动物营养学报 >

2024 , Vol. 36 >Issue 5: 2856 - 2871

DOI: https://doi.org/10.12418/CJAN2024.246

综述

蛋氨酸调控肌肉发育的研究进展

  • 符健慧 ,
  • 王海波 ,
  • 钟金城 , *
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  • 西南民族大学草地资源学院,青藏高原动物遗传资源保护与利用四川省重点实验室,成都 610041
* 钟金城,教授,博士生导师,E-mail:

符健慧(1999—),女,海南五指山人,硕士研究生,从事牦牛遗传育种及营养研究。E-mail:

Office editor: 田艳明

收稿日期: 2023-11-13

  网络出版日期: 2024-05-15

基金资助

国家自然科学基金青年基金项目(32102577)

国家现代农业产业技术体系项目(CARS-37)

四川省自然科学基金项目(2022NSFSC1623)

西南民族大学中央高校基本科研业务费专项资金资助(2023NYXXS096)

国家重点研发计划项目(2022YFD1601601)

青海省重点研发与转化项目(2022-NK-110)

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Research Progress of Methionine Regulating Muscle Development

  • FU Jianhui ,
  • WANG Haibo ,
  • ZHONG Jincheng , *
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  • Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Conservation and Utilization of Sichuan Province, College of Grassland Resources, Southwest Minzu University, Chengdu 610041, China
* professor, E-mail:

Received date: 2023-11-13

  Online published: 2024-05-15

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摘要

近年来,随着生活水平的提高,人们对于肉制品数量及质量的要求越来越高。肌肉占畜禽胴体重量的40%~50%,是人类获取动物源蛋白质的重要来源,其发育过程受遗传、营养及性别等因素的调控,其中营养摄入起着至关重要的作用。蛋氨酸(Met)作为多数动物生长的主要限制性氨基酸,参与机体蛋白质代谢,是畜禽常用的饲料添加剂之一。因此,本文总结了Met吸收和代谢过程及其在肌肉发育中的应用,同时结合肌肉的结构组成、发育和再生过程,详细阐述Met调控肌肉发育的机制,为改善动物饲粮配方和提升产肉性能提供参考依据。

关键词： 蛋氨酸; 肌肉发育; 蛋白质合成; 机制

本文引用格式

符健慧 , 王海波 , 钟金城 . 蛋氨酸调控肌肉发育的研究进展[J]. 动物营养学报, 2024 , 36(5) : 2856 -2871 . DOI: 10.12418/CJAN2024.246

Abstract

In recent years, with the improvement of living standards, people have higher and higher requirements for the quantity and quality of meat products. Muscle accounts for 40% to 50% of the carcass weight of livestock and poultry, and is an important source of animal protein for humans. Its development process is regulated by genetic, nutritional and gender factors, among which nutrient intake plays a crucial role. Methionine (Met), as the main limiting amino acid for most animal growth, participates in protein metabolism and is one of the commonly used feed additives for livestock and poultry. Therefore, this paper summarized the processes of Met absorption and metabolism and its application in muscle development, combined with the structural composition, development and regeneration processes of muscle, elaborated the mechanism of Met regulation of m、uscle development, and provided a reference for improving animal diet formula and improving meat production performance.

Key words： methionine; muscle development; protein synthesis; mechanism

随着社会经济和畜牧业的迅速发展,消费者对肉制品数量和质量的需求大幅度增长[1]。肌肉作为畜禽躯体的重要组成部分,在调控机体新陈代谢、调节运动和储存能量等方面至关重要,其发育状况会对肉制品的产量和品质产生巨大影响[2]。肌肉的生长和发育可大致分为2个阶段:一是在胚胎期,此阶段主要是成肌细胞的生长发育和肌原纤维的增加;二是在动物出生后,此阶段肌纤维数量基本不变,通过肌卫星细胞的增殖和分化促进肌肉的发育[3-4]。同时,肌肉的发育过程受众多转录因子和信号通路的调控,主要包括生肌调控因子(myogenic regulatory factors,MRFs)家族、胰岛素样生长因子-Ⅰ(insulin-like growth factor-Ⅰ,IGF-Ⅰ)、肌肉生长抑制素(myostatin,MSTN)、自噬溶酶体通路(autophagic lysosomal pathway,ALP)和线粒体凋亡通路等[4-5]。研究证实,蛋白质是动物体内不可缺少的营养素,对肌肉发育具有重要的调控作用[6-7]。而豆粕作为饲料工业中最常用的蛋白质原料,由于其成本不断上涨且市场供需紧张,迫使学者们开始通过营养调控手段,降低饲料成本并实现优质肉制品的生产,且目前较多采用的是低蛋白质饲粮添加氨基酸的模式[8⇓-10]。蛋氨酸(methionine,Met)是唯一的含硫必需氨基酸,参与机体多胺和蛋白质合成代谢,是许多动物生长的主要限制性氨基酸,也是畜禽养殖业常用的饲料添加剂之一[11⇓-13]。研究证实,补充适量Met可促进蛋白质的合成,改善动物的肌肉发育,有效提高动物的产肉性能;但Met添加过量亦会引起动物生长抑制、蛋白质合成障碍等一系列疾病产生,严重时甚至会导致死亡[14⇓-16]。因此,本文总结了Met的吸收和代谢过程以及在肌肉发育中的应用,并结合肌肉的结构组成以及其发育和再生过程,阐述Met调控肌肉发育的机制,旨在为Met的利用与开发以及改善动物产肉性能提供理论依据。

