陈淑婷,晁天乐,刘文萍
循环miRNA生物标记物的运动生理研究进展
陈淑婷1,晁天乐2,刘文萍3
1. 山东农业大学体育学院, 山东 泰安 271018 2. 山东农业大学动物科技学院, 山东 泰安 271018 3. 泰安市精神病医院, 山东 泰安 271018
运动是维持健康和预防疾病的最佳方法之一,而miRNA被认为是运动后体增益相关分子机制的关键调控因子。循环miRNA因其稳定性、分布广泛性、以及易检测性,特别有望成为未来的运动相关非侵入性生物标记物。基于循环miRNA的优点,构建比目前更易用、更精准的运动效果、运动能力评估方法,将积极影响当前的运动评估方法,并更好地监测运动反应。这篇综述总结了循环miRNA的当前知识,与运动有关的循环miRNA的最新研究进展,并论述了它们作为运动相关生物标记物的作用和前景。
循环miRNA; 运动生理; 生物标记物
生物标记物是对正常生物学过程、致病过程或对治疗干预的药理反应的客观测量和评估指标,可以提供生物体当前生理状态的准确信息[1]。临床表型测定、代谢产物和蛋白质是生物标记物主要来源[2]。近年来,循环miRNA越来越多的被推荐作为诊断和预后不同生理、病理状态的生物标记物,如糖尿病[3],肌肉损伤[4]和癌症[5,6]。
miRNA是短序列的非编码调控RNA,主要通过转录后负调控发挥功能,在广泛的细胞过程中起重要调节作用。运动训练有助于维持和改善健康,是许多疾病的有效非药物治疗方法[7]。早在2007年[8]和2011年[9]就有报道,miRNA能响应运动训练发生变化。从那时起,关于运动与miRNA之间关联的研究不断开展。这些研究表明,miRNA参与肌肉的发育、恢复和损伤,并与有氧运动能力直接相关。短期或长期运动会大幅改变肌肉和循环系统中miRNA的表达量。其中,循环系统miRNA因其分布特点和稳定性,成为了运动相关非侵入性生物标记物的候选分子[10,11]。但是,由于运动的复杂性及干扰因素的多样性,至今对于循环miRNA与运动间的具体关系所知甚少。此外,由于miRNA作用多样,很难理解不同生理状态下miRNA表达谱变化的实际意义。不同研究间的miRNA检测结果往往存在矛盾,这可能是研究的试验模型、运动条件、样品来源或分析方法差异等因素造成的。尽管如此,仍有迹象表明miRNA与特定运动类型能够对应,这增强了miRNA可用作运动相关生物标记物的可能性。本综述旨在总结运动相关循环miRNA的最新研究进展,探讨循环miRNA作为运动相关生物标记物的作用和面临的问题。
众所周知,坚持运动对维持心血管健康,提高认知和免疫功能,改善能量代谢均起到极大积极作用,也是改善生活质量的最好且最有效的方法之一[12]。定期运动可降低50%心血管疾病患病风险、29%癌症死亡率,以及52%的全因死亡率[13,14]。长期参与体育运动不但可改善生活质量,还能降低抑郁症和肾脏疾病风险[15-17]。由于体育运动能大幅提高人体健康,坚持运动还等于节省了医疗保健开支[18]。根据类型、强度和频率不同,运动可引发身体的急性或慢性变化,有氧/阻力运动、急性/慢性运动引起的生理变化各不相同[19]。在肌肉纤维中,运动通过机械刺激和代谢激活等途径调节蛋白编码基因和非编码基因的表达,其中包括miRNA[2,20]。
当前在人类基因组中,有2600多条miRNA获得正式命名。MicroRNAs是小分子的内源性非编码RNA,广泛参与基因转录后调控[21]。编码miRNA的基因通过RNA聚合酶II或III激活,转录到细胞核中,并通过一系列复杂生物学发生过程形成[22]。
在基因表达转录后调控中,miRNA能够通过靶向mRNA的3'-非翻译区或其他区域发生针对性结合[23]。如果靶标区域完全互补,则蛋白Ago2可以裂解靶标mRNA分子,致其降解;在部分靶向互补情况下,相互作用往往为翻译抑制[24]。因此,miRNA实际作用为引发靶标mRNA降解或翻译抑制,或两种过程组合发生[25]。
在已命名miRNA中,很大一部分被报道能通过多种生物学途径对各种细胞过程(包括发育、增殖和凋亡)起调节作用[25,26]。当前,越来越多的miRNA被发现参与肌肉发育调控,同时这些miRNA的表达受运动的调节。如miR-1,miR-133和miR-206三种miRNA在人体肌肉组织中高表达,且其表达受到运动的影响[27]。
