高强度间歇训练对大鼠骨骼肌细胞自噬的影响及其调节机制
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摘要
目的:探讨10周高强度间歇训练(HIIT)对大鼠骨骼肌细胞自噬的影响及其调节机制。方法:34只8周龄雄性SD大鼠随机分3组:安静对照组(SC,n=10)、中等强度持续训练(MICT,n=12)和HIIT(n=12)组。HIIT组以42m/min×4min和18m/min×5min依次交替进行4轮,MICT组以28m/min速度运动34min;每周5次,共10周。训练结束后次日采用力竭测试测定跑步力竭时间,并在力竭测试前后测定血乳酸浓度;蛋白免疫印迹检测比目鱼肌和股直肌细胞色素C氧化酶亚基IV(COXIV)和琥珀酸脱氢酶(SDH)、自噬相关蛋白(LC3-II、Beclin-1、ATG-3/-5/-7/-12/-16L)及去乙酰化酶3(SIRT3)和乙醛脱氢酶2(ALDH2)蛋白表达;透射电镜(TEM)观察比目鱼肌自噬泡和线粒体的超微结构。结果:与SC组相比,HIIT和MICT组跑步力竭时间明显延长、力竭测试后即刻血乳酸降低(P<0.01);HIIT组跑步力竭时间长于MICT组(P<0.05);HIIT组在力竭测试后10 min血乳酸低于SC组(P<0.05);与SC组相比,HIIT(P<0.01)和MICT(P<0.05)组比目鱼肌和股直肌COXIV、SDH和SIRT3蛋白表达增加;HIIT组比目鱼肌COXIV蛋白表达高于MICT组(P<0.05),HIIT组比目鱼肌LC3-II/LC3-I比值、LC3-II、Beclin-1、ATG-3/-5/-7/-12蛋白表达高于SC(P<0.05);HIIT组股直肌ALDH2(P<0.01)和Beclin-1(P<0.05)、ATG-5/-7(P<0.05)蛋白表达高于SC组;同时,HIIT组股直肌COXIV、ALDH2和SIRT3蛋白表达高于MICT组(P<0.05)。TEM观察到HIIT组大鼠比目鱼肌出现双层膜结构的自噬体,线粒体体积和内膜嵴密度增大。相关分析显示,比目鱼肌和股直肌COXIV和SDH蛋白含量分别与跑步力竭时间呈正相关;比目鱼肌LC3-II/LC3-I比值与SIRT3和SDH蛋白含量呈正相关;股直肌ALDH2蛋白含量与COXIV及SIRT3蛋白含量呈正相关。结论:HIIT能上调比目鱼肌自噬活性和自噬相关蛋白的表达,而股直肌自噬活性未发生改变;线粒体调控因子SIRT3可能与HIIT激活比目鱼肌自噬有关。
Objective: To investigate the effects of 10-wkhigh-intensity interval training(HIIT) on autophagy activities of skeletal muscle and its regulatory mechanisms in rats. Methods: 34 male SD rats were dividedinto three groups: sedentary control(SC,n =10), moderate-intensity continuous training(MICT, n =12), and HIIT(n =12). The exercise protocol of HIIT group was 4 intervals of 9-minute running on a treadmill(i.e.,4 minutes at 42 m/min and 5 minutes at 18 m/min), and the MICT group was 34 min of continuous exercise at a moderate intensity(28 m/min). Both HIIT and MICT groups were trained for 10 weeks, 5 days/wk. After that, the runningtime toexhaustion were measured throughan exhaustive exercise test, and the blood lactate levels were detected before and after the test. The protein expressions of autophagy markers(LC3-II、Beclin-1、ATG-3/-5/-7/-12/-16 L), mitochondrial markers(COXIV and SDH), and SIRT3 and ALDH2 in the soleus and rectus femoris muscles were detected by Western Blotting.The form of autophagic vacuole and the ultrastructure of mitochondria in soleus muscle were observed using a transmission electron microscopy(TEM).Results: Both HIIT and MICT groups were significantly longer in runningtime to exhaustion and lower in blood lactate level after the exhaustive exercise testby comparing with SC group(P<0.01). In addition, the runningtime to exhaustion was longer in HIIT group than that of MICT group(P<0.05), and HIIT groupresulted in alower blood lactate level at 10 min after exhaustive exercise test than SC group(P<0.05).The protein expressions ofthe SDH, COXIV and SIRT3 were significantly higher in the soleus and rectus femoris muscle compared with SC group after HIIT(P<0.01)and MICT training(P<0.05).The higher expression of COXIV protein was observed in HIIT group than MICT group in the soleus muscles(P<0.05);additionally, the HIIT group was greater in the expression of LC3-II/LC3-I ratio, LC3-II, Beclin-1, and ATG-3/-5/-7/-12 proteinsin the soleus muscles compared with SC group(P<0.05). Meanwhile, HIIT group was higher in the expression of ALDH2(P<0.01), Beclin-1(P<0.05),and ATG-5/-7(P<0.05)proteinin the rectus femoris muscle compared with SC group as well. The greater protein expressions of ALDH2, SIRT3, and COXIV in the rectus femoris muscle was observed in HIIT group than that of MICT group(P<0.05).Furthermore, TEM found the appearance of autophagic vacuole and the larger mitochondrial size in soleus muscle in HIIT group.The relative protein contents of COXIV and SDH in the soleus and rectus femoris muscles were positively correlated with runningtime to exhaustion, and the LC3-II/LC3-I ratio was positively correlated with SIRT3 and SDH protein contentsin the soleus muscles.Additionally, ALDH2 protein content was positively correlated with SIRT3 and COXIV protein contents in the rectus femoris muscle. Conclusion:HIIT can increase autophagy activities and autophagy related protein expressions in the soleus muscle butnotthe rectus femoris muscle, and the possible mechanism may be related with mitochondrial regulatory factor SIRT3.