1 Met的吸收和代谢过程及其在肌肉发育的应用

1.1 Met的吸收和代谢过程

Met又称为2-氨基-4-甲疏基丁酸或甲硫氨酸,化学式为C5H11NO2S,相对分子质量为149.21[17]。它是一种白色的粉末状或片状结晶体,具有微弱含硫化合物气味,熔点大约在280 ℃[17-18]。Met既溶于95%乙醇,也溶于稀酸和稀碱;但在强酸下不稳定,易产生脱甲基作用[19]。Met因其旋光性差异可分为L型(左旋)和D型(右旋)[20]。其中,L-Met通过Met转运系统进行主动运输,在回肠和十二指肠中被吸收[21];D-Met也是通过主动运输的方式被吸收,经过D-氨基酸氧化酶和转氨酶的催化可以转化为L-Met[22]。此外,DL-Met、羟基蛋氨酸(OH-Met)、DL-2-羟基-4-甲硫基丁酸(HMTBA)和瘤胃保护性蛋氨酸(RP-Met)均为饲料工业中常用的Met形式[23]。DL-Met含有50%的左旋异构体,主要通过多个载体介导的转运蛋白系统被主动转运吸收[23-24];OH-Met则是羟基取代α-碳上氨基的一种有机酸,可进行主动转运和被动扩散[23];HMTBA为蛋氨酸羟基类似物,主要通过扩散和氢离子依赖性载体介导的转运蛋白系统进行吸收[25-26];RP-Met是利用化学或物理法处理的单体Met,在通过反刍动物瘤胃时可不被微生物降解,直接到达小肠被吸收和利用[22,27]。任何形式的Met最终都需要转化为L-Met才能参与机体内的中间代谢或蛋白质合成过程[28-29]。
Met主要在肝脏中进行代谢,包括4个途径(图1)[30]。1)甲基转移途径:Met首先通过蛋氨酸腺苷转移酶的催化转化为S-腺苷蛋氨酸(S-adenosylmethionine,SAM),然后经过甲基转移酶催化生成S-腺苷同型半胱氨酸(S-adenosine homocysteine,SAH),并将活性甲基转移至不同甲基受体上,参与核酸的合成与修饰,从而影响基因的转录和表达[31]。2)再甲基化途径:SAH在腺苷高半胱氨酸水解酶的作用下,被水解为腺苷和同型半胱氨酸(homocysteine,Hcy);随后通过甜菜碱或叶酸提供甲基再甲基化生成Met,是Met再生的主要途径[28,32]。3)生物胺合成途径:SAM经过S-腺苷蛋氨酸脱羧酶的催化转化为脱羧S-腺苷甲硫氨酸(decarboxyl S-adenosine methionine,dcSAM);随后通过多胺合成酶的催化作用,合成亚精胺和精胺并转变为甲硫腺苷(methyl-adenosine,MTA);最后通过多步催化反应重新合成Met,是Met再生的另一途径[20,33]。4)硫基转移途径:Hcy经过胱硫醚-β-合酶催化转化为胱硫醚(cystathionine,Cysta);随后在胱硫醚γ裂解酶催化转变为半胱氨酸(cysteine,Cys);最后通过一系列酶催化作用,参与谷胱甘肽(glutathione,GSH)、牛磺酸(taurine,Tau)和胱氨酸(dicysteine,Cys-Cys)等物质的合成[11,34]。
图1 Met代谢途径

SAM:S-腺苷蛋氨酸 S-adenosylmethionine;SAH:S-腺苷同型半胱氨酸 S-adenosine homocysteine;Betaine:甜菜碱;DMG:二甲基甘氨酸 dimethylglycine;Met:蛋氨酸 methionine;THF:四氢叶酸 tetrahydrofolate;5,10-CH2-THF:5,10-甲基四氢叶酸 5,10-methyl tetrahydrofolate;5-CH2-THF:5-甲基四氢叶酸 5-methyl tetrahydrofolate;dcSAM:脱羧S-腺苷甲硫氨酸 decarboxyl S-adenosine methionine;Put:腐胺 putrescine;Spd:亚精胺 spermidine;Spm:精胺 spermine;MTA:甲硫腺苷 methyl-adenosine;MTR-1p:5-甲硫核酸-1-磷酸 5-methylthioribose-1-phosphate;KMTB:α-酮-γ-甲硫基丁酸 α-keto-γ-methylthiobutyric acid;Hcy:同型半胱氨酸 homocysteine;Cysta:胱硫醚 cystathionine;Cys:半胱氨酸 cysteine;GSH:谷胱甘肽 glutathione;Tau:牛磺酸 taurine;Cys-Cys:胱氨酸 dicysteine;X:甲基受体 methyl receptor;MTs:甲基转移酶 transmethylase;BHMT:甜菜碱同型半胱氨酸甲基转移酶 betaine homocysteine methyltransferase;MS:5-甲基四氢叶酸高半胱氨酸甲基转移酶 5-methyltetrahydrofolate homocysteine methyltransferase;SAMDC:S-腺苷蛋氨酸脱羧酶 S-adenosylmethionine decarboxylase;SPDS:亚精胺合成酶 spermidine synthase;SPMS:精胺合成酶 spermine synthase;MTAP:甲硫腺苷磷酸化酶 methyl-adenosine phosphorylase。