在运动生理活动中,miRNA能够以组织特异性或时间特异性模式释放到体循环中,而机体中普遍的免疫反应以及活动中骨骼肌和心肌组织的适应性调节进一步影响了这种反应[28]。近年来,有多项研究指出,体循环中miRNA表达谱的改变可以作为某些生理适应或病理变化的分子标记[29-31]。
近年来发现,在血清、血浆、唾液、尿液、乳汁中稳定存在大量miRNA[32-35],这些miRNA被称作循环miRNA(circulating miRNA,ci-miRNA)。根据来源,可将循环miRNA分为三类:(一)遭受损伤、慢性炎症、细胞凋亡的细胞、或半衰期短的细胞(如血小板)发生被动泄漏产生的循环miRNA;(二)通过细胞衍生膜囊泡(如微粒,外泌体,脱落的囊泡和凋亡小体)主动分泌的循环miRNA;(三)通过蛋白质-miRNA复合物主动分泌产生的循环miRNA[31,36,37]。以上三种途径产生的miRNA均可进入循环系统或体液,并在运输至受体细胞位置后被吸收,吸收方式可以为内吞、膜融合或者配体-受体结合等多种方式[36]。
循环miRNA稳定性较高,其原因是:(1)部分循环miRNA被囊泡包裹,如外泌体或凋亡小体,避免了与核糖核酸酶的接触[38];(2)miRNA本身分子较小及特殊结构带来抗降解能力;(3)miRNA与蛋白质、核磷脂或高密度脂蛋白形成复合物提高了自身抗降解能力[38-40]。目前认为miRNA稳定性主要源自其对核糖核酸酶作用的抗性[41-43],这种稳定性意味着miRNA在各种体液中具备较长寿命,因此有成为标记物的潜力[31,40,44]。此外,由于循环miRNA可通过血液或其他体液采集,使得其在针对活体、尤其是人体的研究中应用更为简便,这也表明它们是生物标记物的理想来源[45]。内源性循环miRNA对严酷胁迫(如高温,反复冻融循环)、pH值过低或过高,和长存储时间等条件均有高抗性[40,46,47],但游离循环miRNA相对稳定性弱于囊泡和复合体循环miRNA[30]。此外,已进行稳定性测试的miRNA数量相当有限,是否所有miRNA均能在循环状态下保持高稳定性仍为未知[48]。综上而言,至少一部分循环miRNA已被发现具备较好的稳定性,符合生物标记物基本要求。
循环miRNA能够通过无创或微创方法进行样品收集[49-51],这一特征使循环miRNA具备以下优点:(1)避免了其他标记物样品可能涉及的侵入性手术;(2)为某些不能采集组织的重要器官(如心肌),提供了信息采集的可能;(3)避免了目标组织太小或难以取得带来的采样限制[31,52]。
循环miRNA的便捷性使其能够替代部分目前繁琐昂贵的检测方法,如X射线、计算机断层扫描(CT)、正电子发射断层扫描(PET)-CT、磁共振成像、超声检查等[31,53]。而根据目前病理学方面的研究结果,循环miRNA作为生物标记物的特异性和灵敏度相对较高。例如,循环miRNA表达量变化能够区分乍看相似,却需要不同治疗方案的疾病[31,53]。
如上所述,miRNA存在于几乎所有体液,完全满足生物标记物的相对可及性和最小侵入性原则。然而,与体组织相比,循环系统中的miRNA整体表达量偏低,因此循环miRNA的实际应用仍有许多问题需要注意[54]。
在运动引起的转录后水平分子调控过程中,循环miRNA被认为是重要的调控因子。多种miRNA已被确认在肌肉或心脏中特异性表达,可参与调节肌肉生长发育、代谢适应、肌肉损伤修复等生物学过程。健康状态下,这些miRNA在循环系统中表达量极低。因此,可通过检测表达量来将它们用作生物标记以测试特定运动方案效果或及早发现被测者对高运动量的异常反应(如心肌梗塞)[8,55,56]。
根据被测者、锻炼类型、持续时间和强度的不同,发生上调和下调的循环miRNA也会发生相应的变化[10,57]。例如,在急性耐力训练后,血清中miR-21、miR-221、miR-222和miR-146a的表达水平被发现瞬时升高,进一步分析发现它们主要与炎症、缺氧、血管生成和肌肉分化等生物学途径有关[9]。而其它研究中,在相同类型的锻炼后,miR-146a和miR-221的血清表达水平却非常低[58,59]。
