周 珊(綜述) 葉紅英(審校)

(復(fù)旦大學(xué)附屬華山醫(yī)院內(nèi)分泌科 上海 200040)

代謝相關(guān)性肌細(xì)胞因子的研究進(jìn)展

周 珊(綜述) 葉紅英△(審校)

(復(fù)旦大學(xué)附屬華山醫(yī)院內(nèi)分泌科 上海 200040)

肌細(xì)胞因子(myokines)是由肌細(xì)胞合成和釋放,發(fā)揮自分泌、旁分泌或內(nèi)分泌功能的細(xì)胞因子及多肽類物質(zhì)。肌細(xì)胞因子可作用于骨骼肌自身及脂肪、肝臟、胰腺、骨骼等多種組織器官參與機(jī)體物質(zhì)和能量代謝并影響各組織器官的結(jié)構(gòu)和功能,從而在維持機(jī)體的生物學(xué)穩(wěn)態(tài)中發(fā)揮重要作用。目前已發(fā)現(xiàn)的肌細(xì)胞因子有數(shù)百種,其中鳶尾素(irisin)、肌聯(lián)素(myonectin)、肌肉抑制素(myostatin)、腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor,BDNF)等對機(jī)體糖脂及能量代謝起到重要作用。本文主要闡述上述幾種代謝相關(guān)性肌細(xì)胞因子的合成和分泌、生理作用、作用機(jī)制及潛在臨床應(yīng)用。

骨骼肌; 肌細(xì)胞因子; 鳶尾素; 肌聯(lián)素; 肌肉抑制素; 腦源性神經(jīng)營養(yǎng)因子

2003年,Pedersen等[1]首次提出“肌細(xì)胞因子”的概念,將其定義為“肌細(xì)胞合成和釋放的,發(fā)揮自分泌、旁分泌或內(nèi)分泌功能的細(xì)胞因子及多肽類物質(zhì)”。肌細(xì)胞因子的發(fā)現(xiàn)為研究骨骼肌與其他組織器官的相互作用提供了基礎(chǔ),從整體水平而言,運動對多種代謝性疾病的防治也有可能(部分)通過肌細(xì)胞因子來實現(xiàn)。本文主要針對鳶尾素(irisin)、肌聯(lián)素(myonectin)、肌肉抑制素(myonstatin)、腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor,BDNF)等與機(jī)體代謝密切相關(guān)的肌細(xì)胞因子作一綜述。

鳶尾素:誘導(dǎo)白色脂肪棕色化及增加產(chǎn)熱 運動可激活骨骼肌中的過氧化物酶體增殖激活受體γ共激活因子1α (peroxisome proliferator-activated receptor γ co-activator 1α,PGC1α)并產(chǎn)生一系列生物學(xué)效應(yīng),包括增加骨骼肌線粒體合成、血管生成及肌纖維類型轉(zhuǎn)化等[2]。2012年,Bostr?m等[3]研究發(fā)現(xiàn),將PGC1α基因特異性轉(zhuǎn)入小鼠骨骼肌可誘導(dǎo)其白色脂肪棕色化,將表達(dá)PGC1α的肌細(xì)胞與脂肪細(xì)胞體外混合培養(yǎng)也可引起脂肪細(xì)胞棕色化基因表達(dá)增加;進(jìn)一步研究發(fā)現(xiàn)骨骼肌中PGC1α激活后可誘發(fā)膜蛋白纖維連接蛋白Ⅲ含域蛋白5 (fibronectin type Ⅲ domain-containing protein 5,Fndc5)表達(dá)增加,Fndc5經(jīng)酶切后以一種新的激素形式——鳶尾素(irisin)釋放[3]。運動后小鼠血漿Irisin水平顯著升高,伴隨肌細(xì)胞Irisin表達(dá)量的顯著增加[3];Irisin作用于白色脂肪細(xì)胞,通過激活過氧化物酶體增殖激活受體α (peroxisome proliferator-activated receptor α,PPARα)促使其解偶聯(lián)蛋白1 (uncoupling protein 1,UCP1)及一系列棕色化基因表達(dá),進(jìn)而增加產(chǎn)熱并誘導(dǎo)廣泛的棕色樣改變[3-4]。