Fig.1 Met metabolic pathways[11,28,35]

1.2 Met在肌肉发育中的应用

1.2.1 Met对家禽肌肉发育的作用

Jariyahatthakij等[36]在低蛋白质饲粮中添加0.37% DL-Met,可显著提高生长期肉鸡的胴体重、胸肌重和腿肌重。曾雨佳等[37]饲喂肉鸡3种不同Met水平的饲粮发现,当Met水平为0.25%时,19周龄肉鸡的腹脂率较高;当Met水平为0.34%时,19周龄肉鸡的胸肌率较高;当Met水平为0.42%时,21周龄肉鸡的腿肌率较高。Wu等[38]提高北京鸭饲粮中的L-Met水平(0.31%~0.56%),可显著提高腿肌重,同时胸肌重也有提高的趋势。李德生等[39]对雏鹅胚蛋注射DL-Met营养液,可显著提高雏鹅孵化第27天至出壳后第7天的胸肌重,并且出壳当天和出壳后第7天胸肌纤维直径也显著增大。

1.2.2 Met对单胃动物肌肉发育的作用

Li等[40]在初生重较低的仔猪饲粮中添加0.6% L-Met,可以促进其骨骼肌发育并增加背最长肌横截面积。原培强[29]对三元仔猪饲喂添加DL-Met或HMTBA饲粮,均显著提高母猪背最长肌的持水力和嫩度,但其肌纤维的横截面积减小。Da Silva等[41]在高温条件下饲喂仔猪高水平DL-Met或OH-Met饲粮可显著提高其胴体重和瘦肉率,此外添加OH-Met还会增加其眼肌深度。Edmonds等[42]对后期育肥猪饲粮添加不同水平DL-Met(2.0%~2.8%),可提高其胴体性状,且瘦肉率均超过56%,屠宰率均超过76%,尤其以添加1.5%~2.3% DL-Met改善眼肌深度和背膘厚的效果较好。

1.2.3 Met对反刍动物肌肉发育的作用

Zhang等[43]在围产期母羊饲粮中添加RP-Met可提高饲粮的粗蛋白质利用率,并提高羔羊的生长性能和肉品质,其中添加0.06% RP-Met可使羔羊的屠宰率和净肉重最高。曹广等[44]在湖羊饲粮中添加2 g/kg RP-Met,可显著提高其胴体重、净肉重和净肉率,并降低其背最长肌的蒸煮损失。张艳梅[45]研究发现,提高滩羊饲粮RP-Met水平可提高其宰前活重、屠宰率、胴体重和净肉率,其中添加4.5 g/d RP-Met可使滩羊获得最高的净肉率和最低的骨肉比。Baggerman等[46]研究表明,肉牛背最长肌面积随着饲粮Met水平的提高呈线性提高;其中添加13.47 g/d RP-Met肉牛的细胞核密度相较对照组提高近55%;生肌因子(myogenic factor,Myf)5阳性卫星细胞的密度随着饲粮Met水平的提高而下降,而表达配对盒蛋白7(Pax7)的细胞密度趋于增加,表明饲粮添加Met可能增加卫星细胞融合肌纤维的潜力。
以上研究表明,饲粮中补充适量Met能够促进不同畜禽物种的生长,并提高动物的产肉性能。但由于其物种、身体构造和生长阶段之间的差异,动物生长所需Met的使用形式和最适水平也存在不同。

2 肌肉发育过程

2.1 肌肉结构组成

肌肉是动物胴体中重要组成部分,也是畜牧生产的重要经济性状之一[47]。根据其形态特征和功能差异,肌肉可分为3类:心肌、平滑肌和骨骼肌[48]。心肌仅存在于心脏,组成心壁;平滑肌构成血管壁和内脏器官;骨骼肌负责维持机体运动和能量平衡[49]。同时,骨骼肌还是动物体内最大的肌肉组织,由肌纤维、神经、血管和结缔组织等多种组织组成[48]。肌纤维作为肌肉的基本单位,最外层包裹一层富含肌卫星细胞的肌纤维膜,内部则包含一个由肌浆网包围肌原纤维而成的细胞骨架[1,50]。每条肌原纤维由许多重复的肌节构成,肌节中的肌动蛋白和肌球蛋白可分别形成细肌丝和粗肌丝,二者通过相互嵌合和滑动完成肌肉收缩和舒张功能[47]。成束的肌纤维在肌束膜包裹下形成肌束,各个肌束又由肌内膜进行分隔,最终在富含血管和神经纤维的肌外膜包裹下,通过肌腱附着于骨骼上形成肌肉组织[48,51]。

