负荷量训练对老龄雌性大鼠腓肠肌Bax和Bcl-2蛋白水平及去乙酰化酶1(SIRT1)/去乙酰化酶3(SIRT3)轴基因信使核糖核酸(mRNA)表达的影响。16只18月龄雌性SD大鼠随机分为对照组和运动组(各8只)。运动组在跑台上以15 km/h(60%~75%VO2max)进行有氧运动,15 min/d,5 d/周,持续运动8周;对照组自由生活。第8周末运动后24 h宰杀并测定腓肠肌指数、蛋白免疫印迹法测定腓肠肌Bax和Bcl-2蛋白水平;逆转录聚合酶链式反应(RT-PCR)测定SIRT3、SIRT1、锰超氧化物歧化酶(MnSOD)、半胱氨酸蛋白酶-3(Caspase-3)、过氧化物酶体增殖活化受体γ辅助活化因子-1α(PGC-1α)、线粒体转录因子A(TFAM)和核呼吸因子1(NRF1) mRNA水平。结果显示,运动组腓肠肌质量(P<0.05)和腓肠肌指数均显著增加(P<0.01)、Bax蛋白水平显著降低(P<0.05),Bcl-2蛋白水平和Bcl-2/Bax值显著增加(P<0.05);运动组SIRT3、SIRT1、PGC-1α、NRF1、TFAM、MnSOD mRNA水平显著增加(P<0.05),Caspase-3 mRNA水平显著降低(P<0.05)。结果表明:中等强度低负荷训练可延缓老龄雌性大鼠肌细胞凋亡信号的改变;SIRT1/SIRT3轴介导的内稳态机制在中等强度低负荷训练提升老龄大鼠骨骼肌线粒体更新速率及抗氧化酶水平起重要作用。

关键词:运动生物化学;运动训练;骨骼肌;第三类去乙酰化酶;内稳态;老龄大鼠

中图分类号:G804.7文献标志码:A文章编号:1006-7116(2014)04-0140-05

Effects of 8-week medium intensity low load training on proteins Bax and Bcl-2 and the gene expression of signal axis SIRT1/SIRT3 of skeletal muscle of

aged female rats

LI Fang-hui1,XIAO Lin1,QING Fei2,LIU Cheng-yi2

(1.School of Physical Education and Health,Zhaoqing University,Zhaoqing 526061,China;

2.Laboratory of Laser Sports Medicine,South China Normal University,Guangzhou 510006,China)

Abstract: In order to observe the effects of 8-week medium intensity low load training on the levels of proteins Bax and Bcl-2 and the gene messenger RNA (mRNA) expression of axis sirtuin 1 (SIRT1)/sirtuin 3 (SIRT3) of gastrocnemius of aged rats, the authors divided 16 18-month old female SD rats randomly into a control group and an exercise group, each of which contained 8 rats, let the rats in the exercise group do an aerobic exercise on a treadmill for consecutive 8 weeks, at a speed of 15 km/h (with 60%~75%VO2max), 15 minutes a day, 5 days a week, let the rats in the control group live freely, in 24 hours after rat exercising at the end of week 8, killed the rats, measured gastrocnemius index, measured the levels of proteins Bax and Bcl-2 of gastrocnemius by means of Western blot analysis, measured the mRNA levels of SIRT3, SIRT1, manganese superoxide dismutase (MnSOD), Caspase 3, peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1α), mitochondrial transcription factor A (TFAM) and nuclear respiratory factor 1 (NRF1) by means of RT-PCR, and revealed the following findings: as for the rats in the exercise group, their gastrocnemius mass and gastrocnemius index increased significantly (P<0.05 and P<0.01 respectively), their protein Bax level decreased significantly (P<0.05), their protein Bcl-2 level and Bcl-2/Bax ratio increased significantly (P<0.05); their mRNA levels of SIRT3, SIRT1, PGC-1α, NRF1, TFAM and MnSOD increased significantly (P<0.05), their mRNA level of Caspase-3 decreased significantly (P<0.05). The said findings indicated the followings: medium intensity low load training could delay the changing of muscle cell apoptosis signal of aged rats; the homeostatic mechanism mediated by axis SIRT1/SIRT3 played an important role in medium intensity low load training increasing the mitochondria refreshing rate and antioxidase level of skeletal muscle of aged rats.

