代謝相關性肌細胞因子的研究進展

周 珊(綜述) 葉紅英(審校)

(復旦大學附屬華山醫院內分泌科 上海 200040)

代謝相關性肌細胞因子的研究進展

周 珊(綜述) 葉紅英△(審校)

(復旦大學附屬華山醫院內分泌科 上海 200040)

肌細胞因子(myokines)是由肌細胞合成和釋放,發揮自分泌、旁分泌或內分泌功能的細胞因子及多肽類物質。肌細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體物質和能量代謝并影響各組織器官的結構和功能,從而在維持機體的生物學穩態中發揮重要作用。目前已發現的肌細胞因子有數百種,其中鳶尾素(irisin)、肌聯素(myonectin)、肌肉抑制素(myostatin)、腦源性神經營養因子(brain-derived neurotrophic factor,BDNF)等對機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性肌細胞因子的合成和分泌、生理作用、作用機制及潛在臨床應用。

骨骼肌; 肌細胞因子; 鳶尾素; 肌聯素; 肌肉抑制素; 腦源性神經營養因子

2003年,Pedersen等[1]首次提出“肌細胞因子”的概念,將其定義為“肌細胞合成和釋放的,發揮自分泌、旁分泌或內分泌功能的細胞因子及多肽類物質”。肌細胞因子的發現為研究骨骼肌與其他組織器官的相互作用提供了基礎,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)通過肌細胞因子來實現。本文主要針對鳶尾素(irisin)、肌聯素(myonectin)、肌肉抑制素(myonstatin)、腦源性神經營養因子(brain-derived neurotrophic factor,BDNF)等與機體代謝密切相關的肌細胞因子作一綜述。

鳶尾素:誘導白色脂肪棕色化及增加產熱 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)并產生一系列生物學效應,包括增加骨骼肌線粒體合成、血管生成及肌纖維類型轉化等[2]。2012年,Bostr?m等[3]研究發現,將PGC1α基因特異性轉入小鼠骨骼肌可誘導其白色脂肪棕色化,將表達PGC1α的肌細胞與脂肪細胞體外混合培養也可引起脂肪細胞棕色化基因表達增加;進一步研究發現骨骼肌中PGC1α激活后可誘發膜蛋白纖維連接蛋白Ⅲ含域蛋白5 (fibronectin type Ⅲ domain-containing protein 5,Fndc5)表達增加,Fndc5經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,伴隨肌細胞Irisin表達量的顯著增加[3];Irisin作用于白色脂肪細胞,通過激活過氧化物酶體增殖激活受體α (peroxisome proliferator-activated receptor α,PPARα)促使其解偶聯蛋白1 (uncoupling protein 1,UCP1)及一系列棕色化基因表達,進而增加產熱并誘導廣泛的棕色樣改變[3-4]。

關于人體運動與Irisin的關系,有研究發現短時運動可引起人體血漿Irisin水平顯著升高[5-6],而Timmons等[7]則發現無論耐力或阻力訓練均不能使正常成年人骨骼肌中Fndc5基因表達增加;Raschke等[8]對離體人骨骼肌進行電刺激亦未見Fndc5基因表達增加;Hecksteden等[9]一項隨機對照試驗發現,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、持續時間等)可能是其關鍵影響因素。此外,關于外源性給予重組Irisin能否誘導人體白色脂肪棕色化,仍缺乏相關實驗證據,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,仍需進一步臨床研究來明確。

多項研究結果顯示,血漿Irisin水平與體重、體重指數及體脂含量呈正相關[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因子通過誘導棕色化對抗肥胖,而病理狀態下(肥胖)血漿Irisin水平代償性升高以對抗體重增長及機體脂肪囤積效應。Polyzos等[13]進一步提出“Irisin抵抗”的概念,用以解釋肥胖個體明顯的Irisin不適當分泌過多。另有研究發現,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[15],提示Irisin有可能成為2型糖尿病的獨立預測因子。

肌聯素:聯系骨骼肌與脂肪的橋梁 Seldin等[16]在小鼠骨骼肌中發現一種全新的補體1q/腫瘤壞死因子相關蛋白(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,運動使小鼠Myonectin的基因表達和血漿濃度升高[16]。Myonectin的分泌還與小鼠營養狀態密切相關:饑餓狀態下其合成和分泌明顯受抑制,重新進食后又顯著升高;進一步實驗證實營養物質可直接作用于肌細胞調節Myonectin表達[16]。隨后Rodriguez等[17]研究發現瘦素作用于肌細胞可上調其Myonectin基因表達; Peterson等[18]則發現,與正常大鼠相比,瘦素受體缺乏的肥胖鼠Myonectin基因表達增加,而運動后其肌細胞Myonectin mRNA表達量反而降低,這與Seldin等[16]的研究結果并不一致。因此,目前關于運動對Myonectin合成和分泌的影響仍無定論,推測Myonectin基因表達可能受瘦素調控,而蛋白分泌則主要由機體營養狀態決定。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]發現,在由棕櫚酸誘導的小鼠肌細胞胰島素抵抗狀態下,棕櫚酸可通過下調磷酸肌醇-3-激酶(phosphoinositide 3 kinase,PI3K)和上調p38基因表達等多種信號途徑降低Myonectin基因的表達水平。

