老年肌少癥的肌肉形態(tài)結(jié)構(gòu)病理生理變化

馮麗　盛云露　宗立翎　劉娟　丁國憲

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·講座與綜述·

老年肌少癥的肌肉形態(tài)結(jié)構(gòu)病理生理變化

馮麗盛云露宗立翎劉娟丁國憲

肌少癥是一類以進(jìn)行性的、廣泛性的骨骼肌量和肌力減少以及骨骼肌功能減退為特征,進(jìn)而導(dǎo)致機(jī)體功能和生活質(zhì)量下降甚至死亡的綜合征[1]。在全球其發(fā)病率逐年增高,目前已成為威脅老年人健康,影響老年人生活質(zhì)量的重要危險(xiǎn)因素。肌少癥的診斷包括3個(gè)要素,即肌量減少、肌力減少和肌肉功能減退。肌少癥不僅會增加殘疾、跌倒、骨折的風(fēng)險(xiǎn),降低生活質(zhì)量,還會增加罹患糖尿病、骨關(guān)節(jié)炎、冠狀動脈等疾病的危險(xiǎn)[2]。

肌少癥的發(fā)生與機(jī)體活動量的減少、營養(yǎng)不良、氧化應(yīng)激、生長激素及類固醇激素分泌異常有關(guān)[3]。有研究表明肌肉量在兒童及青中年時(shí)期逐漸增加,到40歲左右達(dá)到穩(wěn)定,之后會以1%～2%的速度逐年降低[4]。據(jù)Patel等[5]統(tǒng)計(jì),人體總的肌肉量從40～80歲下降30%～50%,肌肉功能50歲以后每年下降1%～2%,60歲以后每年下降達(dá)到3%。Vandervoort等[6]及Russ等[7]發(fā)現(xiàn)肌肉橫截面積在60歲以后每年下降1%～2%。HealthABC研究表明肌肉力量的下降速度遠(yuǎn)比肌肉量的下降速度快,肌肉量不變的情況下肌肉力量仍會隨著年齡增加而下降[8]。觀察細(xì)胞水平肌肉結(jié)構(gòu)的增齡性變化,發(fā)現(xiàn)主要表現(xiàn)為肌纖維結(jié)構(gòu)及神經(jīng)肌肉系統(tǒng)的顯著改變,因此本文主要詳細(xì)介紹這一變化。

1　骨骼肌正常生理結(jié)構(gòu)

1.1骨骼肌基本生理結(jié)構(gòu)骨骼肌組織的基本構(gòu)成單位為肌細(xì)胞,因其呈細(xì)長纖維狀,又稱為肌纖維。肌纖維為多核細(xì)胞,細(xì)胞間有結(jié)締組織、毛細(xì)血管及神經(jīng)纖維等,其細(xì)胞膜稱為肌膜,細(xì)胞質(zhì)稱為肌質(zhì),肌質(zhì)中含豐富的肌原纖維，成簇狀依肌細(xì)胞長軸排列,其外由結(jié)締組織膜包裹,肌質(zhì)中還有線粒體為肌肉活動提供能量、糖原儲存能量以及肌紅蛋白儲存和釋放氧。肌纖維由上千條粗細(xì)肌絲依肌細(xì)胞長軸排列,其中粗肌絲由肌球蛋白分子構(gòu)成,細(xì)肌絲由肌動蛋白、原肌球蛋白、肌鈣蛋白構(gòu)成[9]。