關(guān)于人體運動與Irisin的關(guān)系,有研究發(fā)現(xiàn)短時運動可引起人體血漿Irisin水平顯著升高[5-6],而Timmons等[7]則發(fā)現(xiàn)無論耐力或阻力訓(xùn)練均不能使正常成年人骨骼肌中Fndc5基因表達(dá)增加;Raschke等[8]對離體人骨骼肌進(jìn)行電刺激亦未見Fndc5基因表達(dá)增加;Hecksteden等[9]一項隨機(jī)對照試驗發(fā)現(xiàn),長期運動個體其血漿Irisin水平并無顯著性升高,因此,運動對人體Irisin合成分泌的影響目前尚無定論,推測運動所需的閾值(形式、強度、持續(xù)時間等)可能是其關(guān)鍵影響因素。此外,關(guān)于外源性給予重組Irisin能否誘導(dǎo)人體白色脂肪棕色化,仍缺乏相關(guān)實驗證據(jù),且人和小鼠的棕色脂肪含量差異顯著,因此上述動物實驗結(jié)果是否適用于人體以及Irisin能否成為治療肥胖的靶點,仍需進(jìn)一步臨床研究來明確。

多項研究結(jié)果顯示,血漿Irisin水平與體重、體重指數(shù)及體脂含量呈正相關(guān)[5,10-12],即肥胖人群具有更高的Irisin水平,這與其潛在的抗肥胖作用相互矛盾,推測Irisin可能作為生理性保護(hù)因子通過誘導(dǎo)棕色化對抗肥胖,而病理狀態(tài)下(肥胖)血漿Irisin水平代償性升高以對抗體重增長及機(jī)體脂肪囤積效應(yīng)。Polyzos等[13]進(jìn)一步提出“Irisin抵抗”的概念,用以解釋肥胖個體明顯的Irisin不適當(dāng)分泌過多。另有研究發(fā)現(xiàn),糖尿病患者血漿Irisin水平低于正常糖耐量個體[14],而血漿Irisin水平的升高與新診斷2型糖尿病比率降低有關(guān)[15],提示Irisin有可能成為2型糖尿病的獨立預(yù)測因子。

肌聯(lián)素:聯(lián)系骨骼肌與脂肪的橋梁 Seldin等[16]在小鼠骨骼肌中發(fā)現(xiàn)一種全新的補體1q/腫瘤壞死因子相關(guān)蛋白(C1q/TNF-related protein,CTRP)家族成員,并將其命名為CTRP15/Myonectin。Myonectin主要在小鼠骨骼肌中表達(dá),運動使小鼠Myonectin的基因表達(dá)和血漿濃度升高[16]。Myonectin的分泌還與小鼠營養(yǎng)狀態(tài)密切相關(guān):饑餓狀態(tài)下其合成和分泌明顯受抑制,重新進(jìn)食后又顯著升高;進(jìn)一步實驗證實營養(yǎng)物質(zhì)可直接作用于肌細(xì)胞調(diào)節(jié)Myonectin表達(dá)[16]。隨后Rodriguez等[17]研究發(fā)現(xiàn)瘦素作用于肌細(xì)胞可上調(diào)其Myonectin基因表達(dá); Peterson等[18]則發(fā)現(xiàn),與正常大鼠相比,瘦素受體缺乏的肥胖鼠Myonectin基因表達(dá)增加,而運動后其肌細(xì)胞Myonectin mRNA表達(dá)量反而降低,這與Seldin等[16]的研究結(jié)果并不一致。因此,目前關(guān)于運動對Myonectin合成和分泌的影響仍無定論,推測Myonectin基因表達(dá)可能受瘦素調(diào)控,而蛋白分泌則主要由機(jī)體營養(yǎng)狀態(tài)決定。此外,也有研究提及胰島素抵抗對Myonectin合成和分泌的影響。Yang等[19]發(fā)現(xiàn),在由棕櫚酸誘導(dǎo)的小鼠肌細(xì)胞胰島素抵抗?fàn)顟B(tài)下,棕櫚酸可通過下調(diào)磷酸肌醇-3-激酶(phosphoinositide 3 kinase,PI3K)和上調(diào)p38基因表達(dá)等多種信號途徑降低Myonectin基因的表達(dá)水平。

