EPO在高原训练中早期下降的机制及对高原训练效果的预测作用
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摘要
背景和目的:
耐力项目运动员进行高原训练从而改善平原运动能力已成为国内外竞技体育实践的惯例,但高原训练的效果一直存在争议。高原训练回到平原后的运动能力存在显著的个体差异,其部分原因是由于低氧造成的红细胞生成存在个体差异,促红细胞生成素(erythropoietin,EPO)通过调控红细胞生成反应进而影响运动能力,EPO在高原训练中的变化和机制一直是学者们关注的核心(特别是EPO的早期下降现象)。低氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)调控数以百计低氧反应基因(hypoxia response gene,HRG)的表达,包括EPO基因。aHIF(natural antisense transcript of hypoxia-inducible factors 1 alpha)是HIF-1α的天然反义转录本,介导HIF-1αmRNA的降解并反馈调节HIF-1的生成。所以我们推测EPO的早期下降与HIF-1和aHIF有关,而且EPO、HIF-1α和aHIF可能是预测高原训练效果的分子标志物(markers),即EPO、HIF-1α和aHIF对于低氧反应的个体差异间接影响了高原训练的效果。本文的目的在于:
1.揭示高原训练过程中EPO早期下降的机制;
2.探讨暴露于常压低氧(2366 m)环境12 h血清EPO(serum EPO,s-EPO)、血清HIF-1α(s-HIF-1α)以及白细胞aHIF、HIF-1αmRNA的反应是否可以预测中等高度高原训练(2366 m)后运动能力(递增负荷功率车实验)的变化。
方法:
1.动物实验:6周龄雄性SD大鼠随机分成四组:常氧对照组(NC)、低氧对照组(HC)、常氧运动组(NT)、低氧运动组(HT),后三组再按照观察时间点各分为三个亚组:4 h组、12 h组和24 h组。NC组和HC组分别在常氧和低氧(3000m)环境下安静暴露24 h;NT组和HT组以各自70%最大有氧速度(maximalaerobic velocity,MAV)进行一次持续时间为1 h的跑台运动。观察各时间点s-EPO、肾静脉氧分压(renal venous PO_2,RVPO_2)以及肾脏EPO、HIF-1α和aHIF基因表达的变化;
2.人体实验:7名大学生运动员(男性)暴露于常压低氧(模拟2366 m)环境中12h,于0h、4h、8h和12h测定s-EPO、s-HIF-1α以及白细胞aHIF,HIF-1αmRNA的表达,3周高原训练(2366 m)前后测试最大有氧运动能力(递增负荷功率车实验)。
结果:
1.动物实验:HC组和HT组,s-EPO、肾脏EPO mRNA和蛋白水平在4 h显著升高,12 h达峰值,24 h开始下降;RVPO_2在4 h开始下降,24 h仍低于对照组;肾脏HIF-1αmRNA在4 h和12 h变化不显著,24 h显著下降;肾脏HIF-1蛋白在4 h和12 h显著升高,在24 h下降至基础水平;肾脏aHIF在4 h和12 h显著升高,24 h达峰值;
2.人体实验:急性低氧暴露12 h,s-EPO、s-HIF-1α以及白细胞HIF-1αmRNA、aHIF的表达均具有显著个体差异(变化范围分别为-11.1%～+308.4%,-8.6%～+42.6%,-33.3%～+42.6%,-51.1%～+437.1%),高原训练前后VO_(2max)的变化同样具有显著差异(-11.7%～+22.3%);相关分析显示,急性低氧暴露12 h s-EPO、s-HIF-1α、白细胞HIF-1αmRNA、aHIF和aHIF/HIF-1αmRNA的积分变化与VO_(2max)变化的Spearman相关系数分别为0.679(P=0.094)、-0.071(P=0.879)、-0.214(P=0.645)、-0.750(P=0.052)和-0.751(P=0.180)。
结论:
1.动物实验:RVPO_2是肾脏分泌EPO的重要决定因素;持续低氧暴露,s-EPO以及肾脏EPO的表达先升高后降低;低氧在翻译后水平上调控HIF-1α的表达;低氧和低氧训练过程中EPO的早期下降可能是通过肾脏aHIF下调HIF-1αmRNA介导的;
2.人体实验:高原训练效果一直存在争议,其中一个重要原因是人体对于低氧反应具有显著个体差异性;铁缺乏不是高原训练效果存在个体差异的主要原因;急性低氧暴露12 h,s-EPO和白细胞aHIF的积分变化可能是高原训练效果的预测因子。
Background and Objectives:
It becomes more popular for endurance athletes to improve their sea-level performance by altitude training,but its effect is controversial till now. Inter-individual variations in sea-level performance after altitude training have been attributed,at least in part,to an inter-individual variability in hypoxia induced erythropoiesis.Erythropoietin(EPO)may affect athletic performance by regulating erythropoiesis.The pattern and mechanism of EPO during altitude training is focused on by many researchers,especially the intriguing phenomenon—its early decline at altitude.Until now,about 100 target genes(hypoxia response gene,HRG),including EPO gene,have been shown to be regulated by hypoxia-inducible factor-1(HIF-1). aHIF,a natural antisense transcript of hypoxia-inducible factors 1α,complementary to the 3′-untranslated region of HIF-1αmRNA,is involved in HIF-1αmRNA regulation and therefore in HIF-1αprotein synthesis.So we presume that the early decline of EPO will be related to aHIF and response of EPO,HIF-1α,aHIF to acute altitude exposure migh be the sensitive molecular markers to identify poor and good responders to altitude training.The purpose of the research is:
1.reveal the mechanism that EPO is early declined during altitude training;