Objective: To investigate the effects of 10-wkhigh-intensity interval training(HIIT) on autophagy activities of skeletal muscle and its regulatory mechanisms in rats. Methods: 34 male SD rats were dividedinto three groups: sedentary control(SC,n =10), moderate-intensity continuous training(MICT, n =12), and HIIT(n =12). The exercise protocol of HIIT group was 4 intervals of 9-minute running on a treadmill(i.e.,4 minutes at 42 m/min and 5 minutes at 18 m/min), and the MICT group was 34 min of continuous exercise at a moderate intensity(28 m/min). Both HIIT and MICT groups were trained for 10 weeks, 5 days/wk. After that, the runningtime toexhaustion were measured throughan exhaustive exercise test, and the blood lactate levels were detected before and after the test. The protein expressions of autophagy markers(LC3-II、Beclin-1、ATG-3/-5/-7/-12/-16 L), mitochondrial markers(COXIV and SDH), and SIRT3 and ALDH2 in the soleus and rectus femoris muscles were detected by Western Blotting.The form of autophagic vacuole and the ultrastructure of mitochondria in soleus muscle were observed using a transmission electron microscopy(TEM).Results: Both HIIT and MICT groups were significantly longer in runningtime to exhaustion and lower in blood lactate level after the exhaustive exercise testby comparing with SC group(P<0.01). In addition, the runningtime to exhaustion was longer in HIIT group than that of MICT group(P<0.05), and HIIT groupresulted in alower blood lactate level at 10 min after exhaustive exercise test than SC group(P<0.05).The protein expressions ofthe SDH, COXIV and SIRT3 were significantly higher in the soleus and rectus femoris muscle compared with SC group after HIIT(P<0.01)and MICT training(P<0.05).The higher expression of COXIV protein was observed in HIIT group than MICT group in the soleus muscles(P<0.05);additionally, the HIIT group was greater in the expression of LC3-II/LC3-I ratio, LC3-II, Beclin-1, and ATG-3/-5/-7/-12 proteinsin the soleus muscles compared with SC group(P<0.05). Meanwhile, HIIT group was higher in the expression of ALDH2(P<0.01), Beclin-1(P<0.05),and ATG-5/-7(P<0.05)proteinin the rectus femoris muscle compared with SC group as well. The greater protein expressions of ALDH2, SIRT3, and COXIV in the rectus femoris muscle was observed in HIIT group than that of MICT group(P<0.05).Furthermore, TEM found the appearance of autophagic vacuole and the larger mitochondrial size in soleus muscle in HIIT group.The relative protein contents of COXIV and SDH in the soleus and rectus femoris muscles were positively correlated with runningtime to exhaustion, and the LC3-II/LC3-I ratio was positively correlated with SIRT3 and SDH protein contentsin the soleus muscles.Additionally, ALDH2 protein content was positively correlated with SIRT3 and COXIV protein contents in the rectus femoris muscle. Conclusion:HIIT can increase autophagy activities and autophagy related protein expressions in the soleus muscle butnotthe rectus femoris muscle, and the possible mechanism may be related with mitochondrial regulatory factor SIRT3.