關于Myonectin的生物學作用,Seldin等[16]發現在給予重組Myonectin后,小鼠脂肪細胞和肝細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基因白細胞分化抗原36,脂肪酸結合蛋白及脂肪酸轉運蛋白表達增加,提示Myonectin可能通過上調這些基因的表達從而促進脂肪細胞和肝細胞攝取游離脂肪酸。此外,饑餓可誘發小鼠肝細胞自噬,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分泌聯系的體現[20]。以上研究初步證實Myonectin在機體脂代謝中的重要作用,未來還需進一步設計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下的作用及機制。

肌肉抑制素 McPherron等[21]發現一種特異性表達于骨骼肌的轉化生長因子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胞增生肥大[22],而小鼠骨骼肌過表達Myostatin則可導致嚴重肌萎縮[23],充分證實Myostatin可抑制肌細胞生長。關于Myostatin對肌細胞代謝的影響,有研究發現Myostatin基因缺失型/阻斷型小鼠均出現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在負性生長調節之外,還可增加肌細胞的有氧代謝和肌耐力[24]。

此外,Myostatin還對機體糖脂代謝具有重要影響。骨骼肌過表達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的小鼠均表現為肌肉量增加,脂肪量減少[25]。為明確上述作用靶點,研究者進一步設計實驗并發現其抗肥胖效應主要是由于Myostatin受阻后對肌細胞的負性調節減弱所致,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于肌細胞的改變。另有研究發現,接受重組Myostatin注射的小鼠出現胰島素敏感性降低,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,該效應與Myostatin對肌肉量的影響并無相關[27]。另外,特異性阻斷小鼠血漿Myostatin可減少其肝臟葡萄糖產生[25],而給予重組Myostatin后,小鼠體內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。進一步研究發現,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。

腦源性神經營養因子 BDNF是一種神經營養因子,廣泛表達于中樞神經系統并發揮營養神經元的作用[29]。近年研究發現骨骼肌也可表達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BDNF表達量增加[32-34],提示肌肉收縮對肌細胞BDNF的表達具有重要影響。人體在運動后骨骼肌中BDNF表達量也有一定增加[34],但肌細胞來源的BDNF并未釋放入血,而是在局部發揮自分泌/旁分泌作用,經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]。臨床研究發現,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的降低是機體代謝異常的原因還是其結果,對此仍需進一步研究。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介導對肥胖及2型糖尿病等代謝性疾病的防治作用[30]。

結語 骨骼肌作為人體的重要內分泌器官,可以合成和分泌多種肌細胞因子作用于各組織器官,影響其代謝和功能并維持機體的生物學穩態。肌細胞因子的發現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體糖脂及能量代謝密切相關,其中仍有許多機制尚未明確,進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。

[1] PEDERSEN BK,STEENBERG A,FISHER C,etal.Searching for the exercise factor:is IL-6 a candidate?[J].JMuscleResCellMotil,2003,24(2-3):113-119.

[2] HANDSCHIN C,SPIEGELMAN BM.The role of exercise and PGC1α in inflammation and chronic disease[J].Nature,2008,454(7203):463-469.

[3] BOSTROM P,WU J,JEDRYCHOWSKI MP,etal.A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis[J].Nature,2012,481(7382):463-468.

[4] KOMATSU M,TONG Y,LI Y,etal.Multiple roles of PPARα in brown adipose tissue under constitutive and cold conditions[J].GenestoCells,2010,15(2):91-100.

[5] HUH JY,PANAGIOTOU G,MOUGIOS V,etal.FNDC5 and irisin in humans:Ⅰ Predictors of circulating concentrations in serum and plasma and Ⅱ mRNA expression and circulating concentrations in response to weight loss and exercise[J].Metabolism,2012,61(12):1725-1738.

[6] KURDIOVA T,BALAZ M,VICIAN M,etal.Effects of obesity,diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue:invivoandinvitrostudies[J].JPhysiol,2014,592(5):1091-1107.

[7] TIMMONS JA,BAAR K,DAVIDSEN PK,etal.Is irisin a human exercise gene?[J].Nature,2012,488(7413):E9-E10,E10-E11.

[8] RASCHKE S,ELSEN M,GASSENHUBER H,etal.Evidence against a beneficial effect of irisin in humans [J].PLoSOne,2013,8(9):e73680.

[9] HECKSTEDEN A,WEGMANN M,STEFFEN A,etal.Irisin and exercise training in humans-Results from a randomized controlled training trial[J].BMCMed,2013,11:235.

[10] STENGEL A,HOFMANN T,GOEBEL-STENGEL M,etal.Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity-Correlation with body mass index[J].Peptides,2013,39:125-130.

[11] PARDO M,CRUJEIRAS AB,AMIL M,etal.Association of irisin with fat mass,resting energy expenditure,and daily activity in conditions of extreme body mass index[J].IntJEndocrinol,2014,2014:1-9.