關(guān)于Myonectin的生物學(xué)作用,Seldin等[16]發(fā)現(xiàn)在給予重組Myonectin后,小鼠脂肪細(xì)胞和肝細(xì)胞對游離脂肪酸的攝取均明顯增加,且兩者都伴隨脂肪酸攝取相關(guān)基因白細(xì)胞分化抗原36,脂肪酸結(jié)合蛋白及脂肪酸轉(zhuǎn)運蛋白表達(dá)增加,提示Myonectin可能通過上調(diào)這些基因的表達(dá)從而促進(jìn)脂肪細(xì)胞和肝細(xì)胞攝取游離脂肪酸。此外,饑餓可誘發(fā)小鼠肝細(xì)胞自噬,而Myonectin通過激活雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)可抑制其自噬作用,這是骨骼肌和肝臟之間內(nèi)分泌聯(lián)系的體現(xiàn)[20]。以上研究初步證實Myonectin在機(jī)體脂代謝中的重要作用,未來還需進(jìn)一步設(shè)計Myonectin基因失活/獲得性突變等動物模型,從而明確其在不同病理生理狀態(tài)下的作用及機(jī)制。

肌肉抑制素 McPherron等[21]發(fā)現(xiàn)一種特異性表達(dá)于骨骼肌的轉(zhuǎn)化生長因子β超家族成員生長/分化因子8,又稱為肌肉抑制素。定向敲除小鼠骨骼肌Myostatin基因可引起肌肉量顯著增加[21],人體骨骼肌Myostatin基因失活突變亦可引起廣泛的肌細(xì)胞增生肥大[22],而小鼠骨骼肌過表達(dá)Myostatin則可導(dǎo)致嚴(yán)重肌萎縮[23],充分證實Myostatin可抑制肌細(xì)胞生長。關(guān)于Myostatin對肌細(xì)胞代謝的影響,有研究發(fā)現(xiàn)Myostatin基因缺失型/阻斷型小鼠均出現(xiàn)肌肉量增加及肌力增強,但肌耐力顯著下降且極易疲勞,提示Myostatin在負(fù)性生長調(diào)節(jié)之外,還可增加肌細(xì)胞的有氧代謝和肌耐力[24]。

此外,Myostatin還對機(jī)體糖脂代謝具有重要影響。骨骼肌過表達(dá)Myostatin可引起小鼠肌肉量減少及附睪脂肪墊增多[23],而特異性阻斷Myostatin后,無論高脂飲食或是正常飲食喂養(yǎng)的小鼠均表現(xiàn)為肌肉量增加,脂肪量減少[25]。為明確上述作用靶點,研究者進(jìn)一步設(shè)計實驗并發(fā)現(xiàn)其抗肥胖效應(yīng)主要是由于Myostatin受阻后對肌細(xì)胞的負(fù)性調(diào)節(jié)減弱所致,其對脂肪的直接作用較小[26],提示Myostatin對脂代謝的影響很可能繼發(fā)于肌細(xì)胞的改變。另有研究發(fā)現(xiàn),接受重組Myostatin注射的小鼠出現(xiàn)胰島素敏感性降低,而其脂肪和肌肉量均無改變,提示Myostatin可能直接影響骨骼肌對葡萄糖攝取及利用,該效應(yīng)與Myostatin對肌肉量的影響并無相關(guān)[27]。另外,特異性阻斷小鼠血漿Myostatin可減少其肝臟葡萄糖產(chǎn)生[25],而給予重組Myostatin后,小鼠體內(nèi)胰島素作用于肝臟的Akt信號通路明顯受阻[27],提示Myostatin可直接作用于肝臟影響糖代謝。進(jìn)一步研究發(fā)現(xiàn),特異性阻斷Myostatin作用可通過PI3K/Akt/mTOR信號途徑改善小鼠胰島素抵抗[28]。綜上所述,Myostatin有望成為肌萎縮及肥胖、2型糖尿病等代謝性疾病的治療新靶點。