骨骼肌在人體內(nèi)廣泛分布,約600多塊,占人體質(zhì)量的40%,不同人體、不同部位的肌肉中,肌肉纖維類型及分布比例不同,相應(yīng)的功能也不同[10-11],肌纖維的組成受肌肉的功能特征、性別、年齡以及遺傳的影響。在細(xì)胞水平,依據(jù)所含肌球蛋白亞型的不同[如肌球蛋白重鏈(MHC)及肌球蛋白輕鏈,其中肌球蛋白重鏈?zhǔn)怯绊懠∪饫w維類型中最主要的亞型][9],可將骨骼肌纖維分為3種類型,即慢肌纖維、快肌纖維及介于二者之間的耐疲勞肌纖維。慢肌纖維包含較少數(shù)量的肌纖維,由Ⅰ型肌球蛋白重鏈構(gòu)成,其轉(zhuǎn)換能量的速度較慢。富含線粒體及肌紅蛋白,且分布的毛細(xì)血管網(wǎng)豐富,因此為紅色,又稱為紅肌纖維。它可以通過氧化分解脂類及碳水化合物獲得大量ATP,其氧化過程相對緩慢,這樣有益于維持長時(shí)間的有氧活動,如長跑,因此,慢肌纖維多用于較長時(shí)間的肌肉活動以及抗阻運(yùn)動?？旒±w維可產(chǎn)生較大的力量及較快的速度,肌纖維橫截面積較大,所含的肌纖維數(shù)量較多,分布毛細(xì)血管網(wǎng)相對較少,它主要含有Ⅱx肌球蛋白重鏈,能量轉(zhuǎn)換速度快,所含線粒體較少,其活動所需能量來源于糖酵解,可在短時(shí)間內(nèi)提供大量的能量,多用于要求短時(shí)間產(chǎn)生大量能量的運(yùn)動,例如舉重、快跑;第3種肌纖維為耐疲勞肌纖維,其耗氧速度、橫截面積、肌纖維數(shù)量及收縮速度介于Ⅰ、Ⅱ型肌纖維之間,由Ⅱa型肌球蛋白重鏈構(gòu)成[9,12]。

1.2神經(jīng)-運(yùn)動單位神經(jīng)肌肉系統(tǒng)的基本構(gòu)成單位為神經(jīng)-運(yùn)動單位。單個(gè)的運(yùn)動神經(jīng)元及肌肉纖維及支配其的神經(jīng)束總體稱為運(yùn)動單位。通常情況下,較小的肌肉受神經(jīng)的精細(xì)調(diào)節(jié),該類神經(jīng)只支配少量的肌肉纖維;較大的肌肉纖維受單獨(dú)的神經(jīng)束支配,該類神經(jīng)可支配較多數(shù)量的肌肉纖維。當(dāng)神經(jīng)纖維接近肌肉時(shí),失去髓鞘并分成細(xì)支,末端膨大形成卵圓形小板狀隆起附著于肌纖維表面，形成突觸前膜并與之相對應(yīng)的肌纖維膜構(gòu)成運(yùn)動終板。該突觸內(nèi)含有大量的乙酰膽堿,當(dāng)神經(jīng)沖動傳到神經(jīng)纖維終末時(shí),乙酰膽堿從突觸膜釋放,作用于與之相對的肌肉纖維膜上的乙酰膽堿受體,引起肌膜電位發(fā)生變化,導(dǎo)致肌肉收縮。肌肉收縮則是由ATP分解供能,粗細(xì)肌絲間滑行導(dǎo)致肌節(jié)縮短,完成收縮[13]。

2　老年肌少癥肌肉形態(tài)結(jié)構(gòu)病理變化

肌肉年齡相關(guān)的改變包括肌肉量、形態(tài)結(jié)構(gòu)、收縮性能的改變。有研究顯示隨年齡增加,男性肌肉量下降較女性顯著,最先表現(xiàn)為下肢肌肉量的減少,而且下肢肌肉量的減少遠(yuǎn)勝于上肢。肌肉纖維結(jié)構(gòu)的變化則主要為肌纖維變細(xì),尤其是Ⅱ型纖維[14]。Lexell等[15]在鏡下觀察股外側(cè)肌增齡性變化,發(fā)現(xiàn)30歲以后肌肉出現(xiàn)萎縮,最先出現(xiàn)的是肌肉數(shù)量的減少,無明顯纖維類型的區(qū)別,肌肉大小無明顯變化(只有少量的Ⅱ型肌纖維的減小),之后,隨著年齡增加,出現(xiàn)肌肉大小減小,尤其是Ⅱ型肌纖維。Lee等[16]也通過對肌肉橫截面積、肌纖維數(shù)量、大小研究證實(shí)了上述結(jié)果。這些變化主要是由于肌肉纖維形態(tài)結(jié)構(gòu)及運(yùn)動單位的改變引起的。