2.2 肌肉的生长及再生

肌肉的生长发育涉及蛋白质合成、细胞增殖、分化及融合等过程,一般会经历初级肌肉发育和次级肌肉发育2个阶段[52]。初级肌肉发育是指胚胎时期由轴旁中胚层细胞发育形成体节,背侧体节进一步发育生成生肌节,随后增殖形成肌肉祖细胞(也称为肌卫星细胞),经进一步分化为成肌细胞;次级肌肉发育则是由成肌细胞进一步融合形成肌管,肌管延伸并与卫星细胞或其他成肌细胞融合形成肌原纤维,随后进一步分化形成肌纤维,经过持续生长和发育形成肌束,从而发育为成熟的肌肉组织[47]。动物出生前,肌纤维数量的增长是影响肌肉发育的主要因素;动物个体出生后肌纤维数量基本不再增加,动物的肌肉发育主要依赖肌卫星细胞的增殖和分化[53⇓-55]。当骨骼肌受损或受到外界刺激时,静息状态的卫星细胞会被激活并产生大量成肌细胞,经进一步分化及融合修复受损肌纤维,促进骨骼肌的再生[56-57]。

3 Met调控肌肉发育的信号通路

一般来说,骨骼肌质量主要取决于净蛋白质平衡,即蛋白质合成与分解之间的动态平衡[58-59]。正蛋白质平衡会增加肌肉质量,负蛋白质平衡则会减少肌肉质量[59]。并且,肌纤维损失或肌卫星细胞再生亦会对肌肉质量产生一定影响[59]。研究发现,Met水平变化会影响动物体内的净蛋白质平衡。机体Met水平较低,动物体内处于正蛋白质平衡状态,骨骼肌质量减少,肌纤维横截面积也相对减小,导致肌肉力量下降;而Met水平较高,动物体内处于负蛋白质平衡状态,骨骼肌质量则会增加,同时肌纤维的横截面积也相对增加,进而导致肌肉力量的增强。经过汇总发现,Met调控肌肉发育的过程,会受到MRFs、IGF-Ⅰ、MSTN、自噬溶酶体通路和线粒体凋亡通路等转录因子和信号通路的影响(图2)[60⇓-62]。
图2 Met调控肌肉发育的信号通路

4EBP1:4E结合蛋白1 4E-binding protein 1;p70S6K:p70核糖体蛋白S6激酶 p70 ribosomal protein S6 kinase;MuRF-1:肌肉环指蛋白-1 muscle RING-finger protein-1;MAFbx:肌肉萎缩F盒蛋白 muscle atrophy F-box protein;mTOR:哺乳动物雷帕霉素靶蛋白 mammalian target of rapamycin;FoxOs:叉头框蛋白O Forkhead box protein O;Akt:蛋白激酶B protein kinase B;PI3K:磷脂酰肌醇-3-激酶 phosphoinositide 3-kinase;IGF-Ⅰ:胰岛素样生长因子-Ⅰ insulin-like growth factor-Ⅰ;Cyclin D1:细胞周期蛋白D1;SIRT:沉默信息调节因子 silent information regulator;MRFs:生肌调控因子 myogenic regulatory factors;Met:蛋氨酸 methionine;MSTN:肌肉生长抑制素 myostatin;Cyclin B:细胞周期蛋白B;MTA:甲硫腺苷 methyl-adenosine;Bcl-2:B细胞淋巴瘤2 B-cell lymphoma 2;SAM:S-腺苷蛋氨酸 S-adenosylmethionine;PP2A:蛋白磷酸酶2A protein phosphatase 2;PCNA:增殖细胞核抗原 proliferating cell nuclear antigen;Bax:B细胞淋巴瘤2相关X蛋白 B-cell lymphoma 2 associated X protein;SAMTOR:S-腺苷甲硫氨酸传感器 S-adenosylmethionine sensor;GATOR1:RagA GTP酶激活蛋白 GTPase activating protein for RagA;TAS1R1:味觉受体1型成员1 taste receptor type 1 member 1;TAS1R3:味觉受体1型成员3 taste receptor type 1 member 3;H2S:硫化氢 sulfuretted hydrogen;MAPK:丝裂原激活的蛋白激酶 mitogen-activated protein kinase;Caspase-3:半胱氨酸天冬氨酸蛋白酶-3 cysteine aspartate proteinase-3;mTORC1:哺乳动物雷帕霉素靶蛋白复合物1 mammalian target of rapamycin complex 1;dcSAM:脱羧S-腺苷甲硫氨酸 decarboxyl S-adenosine methionine;Spd:亚精胺 spermidine;Ep300:组蛋白乙酰转移酶p300 histone acetyltransferase p300;ATGs:自噬相关基因 autophagy-related genes。