引文
洪平,赵鹏,杨奎生,2002.不同强度运动时大鼠骨骼肌能量代谢产物的变化[J].中国运动医学杂志,21(3):261-267.
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黎涌明,2015.高强度间歇训练对不同训练人群的应用效果[J].体育科学,35(8):59-75.
梁春瑜,王林佳,倪震,等,2017.不同时长高强度间歇训练与中等强度持续运动对大鼠骨骼肌AMPK、PGC-1α表达量及最大摄氧量的影响[J].中国运动医学杂志,05(36):390-399.
漆正堂,丁树哲,2013.运动适应的细胞信号调控:线粒体的角色转换及其研究展望[J].体育科学,33(7):65-69.
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田野,2003.运动生理学高级教程[M].北京:高等教育出版社.
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祖靓,朱荣,2013.力竭运动对小鼠骨骼肌细胞自噬的影响及相关调节机制研究[J].体育科学,33(9):77-84.
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HE C,RHEA SUMPTER J,LEVINE B,2012.Exercise induces autophagy in peripheral tissues and in the brain[J].Autophagy,8(10):1548-1551.
HELGERUD J,H?YDAL K,WANG E,et al.,2007.Aerobic highintensity intervals improve V?O2max more than moderate training[J].Med Sci Sports Exerc,39(4):665-671.
HOKARI F,KAWASAKI E,SAKAI A,et al.,2010.Muscle contractile activity regulates Sirt3 protein expression in rat skeletal muscles[J].JAppl Physiol(1985),109:332-340.
HU N,REN J,ZHANG Y,2016.Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α[J].Oncotarget,7:76398-76414.
LAKER RC,DRAKE JC,WILSON RJ,et al.,2017.AMPKphosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy[J].Nat Commun,8(1):548.
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LIAO J,LI Y,ZENG F,et al.,2015.Regulation of m TOR pathway in exercise-induced cardiac hypertrophy[J].Int J Sports Med,36(5):343-350.
LIN L,CHEN K,ABDEL KHALEK W,et al.,2014.Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3[J].PLoS One,9:e85636.
LIRA VA,OKUTSU M,ZHANG M,et al.,2013.Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance[J].FASEB J,27(10):4184-4193.
LITTLE JP,SAFDAR A,WILKIN GP,et al.,2010.A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle:potential mechanisms[J].JPhysiol,588(Pt 6):1011-1022.
LKAHTANI SA,KING NA,HILLS AP,et al.,2013.Effect of interval training intensity on fat oxidation,blood lactate and the rate of perceived exertion in obese men[J].Springerplus,2:532.
LOVERSO F,CARNIO S,VAINSHTEIN A,et al.,2014.Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity[J].Autophagy,10(11):1883-1894.
MACINNIS MJ,ZACHAREWICZ E,MARTIN BJ,et al.,2017.Superior mitochondrial adaptations in human skeletal muscle after interval compared to continuous single-leg cycling matched for total work[J].J Physiol,595(9):2955-2968.