2.1肌肉纖維形態(tài)結(jié)構(gòu)病理改變老年肌肉改變主要表現(xiàn)為肌肉纖維橫截面積縮小,神經(jīng)支配減少,肌肉組織快肌纖維向慢肌纖維的適應(yīng)性轉(zhuǎn)變。最終這樣的轉(zhuǎn)變導(dǎo)致肌肉量、力量以及功能減弱,造成了身體活動能力減弱、殘疾，增加跌倒的風(fēng)險(xiǎn)。

電鏡下觀察肌纖維變化,可見肌纖維核移至中央,出現(xiàn)環(huán)狀纖維,纖維斷裂、破碎及蟲蝕樣變,甚至出現(xiàn)空泡[17]。有許多原因相互疊加導(dǎo)致肌肉結(jié)構(gòu)的紊亂,其中由于蛋白合成障礙及破壞過多導(dǎo)致的蛋白代謝異常最重要。但最近有研究發(fā)現(xiàn)老年人蛋白合成率與年輕人無明顯差異[18]。近年來新的研究發(fā)現(xiàn)老年人蛋白攝入不足,吸收功能差,活動后蛋白合成反應(yīng)減慢,出現(xiàn)蛋白赤字影響了雷帕霉素信號通路,激活了泛素蛋白酶體通路[19-21],同樣能誘發(fā)細(xì)胞“自噬”,導(dǎo)致肌肉纖維破壞,破壞的細(xì)胞器及細(xì)胞碎片堆積進(jìn)一步加速細(xì)胞死亡,導(dǎo)致肌肉量減少[22]。進(jìn)一步觀察發(fā)現(xiàn),肌少癥肌肉變化在電鏡下表現(xiàn)為肌球蛋白及肌動蛋白量減少,有研究顯示肌球蛋白重鏈的合成率隨年齡增長而降低[23]。有研究發(fā)現(xiàn)老年鼠半膜肌肌球蛋白與肌動蛋白的比例下降,但對中老年人群比目魚肌肌纖維觀察則未發(fā)現(xiàn)二者的比例減少。說明二者比例的減少在不同的年齡階段、不同的肌肉類型表現(xiàn)不同[24-25]。此外Hook等[26]發(fā)現(xiàn)肌動蛋白肌絲滑行速度隨年齡增長而下降。原肌球蛋白及肌鈣蛋白在肌絲滑動過程中起到暴露肌球蛋白上ATP結(jié)合位點(diǎn)的作用,該蛋白異常亦會導(dǎo)致肌肉收縮功能異常。有研究表明隨年齡增長該種蛋白的表達(dá)量下降,轉(zhuǎn)錄后修飾增加[27-28],但此方面的研究較少,還有待于進(jìn)一步研究。

Goodpaster等[29]還發(fā)現(xiàn)隨著年齡增加,各組肌肉間及肌束間脂肪細(xì)胞增加,有研究顯示由于脂肪細(xì)胞釋放細(xì)胞因子導(dǎo)致肌肉損傷,脂肪細(xì)胞越多,肌肉力量下降越明顯[30]。對于肌肉的血供,Jakobsson等[17]在鏡下觀察發(fā)現(xiàn)老年組Ⅱ型肌纖維周圍分布的毛細(xì)血管較青年組明顯減少,而Ⅰ型肌纖維則無明顯改變。

2.2神經(jīng)肌肉系統(tǒng)改變運(yùn)動單位是神經(jīng)肌肉收縮功能的基本單位,由脊髓a神經(jīng)元、運(yùn)動神經(jīng)纖維及其分支以及所支配的肌肉纖維構(gòu)成[31]。每一運(yùn)動神經(jīng)元大約有50000個(gè)神經(jīng)末梢分支作用于肌纖維,其分布受許多因素影響[13]。