miR-486在骨骼肌和心肌组织高表达,以70%最大摄氧量进行60 min稳态自行车运动后,发现miR-486表达量显著下降,且在24 h内恢复到基线水平。该研究也发现循环miR-486的变化率与最大摄氧量显著相关,表明循环系统miR-486表达量可能是有氧运动能力的生物标记物[58]。
循环系统中miR-1、miR-133a、miR-206、miR-208a和miR-499被发现在马拉松比赛后显著增加,且这些miRNA被证明与肌肉分化增殖有关。有观点认为,这种循环miRNA表达量增加是由于组织破坏和细胞凋亡引起的,或是由于骨骼肌细胞持续收缩,导致细胞内miRNA代谢和分泌增强引发的[60;61]。然而在同一项研究中,65%最大摄氧量下运动1 h未能影响循环miRNA表达水平,但这项研究还是发现循环miR-1,miR-133a,miR-206与运动员的有氧运动能力之间的相关性,并推断出它们作为有氧运动能力生物标记物的价值[60]。
近几年,循环miRNA在运动生理中的实际功能逐渐揭示。大鼠和人类志愿者运动试验表明,外泌体循环miRNA miR-342-5p是重要的心肌保护分子。miR-342-5p被发现能够通过靶向Caspase 9和Jnk2抑制缺氧、复氧诱导的心肌细胞凋亡,还通过靶向磷酸酶基因Ppm1f增强了细胞生存率,并在人体内源性心肌保护机制中起关键作用[62]。总的来看,循环miRNA在运动生理中确有实际调控作用,具有很高的生物标记物价值,但仍有待更加广泛和彻底的研究理解。
在运动生理学和运动医学中,试验设计对影响因素的错估或忽视往往是造成结果谬误的主要原因,而循环miRNA的研究应用也必须注意这一问题[63-65]。运动量的差异、被测者运动能力、被测者运动适应性、运动前或运动中饮食饮水等因素均可能影响分析结果[66,67]。
血样采集本身也是引入变异的原因之一。采集血样时的肌肉状态与多种物质含量相关[68]。采集血样时,使用止血带辅助采集会引起静脉淤滞,进而导致穿刺部位血液分析物浓度增加[69]。此外,其他常见误差源有:样品基质、抽血与样品处理之间的时间、样品存储时间、样品存储温度等[70-74]。在多因素影响的外界环境下和机体内不稳定的生化环境下,循环miRNA的准确测量颇为困难[30]。
目前,在不同类型循环miRNA中,最常用的当属血清miRNA。但采血、运输和存储过程可能污染样品[75],采血针头中的少量组织细胞、或血样溶血都可导致血清miRNA污染[75,76]。miRNA可以在凝血过程中由血小板释放,也可从溶血性红细胞中释放出来[76,77]。在后一种情况下,使用miR-23a与miR-451的ΔCT比可用于检查微溶血事件(如果为N 7则为溶血),进而判断样品污染程度[78]。
在开发新型生物标记物时,正确的样品基质至关重要,其对最终研究结果影响极大[79,80]。有报道称相同物种个体之间血清miRNA表达模式稳定,测定结果可重复且一致性较好[32],其他研究证明血浆来源miRNA也有类似性质[33]。
部分抗凝剂对血样中miRNA浓度能够造成影响,因此应慎重选择。肝素和柠檬酸均为常见血液抗凝剂,但它们均能干扰PCR反应酶活性,因此在miRNA的qPCR定量中,不建议将这两种抗凝剂处理过的血样与其它类型样品混用[81,82]。与肝素不同,EDTA可从PCR反应混合物中去除,因此被认为是基于PCR的miRNA分析样品最佳抗凝剂[83]。NaF/KOx抗凝血浆常被认为是EDTA的合适替代品,但可能影响miRNA检测结果[84]。
血样的离心时间和离心速度也会严重影响EDTA血浆样品中的最终miRNA浓度,因为它可能会导致血小板衍生的miRNA污染[48]。血清miRNA则对这种预处理变异不太敏感[85]。
目前,测量循环miRNA的主要方法是qRT-PCR、芯片检测和二代测序技术(NGS)。
qRT-PCR技术可应用于各种不同类型RNA分子的定量检测与比较,在循环miRNA检测中始终起到重要的作用。miRNA的qRT-PCR检测主要有茎环引物法和多聚腺苷酸尾PCR法[86]。qRT-PCR技术特异性好、检测快、成本低,但亦有试验操作繁琐、单次检测miRNA数量少等劣势。
