有氧运动干预父系C57BL/6J小鼠对雄性子代骨骼肌mTOR信号通路的影响
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摘要
目的:探究运动干预父系小鼠对雄性子代骨骼肌mTOR信号通路的影响。方法:同窝C57BL/6J雄性小鼠(F0),自出生21天断乳后随机分为运动组(E)和安静组(C),正常饮食,运动组进行6周跑台训练,6周后两组分别与同窝安静雌性小鼠1︰1交配。运动组F1代雄性小鼠为EM组;安静组F1代雄性小鼠为CM组。F1代小鼠出生21天断乳后,分别检测其表型及骨骼肌mTOR信号通路分子的表达变化。结果:(1) EM组小鼠体重、抓力、股四头肌湿重及股四头肌湿重/体重比值较CM组均显著增加(P<0.05);(2)EM组小鼠股四头肌细胞的横截面积较对照组增加30.26%(P<0.05);(3) EM组小鼠股四头肌PI3K、Akt、mTOR以及S6K1总蛋白表达水平较CM组略有增加(P>0.05);而pAkt,pmTOR,pS6K1以及p4E-BP1蛋白表达水平较对照组显著增加(P<0.05)。结论:(1) 6周跑台运动干预父系小鼠可显著增加雄性子代小鼠的体重、抓力、股四头肌湿重及股四头肌细胞横截面积。(2) 6周跑台运动干预父系小鼠后,其雄性子代小鼠骨骼肌组织mTOR信号通路活性显著高于对照组。提示,运动干预父系小鼠促进子代雄性小鼠骨骼肌发育可能与mTOR信号通路激活密切相关。
Objective To explore the effect of paternal aerobic exercise on the skeletal muscle mTOR signaling pathway in male offsprings of C57BL/6 mice. Methods Sibling males were divided into the control(C) and exercise(E)groups. All mice stopped breast feeding 21 days after their birth and was fed in the same way. The control group and sibling females were kept sedentary,while group E underwent treadmill running for 6 weeks. Then one male and one female were mated. The male newborns(F1) of fathers from group E belonged to group EM,while those of fathers from group C were members of group CE. Twenty-one day after their birth,the skeletal muscle phenotype and the activity of mTOR signaling pathway were assessed. Results Compared to group CM,a significant increase was observed in the body weight,grip,quadriceps femoris muscle wet weight and the ratio of quadriceps femoris muscle wet weight/body weight in group EM(P<0.05). The mean cross sectional area of the quadriceps femoris muscle increased by 30.26% in group EM(P<0.05). The total protein expression of PI3K,Akt,mTOR and S6K1 of group EM increased compared with group CM,but not significantly,while the protein expression of pAkt,pmTOR,pS6K1 and p4E-BP1 levels increased significantly compared with group EM group(P<0.05). Conclusions In our present study, we have found that paternal treadmill exercise can significantly enhances increase the body weight,grip,quadriceps femoris muscle wet weight and cross sectional area of male offsprings. The positive effect of paternal treadmill exercise on skeletal muscle growth of male offsprings might be partially mediated by exerciseinduced activation of mTOR signaling pathway in quadriceps femoris muscle.
Objective To explore the effect of paternal aerobic exercise on the skeletal muscle mTOR signaling pathway in male offsprings of C57BL/6 mice. Methods Sibling males were divided into the control(C) and exercise(E)groups. All mice stopped breast feeding 21 days after their birth and was fed in the same way. The control group and sibling females were kept sedentary,while group E underwent treadmill running for 6 weeks. Then one male and one female were mated. The male newborns(F1) of fathers from group E belonged to group EM,while those of fathers from group C were members of group CE. Twenty-one day after their birth,the skeletal muscle phenotype and the activity of mTOR signaling pathway were assessed. Results Compared to group CM,a significant increase was observed in the body weight,grip,quadriceps femoris muscle wet weight and the ratio of quadriceps femoris muscle wet weight/body weight in group EM(P<0.05). The mean cross sectional area of the quadriceps femoris muscle increased by 30.26% in group EM(P<0.05). The total protein expression of PI3K,Akt,mTOR and S6K1 of group EM increased compared with group CM,but not significantly,while the protein expression of pAkt,pmTOR,pS6K1 and p4E-BP1 levels increased significantly compared with group EM group(P<0.05). Conclusions In our present study, we have found that paternal treadmill exercise can significantly enhances increase the body weight,grip,quadriceps femoris muscle wet weight and cross sectional area of male offsprings. The positive effect of paternal treadmill exercise on skeletal muscle growth of male offsprings might be partially mediated by exerciseinduced activation of mTOR signaling pathway in quadriceps femoris muscle.
