Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and 
exercise-induced skeletal muscle adaptations

doi:10.3969/j.issn.2095-4344.2013.50.020

Abstract

Abstract:

BACKGROUND: Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) may play
an important role in the exercise-induced skeletal muscle adaptation, which is involved in the regulation of a
variety of exercise-induced biological reactions.
OBJECTIVE: To review the PGC-1α and endurance training induced skeletal muscle adaptations.
METHODS: The relevant articles about relationship between PGC-1α and endurance training-induced skeletal muscle adaptations were searched from PubMed database (1995-01/2010-10) by using the keywords of “PGC-1α, skeletal muscle, exercise, mitochondrial biogenesis, adaptations”, and the language was limited to English. Repetitive contents were deleted. The 59 collected articles were searched. According to the criterion, 37 were classified and sorted.
RESULTS AND CONCLUSION: Endurance training can typically increase the expression/activity of membrane transporters and mitochondrial metabolic enzymes as well as increase capillarisation in the skeletal muscle, together enhancing the oxidative capacity of the muscle and the ability to oxidize both carbohydrates and fatty acids. Studies in PGC-1α knockout and overexpression mice have clearly demonstrated that PGC-1α plays an important role in maintaining the expression of mitochondrial metabolic and anti-oxidant enzymes in the skeletal muscle and does influence exercise-induced adaptations of mitochondrial proteins. However, PGC-1α is not exclusively required, and additional factors must be involved in the regulation of both basal expression and exercise-induced adaptations. Exercise-induced PGC-1α expression and potentially increased PGC-1α activity are likely the mechanisms contributing to skeletal muscle mitochondrial adaptations and concomitant health beneficial effects of regular physical activity.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

Key words: activating transcription factor 1, resistance training, muscles, skeleton, mitochondria

CLC Number:

R318

Zhou Jian-xin, Ma Ji-zheng. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and
exercise-induced skeletal muscle adaptations[J]. Chinese Journal of Tissue Engineering Research, doi: 10.3969/j.issn.2095-4344.2013.50.020.