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Key words: sports biochemistry;sports training;skeletal muscle;type 3 sirtuins;homeostasis;aged rat

肌肉衰减综合症(Sarcopenia)作为一种以骨骼肌质量和肌力衰减为主要特征的增龄性机能退化征,长期以来为人们所忽视[1]。Sarcopenia引发的骨质减少、运动平衡能力下降将增加肢体残疾、心血管病变、心理疾病等发生几率[2]。流行病学调查显示,近13%的60岁以上的老年人受Sarcopenia困扰,该比例在80岁以上老人高达50%[3]。肌细胞凋亡被认为在Sarcopenia发展进程中起关键作用[1,4]。弱化肌细胞凋亡信号、阻止肌细胞大范围地进入凋亡程序是延缓Sarcopenia发生重要机制[4]。文献报道,体力活动不足是Sarcopenia诱因之一,而运动能延缓骨骼肌衰老[5],这与体育活动能抑制衰老骨骼肌凋亡有关[6]。Song等[6]研究发现,中等强度大负荷量运动后老龄大鼠腓肠肌凋亡显著减少。Pasini等[7]研究也发现,8周大强度运动使18月龄大鼠Sarcopenia得到明显改善,而这与线粒体细胞色素C氧化酶活性增加有关。漆正堂等[1]研究同样证实,8周耐力运动可通过调控线粒体功能来拮抗Sarcopenia肌细胞凋亡。最新研究发现,中等强度低负荷量训练(Low-loads Medium-intensity Exercise,LME)可用于Sarcopenia的防护[5],但缺乏深入的机理研究。

III型组蛋白去乙酰化酶家族(Sirtuins,SIRTs)是乙酰胺腺嘌呤二核苷酸(Nicotimide Adenosine Dinucleotide+,NAD+)依赖的去乙酰化酶。SIRTs包括7个成员。其中,尽管SIRT1和SIRT3分别位于细胞核和线粒体中,但在调控线粒体功能中具有协同作用[8]。Brenmoehl等[9]将之称为SIRT1/SIRT3双重调控轴。本研究在观察8周LME对18月龄雌性大鼠骨骼肌凋亡相关因子表达影响的基础上,探讨SIRT1/SIRT3轴对肌细胞凋亡的调控机制,为体育运动防护Sarcopenia提供理论依据。

1实验对象与方法

1.1实验动物分组、运动方案及取材

16只18月龄雌性SD大鼠购于广州中医药大学动物中心,体质量为(378±11) g。在室温20~24 ℃、光照时间07:00~19:00,分笼饲养,适应性喂养1周后,随机分为对照组和运动组(各8只)。负荷强度参照Bejma等[10]18月龄大鼠训练负荷进行。运动组进行为期8周、速度15 m/min、坡度5°,每天15 min跑台运动。负荷强度对18月龄大鼠来说相当于60% ~75%VO2max[10]。8周最后一次运动后24 h后将大鼠麻醉处死取材,取大鼠后肢腓肠肌,腓肠肌指数的计算:腓肠肌指数=[腓肠肌质量(mg)/体质量(g)][7]。

1.2信使核糖核酸测定

每组取6个样本。加入1 mL的Trizol进行总RNA提取。按试剂说明书操作步骤提取细胞总RNA并进行逆转录反应和PCR反应。试剂购于大连宝生物公司。去乙酰化酶3(Sirtuin 3,SIRT3)、去乙酰化酶1(Sirtuin1,SIRT1)、锰超氧化物歧化酶(Manganese Superoxide Dismutase,MnSOD)、半胱氨酸蛋白酶-3(Caspase-3)、过氧化物酶体增殖活化受体γ辅助活化因子1α (Peroxisome Proliferator-activated Receptor-γ Coactivator-1,PGC-1α)、线粒体转录因子A(Mitochondrial Transcription Factor A,TFAM)和核呼吸因子(Nuclear Respiratory Factor 1,NRF1)扩增引物见文献[11]。β-actin作为内参,并根据公式2-△△Ct计算目的基因的相对表达量。