引文
[1]Richter EA,Hargreaves M.Exercise,GLUT4,and skeletal muscle glucose uptake[J].Physiol Rev,2013,93(3):993-1017.
[2]Yang J.Enhanced skeletal muscle for effective glucose homeostasis[J].Prog Mol Biol Transl Sci,2014,121:133-163.
[3]Bentzinger CF,Wang YX,Rudnicki MA.Building muscle:molecular regulation of myogenesis[J].Cold Spring Harb Perspect Biol,2012,4(2).pii:a008342.
[4]Zhang P,Liang X,Shan T,et al.mTOR is necessary for proper satellite cell activity and skeletal muscle regeneration[J].Biochem Biophys Res Commun,2015,463(1-2):102-108.
[5]You JS,Anderson GB,Dooley MS,et al.The role of mTOR signaling in the regulation of protein synthesis and muscle mass during immobilization in mice[J].Dis Model Mech,2015,8(9):1059-1069.
[6]Sarbassov DD,Guertin DA,Ali SM,et al.Phosphorylation and regulation of Akt/PKB by the rictor-mTORcomplex[J].Science,2005,307(5712):1098-1101.
[7]Santos M,Rodríguez-González GL,Ibá?ez C,et al.Adult exercise effects on oxidative stress and reproductive programming in male offspring of obese rats[J].Am J Physiol Regul Integr Comp Physiol,2015,308(3):R219-225.
[8]Dhana K,Haines J,Liu G,et al.Association between maternal adherence to healthy lifestyle practices and risk of obesity in offspring:results from two prospective cohort studies of mother-child pairs in the United States[J].BMJ,2018,362:k2486.
[9]Rodriguez JS,Rodríguez-González GL,Reyes-Castro LA,et al.Maternal obesity in the rat programs male offspring exploratory,learning and motivation behavior:prevention by dietary intervention pre-gestation or in gestation[J].Int J Dev Neurosci,2012,30(2):75-81.
[10]Zambrano E,Martinez-Samayoa PM,Rodriguez-Gonzalez GL,et al.Dietary intervention prior to pregnancy reverses metabolic programming in male offspring of obese rats[J].J Physiol,2010,588(Pt 10):1791-1799
[11]Klein CP,Hoppe JB,Saccomori AB,et al.Physical exercise during pregnancy prevents cognitive impairment induced by Amyloid-βin adult off spring rats[J].Mol Neurobiol.2018.
[12]Kasch J,Kanzleiter I,Saussenthaler S,et al.Insulin sensitivity linked skeletal muscle Nr4a1 DNA methylation is programmed by the maternaldiet and modulated by voluntary exercise in mice[J].J Nutr Biochem,2018,57:86-92.
[13]Yin MM,Wang W,Sun J,et al.Paternal treadmill exercise enhances spatial learning and memory related to hippocampus among male offspring[J].Behav Brain Res,2013,253:297-304.
[14]Gilbert JS,Nijland MJ.Sex differences in the developmental origins of hypertension and cardiorenal disease[J].Am J Physiol Regul Integr Comp Physiol,2008,295(6):R1941-1952.
[15]Fernando P,Bonen A,Hoffman-Goetz L.Predicting submaximal oxygen consumption during treadmill running in mice[J].Can J Physiol Pharmacol,1993,71(10-11):854-857
[16]Liu X,Niu Y,Yuan H,et al.AMPK binds to Sestrins and mediates the effect of exercise to increase insulin-sensitivity through autophagy[J].Metabolism,2015,64(6):658-665.