隨著年齡增加,肌肉及其相關(guān)的神經(jīng)系統(tǒng)都會有損傷,進(jìn)而導(dǎo)致肌肉功能下降。有研究檢測腰骶部a運(yùn)動神經(jīng)元(尤其支配快肌纖維的神經(jīng)元)發(fā)現(xiàn),從20～100歲平均減少25%,較嚴(yán)重者60歲以后總量只剩下年輕時(shí)的50%,且脊髓神經(jīng)前根神經(jīng)軸的數(shù)量及直徑均減小[32-33]。Morita等[34]則發(fā)現(xiàn)老年人脊髓的興奮性較年輕人明顯降低。

周圍神經(jīng)及髓鞘鏡下改變,可見肌肉神經(jīng)節(jié)點(diǎn)減少、末端膨大變大,突觸小泡減少,神經(jīng)遞質(zhì)減少,慢肌纖維末梢可見神經(jīng)萌芽及側(cè)支增加[35]。Doherty等[36]測量軸突傳遞速度發(fā)現(xiàn)隨年齡增長而減慢,大量的纖維失神經(jīng)并且階段性脫髓鞘,神經(jīng)節(jié)節(jié)間長度減小。神經(jīng)肌肉系統(tǒng)末端——運(yùn)動單位也發(fā)生年齡相關(guān)的改變。慢肌運(yùn)動單位數(shù)量變化較小,但是每個(gè)運(yùn)動單位所包含的纖維數(shù)量增加3倍;相反的,快肌運(yùn)動單位減少34%,而且每個(gè)運(yùn)動單位所包含的纖維減少86%[37]。

有研究顯示肌肉量的減少最早發(fā)生的是肌肉單元的減少。運(yùn)動單元在生長過程中不斷地經(jīng)歷失神經(jīng)-再重塑的過程。隨年齡增加,運(yùn)動單元的失神經(jīng)大于重塑,最終完全失去神經(jīng)支配直至凋亡[38]。在早期,老年人運(yùn)動單元的失神經(jīng)改變由于神經(jīng)重塑作用不能被檢測到,肌肉量及力量無明顯改變,這一時(shí)期的改變主要為脊髓神經(jīng)元凋亡及軸突變性[39-40]。肌肉纖維失去神經(jīng)支配后,其中部分肌纖維得到鄰近的健全神經(jīng)元新的神經(jīng)萌芽的支配而得以再生,但新生成的運(yùn)動單元較肥大,且運(yùn)動速度減慢。在人類,失神經(jīng)纖維主要為Ⅱ型肌纖維,因此隨著運(yùn)動神經(jīng)纖維的重塑,大部分完好的Ⅰ型運(yùn)動單元的神經(jīng)萌芽伸出側(cè)支支配失神經(jīng)支配的Ⅱ型肌纖維,導(dǎo)致Ⅱ型肌纖維向Ⅰ型肌纖維的轉(zhuǎn)變[41]。

神經(jīng)肌肉接點(diǎn)則表現(xiàn)為運(yùn)動終板重塑。終板突觸前膜及突觸后膜的神經(jīng)末梢分支增加,突觸后膜上乙酰膽堿受體破壞,突觸后結(jié)構(gòu)由神經(jīng)末梢取代。有研究表明老年小鼠廢用性肌肉比健康老年小鼠及青年小鼠肌肉的肌肉神經(jīng)節(jié)點(diǎn)的重塑更加明顯[42]。

肌肉結(jié)構(gòu)、肌肉神經(jīng)系統(tǒng)增齡性改變最終導(dǎo)致肌肉量、肌肉力量、收縮功能下降,對人類健康、壽命、生活質(zhì)量均帶來威脅,明顯增加了患病率及致殘率。近幾年在臨床醫(yī)學(xué)研究中對老年人肌肉減少的問題越來越重視,同時(shí)對該問題的認(rèn)識也逐漸加深。這將有利于我們及早發(fā)現(xiàn)、診斷肌少癥,并及早進(jìn)行干預(yù),改善患者的生活質(zhì)量。

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210029江蘇省南京市，南京醫(yī)科大學(xué)第一附屬醫(yī)院老年內(nèi)分泌科

丁國憲，Email：dinggx@njmu.edu.cn

R 592; R 681

Adoi:10.3969/j.issn.1003-9198.2016.06.017

2016-02-01)