2.examine whether the change of maximal aerobic performance(graded cycle ergometer test)after training at moderate altitude(2366 m)could be predicted by response of serum EPO(s-EPO)and HIF-1α(s-HIF-1α),expression of HIF-1αmRNA and aHIF gene in leukocytes during 12 h exposure to normobaric hypoxia at an ambient PO_2 corresponding to the training altitude.
Methods:
1.Animal experiment:Six-week-old,sea-level native male Sprague-Dawley rats were randomizedly divided into four groups:Normoxic Control group(NC), Hypoxic Control group(HC),Normoxic Training group(NT)and Hypoxic Training group(HT).The latter three groups fell into three sub-groups:4 h group, 12 h group and 24 h group.Rats of NC and HC were exposed in normoxia and hypoxia(3000 m)environment respectively at rest;rats of NT and HT performed a treadmill exercise for 1 h at 70%MAV(maximal aerobic velocity).Serum EPO, RVPO_2(renal venous PO_2),kidney EPO,HIF-1αand aHIF gene expression were observed at corresponding time-point;
2.Human experiment:seven male university athletes were exposed to normobaric hypoxia(12h at 2366 m at rest)and s-EPO,s-HIF-1α,expression of HIF-lαmRNA and aHIF in leukocytes were measured at 0 h,4 h,8 h and 12 h respectively.Maximal aerobic performance was determined(graded cycle ergometer test)before and after 3-week altitude training at 2366 m.
Results:
1.Animal experiment:in HC and HT,EPO mRNA and EPO protein in kidney were significantly inceased at 4 h and 12 h and decreased at 24 h;RVPO_2 descended at 4 h and still lowered than NC;12 h of hypoxia did not change HIF-1αmRNA in kidney but decreased at 24 h;following the rapid induction of the HIF-1αprotein in kidney observed at 4～12 h,HIF-1αprotein levels diminished and fell to base-line level after 24 h;aHIF in kidney were elevated at 4 h and remained sustained until 12 h,reach peak at 24 h.
2.Human experiment:there is considerable inter-individual variation in s-EPO, s-HIF-1α,expression of HIF-1αmRNA and aHIF gene in leukocytes during acute normobaric hypoxia for 12 h(s-EPO:-11.1%～+308.4%,s-HIF-1α:-8.6%～+42.6%,HIF-1αmRNA:-33.3%～+42.6%,aHIF:-51.1%～+437.1%).The change of VO_(2max)also showed a similarly wide variability(-11.7%～+22.3%) after altitude training.Correlation analysis displayed that Spearman's correlation coefficient of the integration change of s-EPO,s-HIF-1α,expression of HIF-1αmRNA,aHIF,aHIF/HIF-lαmRNA in leukocytes and the change of VO_(2max) were 0.679(P=0.094),-0.071(P=0.879),-0.214(P=0.645),-0.750(P=0.052)and -0.751(P=0.180)respectively.
Conclusions:
1.Animal experiment:RVPO_2 is a determinative factor of EPO secreting;during sustained hypoxia,s-EPO and EPO gene expression in kidney are both inceased fast and then deceased;hypoxia-induced increases in HIF-1 are likely due to post-translational changes;aHIF in kidney is likely involed in early decline of serum EPO by down-regulation of HIF-1αmRNA during hypoxia and hypoxic training;
2.Human experiment:inter-individual variation in response to altitude training is mainly responsible for its controversial effect;iron-deficiency is not the predominant factor related to the inter-individual variation in response to altitude training;integration change of s-EPO and aHIF in leukocytes during 12 h exposure at 2366 m in resting conditions probably allows for prediction of poor and good responders to altitude training at 2366 m.