Fig.2 Signal pathways of Met regulating muscle development[60⇓-62]

3.1 Met调控MRFs家族

3.1.1 Met能够促进MRFs表达调控肌肉发育

MRFs是一类参与调控肌肉生长和发育的转录因子,主要包括成肌分化因子(MyoD)、肌细胞生成素(MyoG)、Myf5和Mrf4等,受蛋白激酶和钙调蛋白的调控[63]。Pax7和配对盒蛋白3(Pax3)是其上游调控元件,可分别结合其远端增强子和近端启动子,激活MyoD和Myf5的转录活性,从而调控成肌细胞增殖与分化;再经过MyoG与Mrf4相互作用,促使细胞启动末端分化、融合为肌管,并进一步发育成熟为肌纤维[64]。Latimer等[65]在培养基中去除Met 72 h可显著降低肌肉中MyoD和MyoG的表达,使卫星细胞处于分化停滞状态;补充Met可挽救MyoD和MyoG的表达,恢复卫星细胞分化能力。Yang等[66]研究发现,与饲喂0.15% Met组相比,DL-Met限制饲粮会降低肉猪背最长肌中Mrf4表达,并对生长性能产生影响。Ibrahim等[67]在含有0.05%胍基乙酸的饲粮中分别添加0、0.2%和0.4% Met发现,添加0.2%和0.4% Met均可显著提高肉鸭胸肌中MyoG的表达,并显著改善其胴体和胸肉产量。蒋雪樱[68]提高肉鸡饲粮中的Met水平可显著提高Myf5和Mrf4表达,并提高其胸肌率、胸肌pH且降低滴水损失;降低Met水平则与之相反。

3.1.2 Met可激活哺乳动物雷帕霉素靶蛋白(mTOR)信号通路促进MRFs表达

mTOR是调控细胞増殖、分化及自噬的关键信号分子,含有哺乳动物雷帕霉素靶蛋白复合物1(mTORC1)和哺乳动物雷帕霉素靶蛋白复合物2(mTORC2)这2种形式,mTORC1可调控p70核糖体蛋白S6激酶(p70S6K)和4E结合蛋白1(4EBP1)表达,促进骨骼肌产量增加;而mTORC2可调控蛋白激酶B(Akt)发生磷酸化,进而调节细胞的生长和代谢[69-70]。Sui等[71]研究发现,Met缺乏会抑制mTOR、MyoD和MyoG的表达,导致肌肉中的粗蛋白质含量降低,最终抑制动物的生长。Wen等[72]研究表明,提高快速生长型肉鸡饲粮中Met水平,可以提高mTOR、Myf5、Mrf4的表达以及细胞外信号调节激酶(ERK)磷酸化水平,说明提高Met水平可增强ERK和mTOR的磷酸化,进而促进肌源性基因表达,调控动物的肌肉发育。Baggerman等[46]研究发现,提高肉牛饲粮中RP-Met水平,Pax7阳性细胞密度呈上升趋势,Myf5阳性卫星细胞密度则呈下降趋势,表明补充Met可以促进卫星细胞增殖分化,进而促进肌肉的发育。

3.1.3 Met可激活泛素蛋白酶体系统(UPS)抑制MRFs表达

UPS是真核生物主要的蛋白质降解途径,通过泛素标记降解蛋白,由蛋白酶体识别并进行降解[73-74]。其中,肌肉环指蛋白-1(MuRF-1)和肌肉萎缩F盒蛋白(MAFbx)等E3泛素连接酶表达上调,可特异性介导肌原纤维降解并发生肌肉萎缩[75]。Wu等[76]研究发现,添加D-Met可改善顺铂引起的小鼠MuRF-1和MAFbx表达升高及MyoD和MyoG表达下降,同时增加肌纤维直径和横截面积。Tintignac等[77]提高成肌细胞中MAFbx的表达,可诱导MyoD发生泛素化和降解,从而抑制细胞分化。Ahmad等[78]研究发现,肉鸡饲粮中添加1.0%的Met可降低MAFbx和MuRF-1的表达,而添加0.5%的Met则提高了MyoD的表达,表明添加Met可改善肉鸡的产肉性能并抑制肌肉发生降解。Del Vesco等[79]研究发现,肉鸡饲喂3种Met水平饲粮(不补充Met、推荐水平Met和过量补充Met),补充Met对MAFbx表达有影响,并且饲粮中Met水平较高时,MAFbx表达较低。
综上所述,动物缺乏Met时,会抑制mTOR通路并激活UPS降低MRFs表达,抑制卫星细胞增殖和分化,从而阻碍肌肉的发育;通过适当补充Met,可抑制UPS系统并活化mTOR通路提高MRFs表达,促进卫星细胞增殖和分化,最终促进肌肉的发育。