1.3蛋白免疫印迹

蛋白提取与浓度测定后离心5 min转至-80 ℃保存备用。Bax、Bcl-2分离胶浓度为8%。丽春红预染后,用1%TBST配置5%的脱脂牛奶对NC膜封闭2 h。分别用5%脱脂牛奶和5% BSA配置Bax和Bcl-2的一抗4 ℃摇床过夜。内参为GAPDH。目的条带的二抗均孵育2 h,洗膜后X射线胶片曝光显影。详细操作见文献[6]。

1.4数据处理及分析

所有实验数据均以“均值±标准差”( ±s)表示,统计分析用SPSS17.0软件完成,组间比较采用独立样本T检验,P<0.05表示统计具有显著性意义。蛋白免疫印迹使用Image-ProPlus6.0进行灰度分析。

2结果及分析

2.1运动大鼠腓肠肌指数的改变

表1显示,8周后,与对照组比较,运动组腓肠肌质量平均增加30.0%(P<0.05),腓肠肌指数增加37.5%(P<0.01),但体质量没有显著性差异(P>0.05)。

表1大鼠体质量、腓肠肌质量及腓肠肌指数( ±s)

组别 n/只 体质量/g 腓肠肌

质量/g 腓肠肌

指数/%

对照组

运动组 8

8 378.8±65.7

378.0±27.6 0.61±0.16

0.79±0.131) 1.6±0.20

2.2±0.112)

1)与对照组比较,P<0.05;2)与对照组比较,P<0.01

2.2运动大鼠腓肠肌Bax、Bcl-2蛋白水平及Bcl-2/

Bax值的改变

鉴于图1显示的GAPDH在对照组和运动组蛋白表达相对恒定,故本研究以GAPDH作为Bax和Bcl-2蛋白表达的内部参照,即对照组和运动组Bax和Bcl-2蛋白表达的灰度值分别与该组的GAPDH蛋白灰度值进行校正,将校正后的Bax和Bcl-2以及Bcl-2/Bax值分别进行比较,进而反映两组间的蛋白表达变化。图1、表2结果显示,与对照组相比,运动组腓肠肌Bax蛋白减少了12.2%(P<0.05),Bcl-2蛋白水平增加12.1%(P<0.05),Bcl-2/Bax值增加28.0%(P<0.05)。

图1大鼠腓肠肌中Bax、Bcl-2蛋白表达的免疫印迹图

表2大鼠骨骼肌Bax、Bcl-2蛋白表达及

Bcl-2/Bax值( ±s)变化

组别 n/只 Bax/灰度值 Bcl-2/灰度值 Bcl-2/Bax比值/%

对照组

运动组 8

8 0.056 0±0.006

0.049 2±0.0011) 0.600±0.160

0.670±0.0301) 10.70±0.20

13.70±0.511)

1)与对照组比较,P<0.05

2.3运动大鼠腓肠肌SIRT1/SIRT3信号轴基因mRNA的表达改变

表3结果显示,与对照组比较,运动组SIRT3、SIRT1、PGC-1α、NRF1、TFAM、MnSOD mRNA水平分别增加了150%、140%、104%、380%、160%、97%,Caspase-3 mRNA减少了50%,差异有显著性意义(P<0.05)。

表3各组大鼠骨骼肌SIRT1/SIRT3轴基因mRNA表达变化( ±s)

组别 n/只 SIRT3 SIRT1 PGC-1α NRF1 TFAM MnSOD Caspase-3

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对照组

运动组 8

8 1.00±0.00

2.50±0.241) 1.00±0.00

2.41±0.631) 1.00±0.00

2.04±0.111) 1.00±0.00

4.80±0.401) 1.00±0.00

2.60±0.131) 1.00±0.00

1.97±0.41) 1.00±0.00

0.5±0.061)