[17]Pedersen BK,Febbraio MA.Muscles,exercise and obesity:skeletal muscle as secretory organ[J].Nat Rev Endocrinol,2012,8(8):457-465.
[18]Grossman DC,Bibbins-Domingo K,Curry SJ,et al.Screening for obesity in children and adolescents:US preventive services task force recommendation statement[J].JAMA,2017,317(23):2417-2426.
[19]Ng SF,Lin RC,Laybutt DR,et al.Chronic high-fat diet in fathers programsβ-cell dysfunction in female rat offspring[J].Nature,2010,467(7318):963-966.
[20]H?konsen LB,Thulstrup AM,Aggerholm AS,et al.Does weight loss improve semen quality and reproductive hormones?Results from a cohort of severely obese men[J].Reprod Health,2011,8:24
[21]Murashov AK,Pak ES,Koury M,et al.Paternal longterm exercise programs offspring for low energy expenditure and increased risk for obesity in mice[J].FASEBJ,2016,30(2):775-784
[22]Dorosty AR,Emmett PM,Cowin SD,et al.Factors associated with early adiposity rebound.ALSPAC Study Team[J].Pediatrics,2000,105(5):1115-1118
[23]Krout D,Roemmich JN,Bundy A,et al.Paternal exercise protects mouse offspring from high-fat-diet-induced type 2 diabetes risk by increasing skeletal muscle insulin signaling[J].J Nutr Biochem,2018,57:35-44.
[24]Bodine SC,Stitt TN,Gonzalez M,et al.Akt/mTORpathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo[J].Nat Cell Bio J.2001,11(3):1014-1019.
[25]Proud CG.Regulation of mammalian translation factors by nutrients[J].Eur J Bio Chem,2002,269(22):5338-5349
[26]Laplante M,Sabatini DM.mTOR signaling in growth control and disease[J].Cell,2012,149(2):274-293.
[27]Mounier R,Lantier L,Leclerc J,et al.Antagonistic control of muscle cell size by AMPK and m TORC1[J].Cell Cycle,2011,10(16):2640-2646.
[28]Goodman CA,Miu MH,Frey JW,et al.A phosphatidylinositol 3-kinase/protein kinase B-independent activation of mammalian target of rapamycin signaling is sufficient to induce skeletal muscle hypertrophy[J].Mol Biol Cell,2010,15;21(18):3258-3268.
[2]Yang J.Enhanced skeletal muscle for effective glucose homeostasis[J].Prog Mol Biol Transl Sci,2014,121:133-163.
[3]Bentzinger CF,Wang YX,Rudnicki MA.Building muscle:molecular regulation of myogenesis[J].Cold Spring Harb Perspect Biol,2012,4(2).pii:a008342.
[4]Zhang P,Liang X,Shan T,et al.mTOR is necessary for proper satellite cell activity and skeletal muscle regeneration[J].Biochem Biophys Res Commun,2015,463(1-2):102-108.
[5]You JS,Anderson GB,Dooley MS,et al.The role of mTOR signaling in the regulation of protein synthesis and muscle mass during immobilization in mice[J].Dis Model Mech,2015,8(9):1059-1069.
[6]Sarbassov DD,Guertin DA,Ali SM,et al.Phosphorylation and regulation of Akt/PKB by the rictor-mTORcomplex[J].Science,2005,307(5712):1098-1101.
[7]Santos M,Rodríguez-González GL,Ibá?ez C,et al.Adult exercise effects on oxidative stress and reproductive programming in male offspring of obese rats[J].Am J Physiol Regul Integr Comp Physiol,2015,308(3):R219-225.
[8]Dhana K,Haines J,Liu G,et al.Association between maternal adherence to healthy lifestyle practices and risk of obesity in offspring:results from two prospective cohort studies of mother-child pairs in the United States[J].BMJ,2018,362:k2486.
[9]Rodriguez JS,Rodríguez-González GL,Reyes-Castro LA,et al.Maternal obesity in the rat programs male offspring exploratory,learning and motivation behavior:prevention by dietary intervention pre-gestation or in gestation[J].Int J Dev Neurosci,2012,30(2):75-81.