NAKASHIMA Y,OHSAWA I,NISHIMAKI K,et al.,2014.Preventive effects of Chlorella on skeletal muscle atrophy in musclespecific mitochondrial aldehyde dehydrogenase 2 activity-deficient mice[J].BMC Complement Altern Med,14:390.
NEVES CH,TIBANA RA,PRESTES J,et al.,2017.Digoxin induces cardiac hypertrophy without negative effects on cardiac function and physicalperformance in trained normotensive rats[J].Int J Sports Med,38(4):263-269.
OGURA Y,IEMITSU M,NAITO H,et al.,2011.Single bout of running exercise changes LC3-II expression in rat cardiac muscle[J].Biochem Biophys Res Commun,414(4):756-760.
PALACIOS OM,CARMONA JJ,MICHAN S,et al.,2009.Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle[J].Aging(Albany NY),1(9):771-783.
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胡国鹏,郑阳,孟妍,等,2017.大强度间歇训练与中等强度持续训练对耗氧量动力学特征影响的比较研究[J].体育科学,37(3):58-67.
黎涌明,2015.高强度间歇训练对不同训练人群的应用效果[J].体育科学,35(8):59-75.
梁春瑜,王林佳,倪震,等,2017.不同时长高强度间歇训练与中等强度持续运动对大鼠骨骼肌AMPK、PGC-1α表达量及最大摄氧量的影响[J].中国运动医学杂志,05(36):390-399.
漆正堂,丁树哲,2013.运动适应的细胞信号调控:线粒体的角色转换及其研究展望[J].体育科学,33(7):65-69.
施曼莉,朱荣,2015.高强度间歇运动对骨骼肌糖原含量的影响及机制研究[J].体育科学,35(4):66-71.
田野,2003.运动生理学高级教程[M].北京:高等教育出版社.
王海涛,刘玉倩,赵焕彬,等,2011.运动对骨骼肌线粒体去乙酰化酶3(SIRT3)的影响[J].体育科学,31(1):85-88.
王林佳,苏浩,梁春瑜,等,2016.不同时长HIIT与中等强度运动后大鼠VO2max及血液心血管风险指标的变化[J].中国体育科技,52(6):81-85.
祖靓,朱荣,2013.力竭运动对小鼠骨骼肌细胞自噬的影响及相关调节机制研究[J].体育科学,33(9):77-84.
BEDFORD TG,TIPTON CM,WILSON NC,et al.,1979.Maximum oxygen consumption of rats and its changes with various experimental procedures[J].J Appl Physiol Respir Environ Exerc Physiol,47(6):1278-1283.
CARMELI E,MOAS M,LENNON S,et al.,2005.High intensity exercise increases expression of matrix metalloproteinases in fast skeletal muscle fibres[J].Exp Physiol,90(4):613-619.
CASUSO RA,PLAZA-DíAZ J,RUIZ-OJEDA FJ,et al.,2017.Highintensity high-volume swimming induces more robust signaling through PGC-1αand AMPK activation than sprint interval swimming in m.triceps brachii[J].PLoS One,12:e0185494.
CRISWELL D,POWERS S,DODD S,et al.,1993.High intensity training-induced changes in skeletal muscle antioxidant enzyme activity[J].Med Sci Sports Exerc,25(10):1135-1140.
EDGETT BA,BONAFIGLIA JT,BAECHLER BL,et al.,2016.The effect of acute and chronic sprint-interval training on LRP130,SIRT3,and PGC-1αexpression in human skeletal muscle[J].Physiol Rep,4:pii:e12879.
FINLEY LW,HAAS W,DESQUIRET-DUMAS V,et al.,2011.Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity[J].PLoS One,6:e23295.
FOX EL,BARTELS RL,BILLINGS CE,et al.,1973.Intensity and distance of interval training programs and changes in aerobic power[J].Med Sci Sports,5(1):18-22.