Figures/Tables 1

2.1 文献检索结果及质量评价计算机初检得到59篇文献，均为英文。阅读标题和摘要进行初筛，排除因研究目的与此文无关的10篇，内容重复性的研究12篇，共保留37篇文献做进一步分析。 2.2 文献证据综合提炼 2.2.1 PGC-1α对骨骼肌肌产生的影响 PGC-1α与线粒体的生物合成：PGC-1α广泛表达于心脏、肝脏、脑部、脂肪组织和骨骼肌。已发现PGC-1α在这些组织中相关的功能包括调节糖异生蛋白、抗氧化物和线粒体的生物合成[2]。细胞培养和小鼠骨骼肌PGC-1α高表达的研究表明PGC-1α是线粒体的生物合成重要的刺激物[3-4]。PGC-1α过表达小鼠白色糖酵型骨骼肌转变为红色氧化型骨骼肌，同时伴随着细胞色素氧化酶Ⅱ、Ⅳ、ATP合成酶mRNA表达增加[4]，细胞色素C[4]、肌红蛋白和细胞色素氧化酶Ⅰ的蛋白含量增加[4-5]，柠檬酸合酶活性提高[6]。相反，PGC-1α基因敲除的小鼠线粒体呼吸链蛋白、ATP合成酶mRNA表达/蛋白含量降低[7-8]。这些研究证据表明PGC-1α一个主要功能参与调节线粒体的生物合成。 PGC-1α与脂肪代谢：PGC-1α过表达于细胞培养时，可提高脂肪酸氧化酶mRNA表达，如肉碱棕榈酰转移酶Ⅰ和中链酰基辅酶A脱氢酶[9]。长期的和可诱导PGC-1α过表达小鼠骨骼肌脂肪酸转位酶/CD36、肉碱棕榈酰转移酶Ⅰ和中链酰基辅酶A脱氢酶mRNA表达增加[4-5]，但是，PGC-1α基因敲除的小鼠或过表达这些蛋白动物研究表明PGC-1α参与脂肪代谢调节的作用有限。 PGC-1α与碳水化合物的代谢：同样，PGC-1α过表达于细胞培养时，葡萄糖转运蛋白4(GLUT4)的mRNA表达增加[3]，PGC-1α基因敲除的小鼠GLUT4的mRNA表达和蛋白含量降低[10]，PGC-1α过表达小鼠GLUT4的mRNA表达增加[6]，这些研究表明PGC-1α能够调节骨骼肌GLUT4的表达。但是，PGC-1α基因敲除的小鼠骨骼肌己糖激酶Ⅱ的mRNA表达和蛋白含量不变[11]，骨骼肌特异PGC-1α过表达小鼠己糖激酶Ⅱ的mRNA表达同样不变[6]。另外，研究业已显示可诱导的和骨骼肌特异PGC-1α过表达小鼠己糖激酶Ⅱ的蛋白含量增加[1]，这一研究表明尽管PGC-1α高表达伴随着己糖激酶Ⅱ的蛋白含量增加[1]，但是，PGC-1α不是调节基础己糖激酶Ⅱ表达所必须的，己糖激酶Ⅱ不是PGC-1α的直接目标。 PGC-1α与底物的利用：PGC-1α不但能够影响骨骼肌的氧化能力，同时也能够急性调节底物的选择。丙酮酸脱氢酶复合体是这一调节的中心，催化丙酮酸不可逆的氧化脱羧转化成乙酰辅酶A，将糖的有氧氧化与三羧酸循环和氧化磷酸化连接起来。磷酸化丙酮酸脱氢酶复合体的E1α可激活丙酮酸脱氢酶复合体活性。其活性由丙酮酸脱氢酶激酶和丙酮酸脱氢酶磷酸化蛋白决定。丙酮酸脱氢酶激酶起抑制作用，丙酮酸脱氢酶磷酸化蛋白起激活作用[12]。细胞培养和小鼠均发现PGC-1α参与丙酮酸脱氢酶复合体调节，PGC-1α调节酮酸脱氢酶激酶4的表达[13-14]。另外，大鼠的骨骼肌研究发现，过氧化物酶体增殖物受体δ激动剂可下调丙酮酸脱氢酶复合体活性，上调酮酸脱氢酶激酶4活性[15]。这些研究表明PGC-1α介导的酮酸脱氢酶激酶4活性的调节，可能通过抑制丙酮酸脱氢酶复合体活性、持续增加骨骼肌脂肪的氧化。 PGC-1α介导的调节同样可影响骨骼肌糖原的水平。PGC-1α基因敲除小鼠肌糖原含量下降[16]，PGC-1α过表达小鼠糖原含量增加[10]。但是，Wende等[10]的研究发现过表达骨骼肌特异PGC1α转基因小鼠在进行大强度运动时，运动能力下降，其原因可能是不能利用肌糖原。但是，最近研究认为过表达骨骼肌特异PGC1α转基因小鼠在运动时可利用肌糖原[1]。其中差异的原因有待于进一步研究。相互调节：通过操纵培养的细胞和小鼠骨骼肌PGC-1α含量可影响线粒体的和核编码线粒体蛋白的mRNA表达或蛋白含量的变化[10,16-17]。尽管两种不同基因组编码呼吸链各种蛋白，PGC-1α可能协调物保证这些蛋白变化的平衡。另外，研究发现在培养的细胞，PGC-1α可调节线粒体转录因子Tfam的变化[17]。缺失PGC-1α可降低小鼠骨骼肌Tfam的mRNA表达[1]。PGC-1α基因敲除的小鼠骨骼肌氨基酮戊酸合酶(亚铁血红素合成限速酶)降低[8,16]，表明PGC-1α参与调节细胞色素C。PGC-1α过表达小鼠肌红蛋白含量增加[4,10]，PGC-1α基因敲除的小鼠肌红蛋白含量的mRNA表达降低[16]，进一步证实PGC-1α可能涉及到参与调节骨骼肌氧化代谢的几个重要的途径。 PGC-1α与抗氧化物：随着氧化能力的提高，线粒体氧自由基生成会增加。平衡调节呼吸链的蛋白和线粒体抗氧化酶将非常有利。PGC-1α同样可调节抗氧化蛋白的表达。与野生型小鼠相比，PGC-1α基因敲除小鼠的超氧化物歧化酶1、2和谷胱甘肽过氧化物酶1的mRNA表达降低[8,16]、超氧化物歧化酶2蛋白含量减少[18-19]。