耐力项目运动员进行高原训练从而改善平原运动能力已成为国内外竞技体育实践的惯例,但高原训练的效果一直存在争议。高原训练回到平原后的运动能力存在显著的个体差异,其部分原因是由于低氧造成的红细胞生成存在个体差异,促红细胞生成素(erythropoietin,EPO)通过调控红细胞生成反应进而影响运动能力,EPO在高原训练中的变化和机制一直是学者们关注的核心(特别是EPO的早期下降现象)。低氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)调控数以百计低氧反应基因(hypoxia response gene,HRG)的表达,包括EPO基因。aHIF(natural antisense transcript of hypoxia-inducible factors 1 alpha)是HIF-1α的天然反义转录本,介导HIF-1αmRNA的降解并反馈调节HIF-1的生成。所以我们推测EPO的早期下降与HIF-1和aHIF有关,而且EPO、HIF-1α和aHIF可能是预测高原训练效果的分子标志物(markers),即EPO、HIF-1α和aHIF对于低氧反应的个体差异间接影响了高原训练的效果。本文的目的在于:
1.揭示高原训练过程中EPO早期下降的机制;
2.探讨暴露于常压低氧(2366 m)环境12 h血清EPO(serum EPO,s-EPO)、血清HIF-1α(s-HIF-1α)以及白细胞aHIF、HIF-1αmRNA的反应是否可以预测中等高度高原训练(2366 m)后运动能力(递增负荷功率车实验)的变化。
方法:
1.动物实验:6周龄雄性SD大鼠随机分成四组:常氧对照组(NC)、低氧对照组(HC)、常氧运动组(NT)、低氧运动组(HT),后三组再按照观察时间点各分为三个亚组:4 h组、12 h组和24 h组。NC组和HC组分别在常氧和低氧(3000m)环境下安静暴露24 h;NT组和HT组以各自70%最大有氧速度(maximalaerobic velocity,MAV)进行一次持续时间为1 h的跑台运动。观察各时间点s-EPO、肾静脉氧分压(renal venous PO_2,RVPO_2)以及肾脏EPO、HIF-1α和aHIF基因表达的变化;
2.人体实验:7名大学生运动员(男性)暴露于常压低氧(模拟2366 m)环境中12h,于0h、4h、8h和12h测定s-EPO、s-HIF-1α以及白细胞aHIF,HIF-1αmRNA的表达,3周高原训练(2366 m)前后测试最大有氧运动能力(递增负荷功率车实验)。
结果:
1.动物实验:HC组和HT组,s-EPO、肾脏EPO mRNA和蛋白水平在4 h显著升高,12 h达峰值,24 h开始下降;RVPO_2在4 h开始下降,24 h仍低于对照组;肾脏HIF-1αmRNA在4 h和12 h变化不显著,24 h显著下降;肾脏HIF-1蛋白在4 h和12 h显著升高,在24 h下降至基础水平;肾脏aHIF在4 h和12 h显著升高,24 h达峰值;
2.人体实验:急性低氧暴露12 h,s-EPO、s-HIF-1α以及白细胞HIF-1αmRNA、aHIF的表达均具有显著个体差异(变化范围分别为-11.1%～+308.4%,-8.6%～+42.6%,-33.3%～+42.6%,-51.1%～+437.1%),高原训练前后VO_(2max)的变化同样具有显著差异(-11.7%～+22.3%);相关分析显示,急性低氧暴露12 h s-EPO、s-HIF-1α、白细胞HIF-1αmRNA、aHIF和aHIF/HIF-1αmRNA的积分变化与VO_(2max)变化的Spearman相关系数分别为0.679(P=0.094)、-0.071(P=0.879)、-0.214(P=0.645)、-0.750(P=0.052)和-0.751(P=0.180)。
结论:
1.动物实验:RVPO_2是肾脏分泌EPO的重要决定因素;持续低氧暴露,s-EPO以及肾脏EPO的表达先升高后降低;低氧在翻译后水平上调控HIF-1α的表达;低氧和低氧训练过程中EPO的早期下降可能是通过肾脏aHIF下调HIF-1αmRNA介导的;
2.人体实验:高原训练效果一直存在争议,其中一个重要原因是人体对于低氧反应具有显著个体差异性;铁缺乏不是高原训练效果存在个体差异的主要原因;急性低氧暴露12 h,s-EPO和白细胞aHIF的积分变化可能是高原训练效果的预测因子。
Background and Objectives:
It becomes more popular for endurance athletes to improve their sea-level performance by altitude training,but its effect is controversial till now. Inter-individual variations in sea-level performance after altitude training have been attributed,at least in part,to an inter-individual variability in hypoxia induced erythropoiesis.Erythropoietin(EPO)may affect athletic performance by regulating erythropoiesis.The pattern and mechanism of EPO during altitude training is focused on by many researchers,especially the intriguing phenomenon—its early decline at altitude.Until now,about 100 target genes(hypoxia response gene,HRG),including EPO gene,have been shown to be regulated by hypoxia-inducible factor-1(HIF-1). aHIF,a natural antisense transcript of hypoxia-inducible factors 1α,complementary to the 3′-untranslated region of HIF-1αmRNA,is involved in HIF-1αmRNA regulation and therefore in HIF-1αprotein synthesis.So we presume that the early decline of EPO will be related to aHIF and response of EPO,HIF-1α,aHIF to acute altitude exposure migh be the sensitive molecular markers to identify poor and good responders to altitude training.The purpose of the research is:
1.reveal the mechanism that EPO is early declined during altitude training;
2.examine whether the change of maximal aerobic performance(graded cycle ergometer test)after training at moderate altitude(2366 m)could be predicted by response of serum EPO(s-EPO)and HIF-1α(s-HIF-1α),expression of HIF-1αmRNA and aHIF gene in leukocytes during 12 h exposure to normobaric hypoxia at an ambient PO_2 corresponding to the training altitude.