腦源性神經(jīng)營養(yǎng)因子 BDNF是一種神經(jīng)營養(yǎng)因子,廣泛表達(dá)于中樞神經(jīng)系統(tǒng)并發(fā)揮營養(yǎng)神經(jīng)元的作用[29]。近年研究發(fā)現(xiàn)骨骼肌也可表達(dá)BDNF[30-31],動物實驗證實,無論是運動還是電刺激骨骼肌均可誘導(dǎo)BDNF表達(dá)量增加[32-34],提示肌肉收縮對肌細(xì)胞BDNF的表達(dá)具有重要影響。人體在運動后骨骼肌中BDNF表達(dá)量也有一定增加[34],但肌細(xì)胞來源的BDNF并未釋放入血,而是在局部發(fā)揮自分泌/旁分泌作用,經(jīng)由腺苷酸活化蛋白激酶途徑增加骨骼肌自身的脂肪酸氧化[31]。臨床研究發(fā)現(xiàn),肥胖及2型糖尿病患者較正常個體的血漿BDNF水平更低[35],但目前尚不明確血漿BDNF的降低是機(jī)體代謝異常的原因還是其結(jié)果,對此仍需進(jìn)一步研究。綜合BDNF對骨骼肌能量及脂代謝的影響,初步推測運動可能通過BDNF介導(dǎo)對肥胖及2型糖尿病等代謝性疾病的防治作用[30]。

結(jié)語 骨骼肌作為人體的重要內(nèi)分泌器官,可以合成和分泌多種肌細(xì)胞因子作用于各組織器官,影響其代謝和功能并維持機(jī)體的生物學(xué)穩(wěn)態(tài)。肌細(xì)胞因子的發(fā)現(xiàn)為骨骼肌與其他組織器官的相互作用提供了一種全新模式。本文介紹的Irisin、Myonectin、Myostatin、BDNF這幾種因子主要與機(jī)體糖脂及能量代謝密切相關(guān),其中仍有許多機(jī)制尚未明確,進(jìn)一步深入研究有望為肌萎縮、肥胖及2型糖尿病等代謝性疾病的治療提供新思路。

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A research progress on metabolism-associated myokines

ZHOU Shan, YE Hong-ying△

(DepartmentofEndocrinology,HuashanHospital,FudanUniversity,Shanghai200040,China)

Cytokines and peptides produced and released by muscle cells and exert either autocrine,paracrine or endocrine effects are defined as myokines.Myokines are capable of exerting specific endocrine effects on organs such as adipose tissue,liver,pancreas and bone,thereby impacting the structure and function of numerous organs and tissues,as well as playing an important role in the maintenance of biological homeostasis.So far,researches have confirmed hundreds of different myokines,including irisin,myonectin,myostatin and brain-derived neurotrophic factor (BDNF),which can affect glucose and lipid metabolism,as well as energy equilibrium.The generation、physiology、mechanism of action and potential clinical value of these metabolism-associated myokines will be reviewed in this article.

sketelal muscle; myokines; irisin; myonectin; myostatin; brain-derived neurotrophic factor

R586.2+4

B

10.3969/j.issn.1672-8467.2017.02.019

2016-07-15;編輯:王蔚)

△Corresponding author E-mail:janeyhy@163.com