1)与对照组比较,P<0.05

3讨论

3.18周中等强度低负荷量训练对大鼠腓肠肌质量和凋亡相关因子表达的影响

蛋白质合成减少和分解增加导致的肌肉质量下降是Sarcopenia发生机制之一。力量训练能增加肌肉蛋白质合成,从而延缓老年人肌肉质量和肌力下降[12]。但也有研究认为,耐力运动能减损力量训练积累起来的肌肉质量[12]。这也使得人们对耐力运动可否用于防治Sarcopenia仍存在争议。Pasini等[7]研究发现,8周中等强度大负荷量耐力运动可将18月龄雄性大鼠股四头肌质量增加近38%。本研究结果显示,8周中等负荷低强度训练后大鼠的腓肠肌重量增加约30.0%,腓肠肌指数增加37.5%。值得指出的是,18月龄雌性大鼠到20月龄时腓肠肌质量减少11.2%[6]。提示中等负荷低强度训练不仅延缓Sarcopenia骨骼肌丢失,甚至进一步增加老龄大鼠腓肠肌质量。然而,Andersen等[13]将18月龄雌性大鼠分为运动前、9周低强度大负荷量跑台运动组及20月龄安静对照组。结果却发现,与安静组相比,18月龄雌性大鼠经过9周运动后腓肠肌质量虽有显著增加,但仍明显低于运动前。这一结果说明运动强度是体育运动对抗Sarcopenia肌肉质量丢失的关键参数。

肌细胞凋亡被认为在Sarcopenia病理进程起关键作用[4]。Bcl-2是参与调控线粒体凋亡途径的凋亡抑制蛋白,而Bax是促凋亡蛋白。值得指出的是,当Bcl-2/Bax值增大,细胞更趋向于存活;Bcl-2/Bax值减小细胞则趋向于凋亡[6]。图1和表2显示,运动组Bcl-2蛋白表达增加20%,Bax蛋白表达减少10%,Bcl-2/Bax值增加33.3%,Caspase-3 mRNA表达减少50%。Song等[6]研究也证实,与27月龄雌性安静大鼠相比,12周中等强度大负荷量运动后的同龄大鼠腓肠肌Bcl-2蛋白表达及Bcl-2/Bax值显著增加、Bax和Caspase-3蛋白表达则显著减少。本实验与Song等[6]采用的运动强度一致,而本研究采用低负荷量,说明负荷量是对抗Sarcopenia的非必需参数,这与上述运动强度抗肌肉质量丢失相似。

3.2去乙酰化酶介导中等强度低负荷量训练的内稳态康复作用

功能内稳态(Function-Specific Homeostasis,FSH)是维持功能充分稳定发挥的负反馈机制[14]。SIRTs具有抗衰老效应[14]。研究表明,SIRTs是FSH最贴切标示物,存在FSH特异的SIRTs活性(FSH-Specific SIRT Activities,FASAs)[14]。Baker等[15]研究表明,体育运动可促进远离FSH的功能恢复。Costford等[16]研究发现,与健康者相比,老龄2型糖尿病患者骨骼肌代谢失调与SIRTs活性低于FASAs有关,而运动训练能将患者骨骼肌SIRTs活性康复至FASAs,提示体育运动可通过调节SIRT1维持骨骼肌FSH。

然而,骨骼肌远离FSH将导致细胞凋亡,诱发Sarcopenia[4]。肌细胞凋亡与SIRT1和SIRT3活性低于FASAs有关[17]。本研究结果显示,中等强度低负荷训练可显著增加老龄大鼠腓肠肌SIRT3和SIRT1 mRNA表达。Kang等[18]对22月龄大鼠进行12周中等强度跑台运动干预后也发现,运动后大鼠骨骼肌SIRT1蛋白表达显著高于安静组。Lanza等[19]对59~76岁健康受试者进行为期4年、每周6 d、每天不少于1 h的中等强度耐力运动后发现,骨骼肌SIRT3蛋白表达增加,甚至高于青年人,提示中等强度低负荷训练使衰老骨骼肌SIRT3和SIRT1表达水平康复到FASAs,后者可提高凋亡阈值、抑制肌细胞凋亡。由此可见,中等强度运动是促进肌细胞SIRT3和SIRT1基因表达的必需参数。此外,研究表明,力竭运动和高强度间歇训练均能促进老年人骨骼肌SIRT1和SIRT3表达[20],提示体育运动刺激SIRT1和SIRT3表达与运动方式和运动强度有关[14,21]。