相反，PGC-1α过表达小鼠骨骼肌超氧化物歧化酶2蛋白含量增加[5]。另外，研究还发现与野生型小鼠成纤维细胞相比，PGC-1α基因敲除小鼠的成纤维细胞表现出：减少H2O2可诱导超氧化物歧化酶 2、过氧化氢酶和谷胱甘肽过氧化物酶1的mRNA表达增加。进一步表明PGC-1α参与调节抗氧化蛋白的表达[20]。在培养细胞，PGC-1α参与调节脱偶连蛋白2和3的表达，表明PGC-1α可以增加脱偶连能力，降低线粒体氧自由基生成[21]。这些研究表明PGC-1α可通过调节两种蛋白：减少氧自由基生成的蛋白和清除氧自由基蛋白来提高骨骼肌抗氧化的能力。 2.2.2 PGC-1α介导代谢调节功能性作用 PGC-1α基因敲除小鼠的耐力跑的能力降低，相反，PGC-1α过表达小鼠的耐力跑的成绩和最大摄氧量提高[1]。另外，在低强度和最大强度运动时，PGC-1α过表达小鼠的气体交换率较低，表明高表达PGC-1α的骨骼肌在运动时可提高脂肪酸的利用。在最大强度运动时，PGC-1α过表达小鼠的气体交换率值低于1，表明过表达PGC-1α的小鼠在最大强度运动时能够维持较高碳水化合物的氧化，避免乳酸在血液和骨骼肌中的积累[6]。这些研究表明由于分子的变化可引起运动时骨骼肌出现生理性改变。 2.2.3 PGC-1α和炎症最近的一些研究表明PGC-1α可能具有抗炎症效果[22]。PGC-1α基因敲除小鼠骨骼肌炎症标志物的基础mRNA高表达，如肿瘤坏死因子α、白细胞介素6、细胞因子信号传导抑制因子1和2[23-24]。相反，骨骼肌特异PGC-1α过表达小鼠骨骼肌肿瘤坏死因子α和白介素6的mRNA较低，生命延长，降低与年龄相关肿瘤坏死因子α和白细胞介素6的增加；与老龄野生小鼠相比，血清中的肿瘤坏死因子α和白细胞介素6降低[5]。一次急性运动可显著增加PGC-1α基因敲除小鼠骨骼肌肿瘤坏死因子α的mRNA的表达，提高血清中的肿瘤坏死因子α含量[23]。这些研究表明PGC-1α可保护性抵抗运动诱导肿瘤坏死因子α增加，但其中确切机制不明。 2.2.4 PGC-1α的调节 PGC-1α的表达：一次急性运动可调节骨骼肌PGC-1α的表达。一次急性游泳可上调PGC-1α的mRNA表达[25]。同样的，一次急性运动可提高人类骨骼肌PGC-1α的mRNA含量[26]。细胞培养和转基因动物研究表明细胞内钙的浓度可能参与调节PGC-1α基因的表达[27-28]。运动时，氧自由基的增加可能参与PGC-1α调节。αβγ三聚体腺苷酸活化蛋白激酶(AMPK)可能涉及到PGC-1α调节[29]。另外，运动后恢复期8h内，通过饮食操纵，降低骨骼肌的肌糖原可提高PGC-1α的mRNA，表明底物可利用性同样影响PGC-1α表达[30]。运动时，上述这些因素均会发生变化，从而参与调节运动诱导PGC-1α的变化。转录后修饰：PGC-1α不但可通过表达的变化进行调节，而且存在还存在共价修饰包括磷酸化、乙酰化、甲基化和泛素化[1,31-32]。体外实验研究显示p38丝裂原活化蛋白激酶(MAPK)可在3个位点上磷酸化PGC-1α，激活和维持PGC-1α蛋白的稳定[32]。同样的，AMPK可在2个位点上进行磷酸化，激活PGC-1α。另外，乙酰基转移酶可乙酰化PGC-1α进行重新定位[31]。依赖于烟酰胺腺嘌呤二核苷酸(NAD+)的组蛋白脱乙酰酶1(Sirt1)可去乙酰化PGC-1α，维持其活性[33]。 2.2.5 PGC-1α和训练诱导的适应机制 PGC-1α基因敲除或过表达转基因小鼠研究表明PGC-1α可能在耐力性的骨骼肌适应方面起着主要的作用，另外，运动可诱导AMPK、p38 MAPK和Sirt1发生适应[31-32,34]，从而调节PGC-1α的变化。与野生小鼠相比，4周耐力训练后，PGC-1α基因敲除小鼠骨骼肌细胞色素C、CD31和COXIV的增加减少[18]，2周耐力训练，不能增加PGC-1α基因敲除小鼠骨骼肌线粒体的密度[13]。研究同样发现PGC-1α参与运动性超氧化物歧化酶2适应[19]。另外，运动训练诱导补偿机制不但出现于PGC-1α基因敲除，同时还出现AMPK基因敲除小鼠[35]，表明多种信号通路涉及到运动性骨骼肌的适应机制，PGC-1α只是其中的一种。Leick等[16]研究发现整体PGC-1α基因敲除小鼠5周耐力训练后，骨骼肌细胞色素C、CD31、COXI和己糖激酶Ⅱ表达增加，表明PGC-1α不是运动性骨骼肌适应机制的唯一通路。 2.2.6 PGC-1α和体力活动缺少体力活动骨骼肌氧化能力的降低可能和缺少运动诱导PGC-1α表达有关。老龄化和2型糖尿病患者骨骼肌氧化酶活性和含量降低[36-37]。随着年龄的增加，PGC-1α表达减少。部分原因可能和缺少运动有关：缺少运动诱导的相关基因的表达。研究发现对于胰岛素抵抗患者，运动后PGC-1α表达的增加减少，表明2型糖尿病患者需要更多的运动刺激来获得运动的益处[36]。"

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