3.2 Met调控IGF-Ⅰ通路

3.2.1 Met能够促进IGF-Ⅰ表达调控肌肉发育

IGF-Ⅰ是70个氨基酸组成的单链多肽,可激活细胞膜上的酪氨酸蛋白酶受体系统,诱导胰岛素受体底物-1(IRS-1)磷酸化,促使磷脂酰肌醇-3-激酶(PI3K)募集并活化,从而将磷脂酸肌醇4,5-双磷酸(PIP2)转化为磷脂酰肌醇3,4,5-三磷酸(PIP3)并激活Akt[29,69]。磷酸化Akt不仅可调控mTOR进行蛋白质合成,还可通过叉头框蛋白O(FoxOs)调控UPS进行蛋白质分解[69]。张永翠等[80]研究发现,饲粮添加0.4% Met时,断奶至2月龄肉兔肝脏和血清IGF-Ⅰ表达最高;而饲粮添加0.6% Met时,2~3月龄肉兔肝脏和血清IGF-Ⅰ表达最高。

3.2.2 Met调控IGF-Ⅰ表达激活mTOR通路

蒋雪樱[68]分别在爱拔益加和青脚麻鸡的饲粮中补充Met,2种肉鸡的胸肌IGF-Ⅰ含量显著提高;而饲粮缺乏Met,2种肉鸡胸肌IGF-Ⅰ和mTOR含量均显著降低。Wen等[72]研究表明,提高快速生长型肉鸡饲粮中Met含量,可以提高肉鸡胸肌中IGF-Ⅰ和mTOR含量,从而促进动物肌肉发育。Zhu等[81]研究证实,山羊饲粮添加DL-Met可显著提高mTOR通路的下游调节因子——真核翻译起始因子4B(EIF4B)及相关氨基酸转运蛋白的表达变化,从而增强蛋白质的合成。此外,Met还可通过溶质载体家族7成员5(SLC7A5)蛋白转运至细胞内可直接激活mTORC1通路,促进蛋白质的合成[82]。

3.2.3 Met调控IGF-Ⅰ表达抑制UPS

滕战伟[83]对雏鹅胚蛋注射1.5 mL的Met营养液,可提高胸肌IGF-Ⅰ的表达,并降低叉头框蛋白O4(FoxO4)和MAFbx的表达。Gondret等[84]在屠宰前14天在猪饲粮中补充1.10%的Met可提高MuRF-1表达水平。这表明Met过量补充,会激活UPS促进蛋白质分解,导致肌肉萎缩。原培强[29]发现IGF-Ⅰ可以促进肌肉蛋白质的合成,并通过UPS和溶酶体自噬途径抑制肌肉蛋白降解。
综上所述,机体缺乏Met可抑制IGF-Ⅰ表达,进而调控UPS促进肌肉降解,并抑制mTOR通路减少蛋白质合成;而适量补充Met可促进IGF-Ⅰ的表达,进而激活mTOR通路增加蛋白质合成,并调控UPS抑制肌肉分解。

3.3 Met调控MSTN信号通路

3.3.1 Met可抑制MSTN表达促进肌肉发育

MSTN是肌肉生长和发育的负调控因子,对于调节肌纤维的类型、组成和肌肉功能具有重要作用[85-86]。MSTN能够激活细胞膜上的活化素activinⅡ型A/B受体(ActRⅡA/B)[87]。当MSTN与ActRⅡB结合时,可进一步与激活素受体样激酶4(ALK4)或者激活素受体样激酶5(ALK5)结合并磷酸化Smad2/3,使得Smad进入细胞核,促进靶基因的表达[88]。Wen等[89]提高肉鸡饲粮中Met水平,可降低胸肌MSTN的表达,并显著增加其胸肌产量。滕战伟[83]对朗德鹅胚蛋注射1.5 mL的Met营养液可降低MSTN的表达。蒋雪樱[68]研究表明,向青脚麻鸡的饲粮中添加高水平Met可以降低胸肌MSTN的表达,而添加低水平的Met则会提高MSTN的表达。李德生等[39]研究发现,对吉林白鹅胚蛋注射浓度为5 g/L的Met能够降低MSTN的表达,并显著提高雏鹅出壳当天、第7天及第28天其胸肌重和肌纤维直径。

3.3.2 Met抑制MSTN表达并促进肌源性基因表达

Liu等[89]研究表明,妊娠期间母体补充Met可显著改善后代犊牛骨骼肌的选择性剪接和DNA甲基化。Liu等[90]研究指出,低Met水平和高Met水平组肉鸡MSTN外显子的甲基化百分比分别为46%和84%,表明骨骼肌组织中MSTN基因外显子的甲基化程度与基因表达呈负相关。而Li等[40]对低出生体重仔猪补充Met,可以提高背最长肌中的SAM含量,增加DNA甲基转移酶活性,并提高MSTN基因外显子的CpG甲基化水平;与此同时,MSTN的表达水平下降,而MyoG、肌细胞增强子结合因子2A(MEF2A)和肌细胞增强子结合因子2D(MEF2D)的表达水平提高,进一步促进了背最长肌的增长,使其面积显著增加。Wen等[91]提高肉鸡饲粮中DL-Met水平,提高了Myf5、肌细胞增强子结合因子2B(MEF2B)表达并降低了MSTN表达,从而促进胸肌的发育。
综上所述,机体缺乏Met,会促进MSTN表达进而抑制MRFs表达,从而抑制肌肉的发育;经适量补充Met,可抑制MSTN的表达并促进MRFs表达,促进肌肉的发育。