GARBER K,2012.Autophagy.Explaining exercise[J].Science,335(6066):281-281.
GIBALA MJ,MCGEE SL,GARNHAM AP,et al.,2009.Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1alpha in human skeletal muscle[J].J Physiol,106(3):929-934.
GUO Y,YU W,SUN D,et al.,2015.A novel protective mechanism for mitochondrial aldehyde dehydrogenase(ALDH2)in type I diabetesinduced cardiac dysfunction:Role of AMPK-regulated autophagy[J].Biochim Biophys Acta,1852(2):319-331.
HE C,RHEA SUMPTER J,LEVINE B,2012.Exercise induces autophagy in peripheral tissues and in the brain[J].Autophagy,8(10):1548-1551.
HELGERUD J,H?YDAL K,WANG E,et al.,2007.Aerobic highintensity intervals improve V?O2max more than moderate training[J].Med Sci Sports Exerc,39(4):665-671.
HOKARI F,KAWASAKI E,SAKAI A,et al.,2010.Muscle contractile activity regulates Sirt3 protein expression in rat skeletal muscles[J].JAppl Physiol(1985),109:332-340.
HU N,REN J,ZHANG Y,2016.Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α[J].Oncotarget,7:76398-76414.
LAKER RC,DRAKE JC,WILSON RJ,et al.,2017.AMPKphosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy[J].Nat Commun,8(1):548.
LAURSEN PB,MARSH SA,JENKINS DG,et al.,2007.Manipulating training intensity and volume in already well-trained rats:Effect on skeletal muscle oxidative and glycolytic enzymes and buffering capacity[J].Appl Physiol Nutr Metab,32(3):434-442.
LIAO J,LI Y,ZENG F,et al.,2015.Regulation of m TOR pathway in exercise-induced cardiac hypertrophy[J].Int J Sports Med,36(5):343-350.
LIN L,CHEN K,ABDEL KHALEK W,et al.,2014.Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3[J].PLoS One,9:e85636.
LIRA VA,OKUTSU M,ZHANG M,et al.,2013.Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance[J].FASEB J,27(10):4184-4193.
LITTLE JP,SAFDAR A,WILKIN GP,et al.,2010.A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle:potential mechanisms[J].JPhysiol,588(Pt 6):1011-1022.
LKAHTANI SA,KING NA,HILLS AP,et al.,2013.Effect of interval training intensity on fat oxidation,blood lactate and the rate of perceived exertion in obese men[J].Springerplus,2:532.
LOVERSO F,CARNIO S,VAINSHTEIN A,et al.,2014.Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity[J].Autophagy,10(11):1883-1894.
MACINNIS MJ,ZACHAREWICZ E,MARTIN BJ,et al.,2017.Superior mitochondrial adaptations in human skeletal muscle after interval compared to continuous single-leg cycling matched for total work[J].J Physiol,595(9):2955-2968.
NAKASHIMA Y,OHSAWA I,NISHIMAKI K,et al.,2014.Preventive effects of Chlorella on skeletal muscle atrophy in musclespecific mitochondrial aldehyde dehydrogenase 2 activity-deficient mice[J].BMC Complement Altern Med,14:390.
NEVES CH,TIBANA RA,PRESTES J,et al.,2017.Digoxin induces cardiac hypertrophy without negative effects on cardiac function and physicalperformance in trained normotensive rats[J].Int J Sports Med,38(4):263-269.
OGURA Y,IEMITSU M,NAITO H,et al.,2011.Single bout of running exercise changes LC3-II expression in rat cardiac muscle[J].Biochem Biophys Res Commun,414(4):756-760.
PALACIOS OM,CARMONA JJ,MICHAN S,et al.,2009.Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle[J].Aging(Albany NY),1(9):771-783.
PEREIRA F,MORAES RD,TIBIRI?áE,et al.,2013.Interval and continuous exercise training produce similar increases in skeletal muscle and left ventricle microvascular density in rats[J].Biomed Res Int,(3):752817.
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