Methods:
1.Animal experiment:Six-week-old,sea-level native male Sprague-Dawley rats were randomizedly divided into four groups:Normoxic Control group(NC), Hypoxic Control group(HC),Normoxic Training group(NT)and Hypoxic Training group(HT).The latter three groups fell into three sub-groups:4 h group, 12 h group and 24 h group.Rats of NC and HC were exposed in normoxia and hypoxia(3000 m)environment respectively at rest;rats of NT and HT performed a treadmill exercise for 1 h at 70%MAV(maximal aerobic velocity).Serum EPO, RVPO_2(renal venous PO_2),kidney EPO,HIF-1αand aHIF gene expression were observed at corresponding time-point;
2.Human experiment:seven male university athletes were exposed to normobaric hypoxia(12h at 2366 m at rest)and s-EPO,s-HIF-1α,expression of HIF-lαmRNA and aHIF in leukocytes were measured at 0 h,4 h,8 h and 12 h respectively.Maximal aerobic performance was determined(graded cycle ergometer test)before and after 3-week altitude training at 2366 m.
Results:
1.Animal experiment:in HC and HT,EPO mRNA and EPO protein in kidney were significantly inceased at 4 h and 12 h and decreased at 24 h;RVPO_2 descended at 4 h and still lowered than NC;12 h of hypoxia did not change HIF-1αmRNA in kidney but decreased at 24 h;following the rapid induction of the HIF-1αprotein in kidney observed at 4～12 h,HIF-1αprotein levels diminished and fell to base-line level after 24 h;aHIF in kidney were elevated at 4 h and remained sustained until 12 h,reach peak at 24 h.
2.Human experiment:there is considerable inter-individual variation in s-EPO, s-HIF-1α,expression of HIF-1αmRNA and aHIF gene in leukocytes during acute normobaric hypoxia for 12 h(s-EPO:-11.1%～+308.4%,s-HIF-1α:-8.6%～+42.6%,HIF-1αmRNA:-33.3%～+42.6%,aHIF:-51.1%～+437.1%).The change of VO_(2max)also showed a similarly wide variability(-11.7%～+22.3%) after altitude training.Correlation analysis displayed that Spearman's correlation coefficient of the integration change of s-EPO,s-HIF-1α,expression of HIF-1αmRNA,aHIF,aHIF/HIF-lαmRNA in leukocytes and the change of VO_(2max) were 0.679(P=0.094),-0.071(P=0.879),-0.214(P=0.645),-0.750(P=0.052)and -0.751(P=0.180)respectively.
Conclusions:
1.Animal experiment:RVPO_2 is a determinative factor of EPO secreting;during sustained hypoxia,s-EPO and EPO gene expression in kidney are both inceased fast and then deceased;hypoxia-induced increases in HIF-1 are likely due to post-translational changes;aHIF in kidney is likely involed in early decline of serum EPO by down-regulation of HIF-1αmRNA during hypoxia and hypoxic training;
2.Human experiment:inter-individual variation in response to altitude training is mainly responsible for its controversial effect;iron-deficiency is not the predominant factor related to the inter-individual variation in response to altitude training;integration change of s-EPO and aHIF in leukocytes during 12 h exposure at 2366 m in resting conditions probably allows for prediction of poor and good responders to altitude training at 2366 m.
引文
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