芯片检测也称微阵列,是检测核酸突变和RNA表达量的常用技术。核酸芯片基于qPCR或杂交技术,通过探针一次测定大量靶RNA的表达量或碱基突变信息[5,87]。芯片的局限性包括酶标记中的序列特异性标记偏倚,缺乏绝对定量能力以及相对较低的动态范围。此外,miRNA芯片的另一缺陷是对探针设计的依赖性,无法用于检测和发现新miRNA[5]。
二代测序技术具有很高的动态检测范围、灵敏度和可重复性,在扩大检测范围,提高结果准确性方面均具有优势。该技术既能检测已知miRNA,也可以鉴定新型miRNA。二代测序的局限性主要涉及技术问题,如酶促连接导致的序列特异性偏倚。值得注意的是,尽管二代测序技术成本快速下降,miRNA测序的价格却始终变化不大,因此循环miRNA的检测仍需注意多方法结合使用。
近年来,循环miRNA作为运动相关生物标记物的潜力越来越重要。通过检测各种体液中大量存在的循环miRNA,可实现对各种类型运动适应症状或运动能力的快速无创或微创检测分析。此外,低成本、易检测使循环miRNA成为运动相关分子机制研究中的潜在生物标记。当前,循环miRNA广泛应用的主要障碍是难以保证样本质量和完整性。尽管目前仍有方法学上的问题存在,但只要正确使用试剂、选择适合的RNA提取方法、以及避免样本污染,循环miRNAs仍可为运动生理学的检测、诊断和分析提供准确的信息。总的来说,循环miRNAs作为运动相关生物标记物的临床应用潜力极大,但还需通过更多研究来进一步验证。
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Research Progress of Circulating miRNA as Biomarker in Exercise Physiology
CHEN Shu-ting1, CHAO Tian-le2, LIU WEN-ping3
1.271018,2.271018,3.271000,
Exercise is one of the best ways to maintain health and prevent disease, and miRNA is considered to be a key regulatory factor related to exercise benefits. Because of its stability, wide distribution and easy detection, circulating miRNA is expected to become a non-invasive exercise related biomarker in the future. Based on the advantages of circulating miRNA, the construction of a more easy-to-use and more accurate method for the evaluation of motor effect and motor ability will positively affect the current method of motor evaluation and better monitor the exercise response. This review summarizes the current knowledge of circulating miRNAs, the latest research progress of miRNAs related to exercise, and discusses their functions and prospects as biomarkers related to exercise.
Circulating miRNA; exercise physiology; biomarker
G804.23
A
1000-2324(2022)01-0163-08
10.3969/j.issn.1000-2324.2022.01.025
2021-02-10
2021-03-21
陈淑婷(1975-),女,硕士,副教授,长期从事高校体育教育与运动生理学研究. E-mail:wfdzz@sdau.edu.cn