[12] CRUJEIRAS AB,PARDO M,ARTURO R,etal.Longitudinal variation of circulating irisin after an energy restriction-induced weight loss and following weight regain in obese men and women[J].AmJHumBiol,2014,26(2):198-207.

[13] POLYZOS SA,KOUNTOURAS J,SHIELDS K,etal.Irisin:A renaissance in metabolism?[J].Metabolism,2013,62(8):1037-1044.

[14] MORENO-NAVARRETE JM,ORTEGA F,SERRANO M,etal.Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance[J].JClinEndocrinolMetab,2013,98(4):E769-E778.

[15] CHOI YK,KIM MK,BAE KH,etal.Serum irisin levels in new-onset type 2 diabetes[J].DiabetesResClinPract,2013,100(1):96-101.

[16] SELDIN MM,PETERSEN JM,BYERLY MS,etal.Myonectin (CTRP15),a novel myokine that links skeletal muscle to systemic lipid homeostasis[J].JBiolChem,2012,287(15):11968-11980.

[17] RODRIGUEZ A,BECERRIL S,MENDES-GIMENEZ L,etal.Leptin administration activates irisin-induced myogenesis via nitric oxide-dependent mechanisms,but reduces its effect on subcutaneous fat browning in mice[J].IntJObes(Lond),2015,39(3):397-407.

[18] PETERSEN JM,MART R,BOND CE.Effect of obesity and exercise on the expression of the novel myokines,myonectin and fibronectin type Ⅲ domain containing 5[J].PeerJ,2014,2:e605.

[19] YANG M,WEI D,MO C,etal.Saturated fatty acid palmitate-induced insulin resistance is accompanied with myotube loss and the impaired expression of health benefit myokine genes in C2C12 myotubes[J].LipidsHealthDis,2013,12(1):104.

[20] SELDIN MM,LEI X,TAN SY,etal.Skeletal muscle-derived myonectin activates the mammalian target of rapamycin (mTOR) pathway to suppress autophagy in liver[J].JBiolChem,2013,288(50):36073-36082.

[21] MCPHERRON AC,LAWLER AM,LEE SJ.Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member[J].Nature,1997,387(6628):83-90.

[22] SCHUELKE M,WAGNER KR,STOLZ LE,etal.Myostatin mutation associated with gross muscle hypertrophy in a child [J].NEnglJMed,2004,350(26):2682-2688.

[23] REISZ-PORSZASZ S,BHASIN S,ARTAZA JN,etal.Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin[J].AmJPhysiolEndocrinolMetab,2003,285(4):E876-E888.

[24] MOUISEL E,RELIZANI K,MILLE-HAMARD L,etal.Myostatin is a key mediator between energy metabolism and endurance capacity of skeletal muscle[J].AmJPhysiolRegulIntegrCompPhysiol,2014,307(4):R444-R454.

[25] AKPAN I,GONCALVES MD,DHIR R,etal.The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity[J].IntJObes(Lond),2009,33(11):1265-1273.

[26] GUO T,JOU W,CHANTURIYA T,etal.Myostatin inhibition in muscle,but not adipose tissue,decreases fat mass and improves insulin sensitivity[J].PLoSOne,2009,4(3):e4937.

[27] HITTEL DS,AXELSON M,SARNA N,etal.Myostatin decreases with aerobic exercise and associates with insulin resistance [J].MedSciSportsExerc,2010,42(11):2023-2029.

[28] TANG L,LIU CT,WANG XD,etal.A prepared anti-MSTN polyclonal antibody reverses insulin resistance of diet-induced obese rats via regulation of PI3K/Akt/mTOR&FoxO1 signal pathways[J].BiotechnolLett,2014,36(12):2417-2423.

[29] HUANG EJ,REICHARDT LF.Neurotrophins:Roles in neuronal development and function[J].AnnuRevNeurosci,2001,24:677-736.

[30] PEDERSEN BK,PEDERSEN M,KRABBE KS,etal.Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals[J].ExpPhysiol,2009,94(12):1153-1160.

[31] PEDERSEN BK.Exercise-induced myokines and their role in chronic diseases [J].BrainBehavImmun,2011,25(5):811-816.

[32] COPRAY S,LIEM R,BROUWER N,etal.Contraction-induced muscle fiber damage is increased in soleus muscle of streptozotocin-diabetic rats and is associated with elevated expression of brain-derived neurotrophic factor mRNA in muscle fibers and activated satellite cells[J].ExpNeurol,2000,161(2):597-608.

[33] GOMEZ-PINILLA F,YING Z,ROY RR,etal.Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity[J].JNeurophysiol,2002,88(5):2187-2195.

[34] MATTHEWS VB,ASTROM MB,CHAN MH,etal.Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase[J].Diabetologia,2009,52(7):1409-1418.

[35] KRABBE KS,NIELSEN AR,KROGH-MADSEN R,etal.Brain-derived neurotrophic factor (BDNF) and type 2 diabetes[J].Diabetologia,2007,50(9):431-438.

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