3.4 Met调控自噬溶酶体通路

3.4.1 Met可抑制mTOR信号通路激活细胞自噬

自噬是动物细胞内溶酶体的降解过程,通过将受损蛋白、细胞器和代谢产物包裹成溶酶体,降解为氨基酸和核苷酸等小分子物质[92-93]。Sun等[94]研究发现,小鼠喂食Met限制饲粮会降低肝脏组织中mTOR磷酸化水平。Sutter等[95]降低酵母细胞培养基的Met水平会降低SAM含量,在蛋白磷酸酶甲基转移酶1(Ppm1p)的作用下,蛋白磷酸酶2A(PP2A)发生甲基化,促进磷酸蛋白Npr2p的去磷酸化,进而抑制Pml1p-Npr2p-Npr3p复合物相互作用,导致mTORC1活化,从而抑制自噬并促进细胞生长。Gu等[96]试验证明,当Met充足时,SAM以约7 μmol/L的解离常数直接与S-腺苷甲硫氨酸传感器(SAMTOR)结合,破坏SAMTOR-RagA GTP酶激活蛋白(GATOR1)复合物,促进mTORC1信号传导;而Met缺乏时,会降低SAM含量至该解离常数以下,促进SAMTOR与GATOR1的结合,从而抑制mTORC1促进细胞自噬。钟和局[97]研究表明,Met代谢途径产生的SAM可直接激活mOTRC1信号通路,并抑制细胞自噬。

3.4.2 Met促进自噬基因表达、溶酶体酸化抑制肌肉发育

Wu等[98]研究表明,Met限制通过miR-328-3p增加肥胖小鼠的内源性硫化氢(H2S),降低了蛋白质合成[mTORC1和核糖体蛋白S6激酶(S6K1)],并促进自噬相关基因Beclin表达。杨玉辉[99]研究表明,肥胖小鼠饲喂Met限制饲粮可提高沉默信息调节因子1(SIRT1)、轻链3A(LC3A)、轻链3B(LC3B)和Beclin1的表达,并降低mTOR和p62蛋白的表达,导致肝脏细胞中自噬空泡的数量增加,从而促进肝脏的自噬作用。陈秋月[100]研究表明,Met限制可促进转录因子EB(TFEB)在细胞核内聚集并激活其转录,进而调控靶基因表达,从而增加自噬-溶酶体通路活性。Ruckenstuhl等[101]研究指出,Met限制可诱导酵母细胞发生自噬,提高V-ATP酶的活性,导致自噬空泡酸化,从而延长寿命。Xin等[102]研究发现,Met缺乏可下调长链非编码核糖核酸(lncRNA)浆细胞瘤变异体易位1(PVT1)的表达,抑制lncRNA PVT1与DNA甲基转移酶1(DNMT1)的结合,使B细胞淋巴瘤2相互作用蛋白3(BNIP3)启动子去甲基化,从而激活线粒体自噬并抑制癌症细胞的增殖。
综上所述,机体缺乏Met会降低SAM含量,进而抑制mTORC1的激活,从而促进细胞自噬的发生;当机体Met充足时,会提高SAM含量,促进mTORC1信号通路的活化,从而抑制细胞自噬;此外,Met还可以通过促进自噬基因的表达和调节溶酶体酸化等方式,诱导细胞发生自噬作用。

3.5 Met调控线粒体凋亡通路

3.5.1 Met能够介导细胞凋亡抑制肌肉的生长和再生过程

细胞凋亡是由一系列基因的激活、表达和调控下细胞主动性死亡的过程,线粒体通路是其内在途径之一[103-104]。其中,半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)、B细胞淋巴瘤2相关X蛋白(Bax)和B细胞淋巴瘤2(Bcl-2)均为反映细胞凋亡的重要指标[105]。Caspase-3是一种可水解具有凋亡特征的蛋白水解酶[106]。Bax是一种促凋亡因子,可与Bcl-2结合形成复合物并促进Bcl-2降解,从而介导细胞凋亡[107-108]。Bcl-2为抗凋亡因子,能够抑制Bax通道形成,阻止钙离子(Ca2+)和凋亡诱导因子(AIF)释放,或阻止线粒体释放凋亡信号分子,从而阻断半胱氨酸天冬氨酸蛋白酶(Caspase)级联反应抑制细胞凋亡[109-110]。当细胞发生凋亡时,会增加线粒体膜通透性,导致凋亡信号分子进入胞浆与凋亡蛋白酶激活因子结合,并招募半胱氨酸天冬氨酸蛋白酶-9(Caspase-9)形成凋亡体,进而激活Caspase-3触发细胞凋亡[111]。