3.3SIRT1/SIRT3轴双重调控线粒体更新和抗氧化酶的表达

线粒体功能充分稳定发挥由线粒体内稳态(Mitochondrial Function-Specific Homeostasis,MTH)维持。维持MTH需要高水平的线粒体更新速率保证线粒体新老更替。体力活动缺乏的老年人骨骼肌代谢紊乱与线粒体远离MTH密切相关[22]。SIRT1/SIRT3轴在维持MTH过程中具有协同效应[23]。研究表明,SIRT1/SIRT3轴可双重调控线粒体代谢酶的活性[8]。Cantó等[11]研究证实,SIRTs催化底物NAD﹢能激活SIRT1/SIRT3轴,进而更有效地维持衰老小鼠骨骼肌MTH。然而,SIRT1/SIRT3轴任一个基因敲除都会导致线粒体更新受阻[24]。

线粒体更新主要由PGC-1α介导。PGC-1α是SIRT1/SIRT3轴下游的调控因子[25]。衰老导致PGC-1α活性下调将导致肌细胞远离MTH[26]。PGC-1α活性下调与SIRT1和SIRT3水平低于FASAs有关[23]。PGC-1α可调控下游基因表达促进线粒体生物合成,如NRF1和TFAM。NRF1进一步上调TFAM基因表达,而TFAM促进mtDNA复制[27]。本研究结果显示,LME显著性增加老龄大鼠腓肠肌PGC-1α、TFAM、NRF1 mRNA水平,提示LME通过上调SIRT1/SIRT3轴调控PGC-1α表达,后者促进TFAM与NRF1表达,最终维持衰老骨骼肌MTH。

MnSOD位于线粒体内,是维持MTH抗氧化酶之一[26]。研究发现,MnSOD表达减少会导致肌细胞远离MTH[27]。MnSOD也是PGC-1α下游靶基因[28]。因此,衰老MnSOD表达减少也可能与SIRT1/SIRT3轴对PGC-1α调控缺失有关[29]。本研究结果显示,中等强度低负荷训练使衰老腓肠肌MnSOD、PGC-1α、SIRT1和SIRT3 mRNA表达增加,提示中等强度低负荷训练可通过SIRT1/SIRT3轴双重调控PGC-1α来促进MnSOD表达,实现对衰老骨骼肌MTH康复,后者将有利于阻止肌细胞进入线粒体依赖的凋亡程序。

8周中等强度低负荷量训练增加老龄雌性大鼠腓肠肌的Bcl-2蛋白水平和Bcl-2/Bax比值、抑制Bax蛋白和Caspase-3 mRNA表达,提示8周中等强度低负荷量训练可抑制老龄大鼠骨骼肌细胞凋亡、减少Sarcopenia肌肉质量丢失、延缓骨骼肌衰老;SIRT1/SIRT3轴介导中等强度低负荷量训练有利于对老龄大鼠腓肠肌内稳态的维持。

参考文献:

[1] 漆正堂,贺杰,张媛,等. 65%~75%最大强度的耐力运动对老龄小鼠骨骼肌线粒体氧化应激与膜电位的影响[J]. 体育科学,2010,30(10):46-51.

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[21] 王海涛. 运动对骨骼肌线粒体去乙酰化酶3(SIRT3)的影响[J]. 体育科学,2011,31(1):85-88.

[22] Safdar A,Hamadeh M J,Kaczor J J,et al. Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults[J]. PLoS One,2010,5(5):e10778.