[10]Zambrano E,Martinez-Samayoa PM,Rodriguez-Gonzalez GL,et al.Dietary intervention prior to pregnancy reverses metabolic programming in male offspring of obese rats[J].J Physiol,2010,588(Pt 10):1791-1799
[11]Klein CP,Hoppe JB,Saccomori AB,et al.Physical exercise during pregnancy prevents cognitive impairment induced by Amyloid-βin adult off spring rats[J].Mol Neurobiol.2018.
[12]Kasch J,Kanzleiter I,Saussenthaler S,et al.Insulin sensitivity linked skeletal muscle Nr4a1 DNA methylation is programmed by the maternaldiet and modulated by voluntary exercise in mice[J].J Nutr Biochem,2018,57:86-92.
[13]Yin MM,Wang W,Sun J,et al.Paternal treadmill exercise enhances spatial learning and memory related to hippocampus among male offspring[J].Behav Brain Res,2013,253:297-304.
[14]Gilbert JS,Nijland MJ.Sex differences in the developmental origins of hypertension and cardiorenal disease[J].Am J Physiol Regul Integr Comp Physiol,2008,295(6):R1941-1952.
[15]Fernando P,Bonen A,Hoffman-Goetz L.Predicting submaximal oxygen consumption during treadmill running in mice[J].Can J Physiol Pharmacol,1993,71(10-11):854-857
[16]Liu X,Niu Y,Yuan H,et al.AMPK binds to Sestrins and mediates the effect of exercise to increase insulin-sensitivity through autophagy[J].Metabolism,2015,64(6):658-665.
[17]Pedersen BK,Febbraio MA.Muscles,exercise and obesity:skeletal muscle as secretory organ[J].Nat Rev Endocrinol,2012,8(8):457-465.
[18]Grossman DC,Bibbins-Domingo K,Curry SJ,et al.Screening for obesity in children and adolescents:US preventive services task force recommendation statement[J].JAMA,2017,317(23):2417-2426.
[19]Ng SF,Lin RC,Laybutt DR,et al.Chronic high-fat diet in fathers programsβ-cell dysfunction in female rat offspring[J].Nature,2010,467(7318):963-966.
[20]H?konsen LB,Thulstrup AM,Aggerholm AS,et al.Does weight loss improve semen quality and reproductive hormones?Results from a cohort of severely obese men[J].Reprod Health,2011,8:24
[21]Murashov AK,Pak ES,Koury M,et al.Paternal longterm exercise programs offspring for low energy expenditure and increased risk for obesity in mice[J].FASEBJ,2016,30(2):775-784
[22]Dorosty AR,Emmett PM,Cowin SD,et al.Factors associated with early adiposity rebound.ALSPAC Study Team[J].Pediatrics,2000,105(5):1115-1118
[23]Krout D,Roemmich JN,Bundy A,et al.Paternal exercise protects mouse offspring from high-fat-diet-induced type 2 diabetes risk by increasing skeletal muscle insulin signaling[J].J Nutr Biochem,2018,57:35-44.
[24]Bodine SC,Stitt TN,Gonzalez M,et al.Akt/mTORpathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo[J].Nat Cell Bio J.2001,11(3):1014-1019.
[25]Proud CG.Regulation of mammalian translation factors by nutrients[J].Eur J Bio Chem,2002,269(22):5338-5349
[26]Laplante M,Sabatini DM.mTOR signaling in growth control and disease[J].Cell,2012,149(2):274-293.
[27]Mounier R,Lantier L,Leclerc J,et al.Antagonistic control of muscle cell size by AMPK and m TORC1[J].Cell Cycle,2011,10(16):2640-2646.
[28]Goodman CA,Miu MH,Frey JW,et al.A phosphatidylinositol 3-kinase/protein kinase B-independent activation of mammalian target of rapamycin signaling is sufficient to induce skeletal muscle hypertrophy[J].Mol Biol Cell,2010,15;21(18):3258-3268.