3.5.2 Met介导线粒体凋亡通路影响肌肉发育

段晓翔[63]研究表明,肉鸡低蛋白质饲粮缺乏Met,会提高其胸肌和肝脏中Caspase-3表达并降低其胸肌重;添加适量DL-Met可抑制Caspase-3的表达,提高肉鸡的胸肌重。Chen等[112]研究发现,添加L-Met会增加断奶仔猪的空肠紧密连接蛋白丰度并降低Caspase-3的活性。Song等[113]研究发现,肉鸡饲粮缺乏Met会降低Bcl-2的表达,并提高Bax和Caspase-3的表达,从而导致肾脏凋亡细胞的数量增加;此外,还会提高p53和p21的表达,降低细胞周期蛋白B(Cyclin B)和PCNA表达,说明Met缺乏会诱导肾脏细胞发生凋亡和细胞周期停滞。Tang等[114]研究表明,感染产肠毒素性大肠杆菌的猪上皮细胞中缺乏Met,会提高Caspase-3表达并降低Bcl-2表达,从而促进细胞凋亡。Han等[115]补充Met可降低牛乳腺上皮细胞Bax/Bcl-2的表达,阻止热应激引起Caspase-3活性增加,并抑制牛乳腺上皮细胞中热应激诱导的细胞凋亡。Zhou等[116]对奶牛乳腺上皮细胞补充Met,可提高Bcl-2的表达,并降低Bax、Caspase-3和Caspase-9的表达。并且,mTOR、Akt、核糖体蛋白S6激酶B1(RPS6KB1)和核糖体蛋白S6(RPS6)表达水平随Met补充量的增加而提高,表明补充Met可能通过抑制细胞凋亡、激活Akt-mTOR-RPS6KB1信号通路来促进乳蛋白合成。

3.5.3 Met介导线粒体凋亡通路影响肌肉发育

蔡海青[117]研究表明,经过24 h锰处理的神经母细胞瘤细胞缺乏Met,会增加细胞内SAH和活性氧(ROS)含量,导致蛋白磷酸酶2A催化亚基(PP2Ac)去甲基化、微管相关蛋白tau磷酸化及蛋白磷酸酶甲酯酶1(PPME1)蛋白增加,同时降低PP2Ac甲基化和亮氨酸羧甲基转移酶1(LCMT1)蛋白表达,从而降低细胞活性并触发细胞凋亡;而补充Met会降低细胞内SAH和ROS含量,进而抑制tau蛋白磷酸化,导致PP2Ac甲基化和LCMT1蛋白表达增加,从而增强细胞活性并抑制细胞发生凋亡。此外还有另一种机制,分布于线粒体中的蛋氨酸亚砜还原酶B2(MSRB2),可将游离态或蛋白质中的蛋氨酸亚砜还原为Met,其表达降低会增强氧化应激诱导的细胞死亡[118-119]。Xiang等[120]研究发现,MSRB2过表达可通过抑制ERK磷酸化和单磷酸腺苷活化蛋白激酶(AMPK)活性,抑制Bax和Caspase-3的表达并增强Bcl-2表达,进而降低阿尔茨海默病小鼠体内的ROS含量以及tau蛋白过磷酸化,从而发挥抗氧化作用。
综上所述,动物体内缺乏Met时,会增加细胞内SAH含量抑制Bcl-2表达,并促进Bax和Caspase-3表达,从而促进细胞凋亡;经过适当补充Met,则会降低细胞内SAH含量,促进Bcl-2表达,并抑制Bax和Caspase-3表达,从而抑制细胞凋亡的发生,同时介导mTOR通路促进肌肉发育。

4 小结

Met作为动物生长发育的主要限制性氨基酸,参与机体诸多代谢过程,目前已作为常用的饲料添加剂广泛应用于畜牧生产。经大量研究证实,生长期的畜禽对Met的需求会增大,通过饲粮补充适宜Met可促进蛋白质合成及细胞增殖分化,进而促进动物骨骼肌发育,从而有效提高动物的产肉性能。此外,Met通过MRFs家族、IGF-Ⅰ等信号通路促进骨骼肌合成,并通过MSTN、Caspase-3、自噬溶酶体系统等信号通路抑制骨骼肌分解,从而协调控制畜禽动物的肌肉发育过程。不过,仍然存在一些问题:1)众多研究学者在不同物种、生长阶段和生长环境中均已开展关于Met种类和用量方面的研究,但关于Met调控肌纤维生长发育、转录因子及信号通路方面研究仍有待探究,尤其是在单胃和反刍动物[121];2)Met通过不同信号通路之前的相互作用调控动物分化形成不同类型的肌纤维是目前的研究热点之一,其具体的调控机制还有待进一步完善;3)Met通过激活相关信号通路调控MRFs家族表达促进肌肉发育,以及调控细胞自噬系统促进肌肉萎缩的相关机制目前取得一定的进展,但许多细节仍然需要深入研究和探索;4)Met通过表观遗传修饰和基因表达调控肌肉发育的具体机制也是目前研究热点。本文总结了蛋氨酸调控肌肉发育过程的机制,同时亦可为畜禽养殖及饲料配方改良提供一定的理论参考价值。

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