[23] Nogueiras R,Habegger K M,Chaudhary N,et al. Sirtuin 1 and sirtuin 3:physiological modulators of metabolism[J]. Physiol Rev,2012,92(3):1479-1514.

[24] Palacios O M,Carmona J J,Michan S,et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle[J]. Aging (Albany NY),2009,1(9):771-783.

[25] Nemoto S. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1(alpha)[J]. J Biol Chem,2005,280(16):16456-16460.

[26] Li L,Mühlfeld C. Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise:differential response in cardiac and skeletal muscle[J]. Basic Res Cardiol,2011,106(6):1221-1234.

[27] Ji L L. Modulation of skeletal muscle antioxidant defense by exercise: Role of redox signaling[J]. Free Radic Biol Med,2008,44(2):142-152.

[28] Olmos Y,Valle I,Borniquel S,et al. Mutual dependence of Foxo3a and PGC-1alpha in the induction of oxidative stress genes[J]. J Biol Chem,2009,284(21):14476-14484.

[29] Zhang Y,Ikeno Y,Qi W,et al. Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity[J]. J Gerontol A Biol Sci Med Sci,2009,64(12):1212-1220.

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[21] 王海涛. 运动对骨骼肌线粒体去乙酰化酶3(SIRT3)的影响[J]. 体育科学,2011,31(1):85-88.

[22] Safdar A,Hamadeh M J,Kaczor J J,et al. Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults[J]. PLoS One,2010,5(5):e10778.

[23] Nogueiras R,Habegger K M,Chaudhary N,et al. Sirtuin 1 and sirtuin 3:physiological modulators of metabolism[J]. Physiol Rev,2012,92(3):1479-1514.

[24] Palacios O M,Carmona J J,Michan S,et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle[J]. Aging (Albany NY),2009,1(9):771-783.

[25] Nemoto S. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1(alpha)[J]. J Biol Chem,2005,280(16):16456-16460.

[26] Li L,Mühlfeld C. Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise:differential response in cardiac and skeletal muscle[J]. Basic Res Cardiol,2011,106(6):1221-1234.

[27] Ji L L. Modulation of skeletal muscle antioxidant defense by exercise: Role of redox signaling[J]. Free Radic Biol Med,2008,44(2):142-152.

[28] Olmos Y,Valle I,Borniquel S,et al. Mutual dependence of Foxo3a and PGC-1alpha in the induction of oxidative stress genes[J]. J Biol Chem,2009,284(21):14476-14484.

[29] Zhang Y,Ikeno Y,Qi W,et al. Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity[J]. J Gerontol A Biol Sci Med Sci,2009,64(12):1212-1220.

endprint

[21] 王海涛. 运动对骨骼肌线粒体去乙酰化酶3(SIRT3)的影响[J]. 体育科学,2011,31(1):85-88.

[22] Safdar A,Hamadeh M J,Kaczor J J,et al. Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults[J]. PLoS One,2010,5(5):e10778.

[23] Nogueiras R,Habegger K M,Chaudhary N,et al. Sirtuin 1 and sirtuin 3:physiological modulators of metabolism[J]. Physiol Rev,2012,92(3):1479-1514.

[24] Palacios O M,Carmona J J,Michan S,et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle[J]. Aging (Albany NY),2009,1(9):771-783.

[25] Nemoto S. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1(alpha)[J]. J Biol Chem,2005,280(16):16456-16460.

[26] Li L,Mühlfeld C. Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise:differential response in cardiac and skeletal muscle[J]. Basic Res Cardiol,2011,106(6):1221-1234.

[27] Ji L L. Modulation of skeletal muscle antioxidant defense by exercise: Role of redox signaling[J]. Free Radic Biol Med,2008,44(2):142-152.

[28] Olmos Y,Valle I,Borniquel S,et al. Mutual dependence of Foxo3a and PGC-1alpha in the induction of oxidative stress genes[J]. J Biol Chem,2009,284(21):14476-14484.

[29] Zhang Y,Ikeno Y,Qi W,et al. Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity[J]. J Gerontol A Biol Sci Med Sci,2009,64(12):1212-1220.

endprint

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