2023, Vol. 59
2. 山东大学齐鲁医院(青岛)
运动可以降低一系列疾病的发生风险，是各种慢性疾病的一线治疗方法[1-2]。既往研究发现，骨骼肌可以产生并释放白细胞介素-6(IL-6)，从此确立了骨骼肌是一种内分泌器官[3]。由肌肉纤维产生、表达和释放并以自分泌、旁分泌或内分泌方式发挥作用的细胞因子和其他多肽类物质，称为肌因子[4]。后续实验证明骨骼肌是一个活跃的内分泌器官，能产生和分泌数百种肌因子。骨骼肌分泌的肌因子以自分泌、旁分泌或内分泌的方式发挥作用。肌因子被释放到血液中，除在肌肉内部发挥作用外，还使得肌肉与大脑、脂肪组织、骨骼、肝脏、肠道、胰腺、血管床和皮肤等器官之间可以相互作用[5-7]，介导代谢调节、炎症、血管和肌肉生成等过程[8-11]。本文主要对肌因子介导肌肉与其他器官相互作用的相关研究进展进行综述。
1 肌肉内部的肌因子研究发现，一些肌因子在骨骼肌内部发挥作用，参与肌肉生成的调节[12]。肌肉生长抑制素是第一个被发现符合上述肌因子定义的细胞因子[13]。肌生长抑制素是转化生长因子-β(TGF-β)超家族的成员，并以自分泌方式负调控肌肉生成[13]。核心蛋白聚糖作为肌生长抑制素的拮抗剂，是一种受运动调节的肌因子[14]。运动使得血液中的核心蛋白聚糖水平增加[14]，但却使肌肉和循环中的肌肉生长抑制素水平降低[15-16]。肌肉细胞及相关卫星细胞产生的IL-6以旁分泌的形式刺激肌肉增殖，相反，IL-6的遗传缺失会抑制肌肉的生长[17]。
人体循环中的IL-6低水平与身体活动不足有关[18]。在经过训练的人类肌肉中，IL-6受体表达升高[19]，提示可通过训练增加肌肉对IL-6的敏感性。肌肉中的IL-6可以影响葡萄糖摄取和脂肪氧化。研究表明，IL-6可增加基础葡萄糖摄取和葡萄糖转运蛋白(GLUT-4)的转位[20]。同时，在体外和健康人体中IL-6还可增加胰岛素刺激的葡萄糖摄取。
2 肌因子对大脑的作用近年来的研究表明，肌肉与大脑之间确实存在内分泌循环，其中部分是由肌因子信号介导的。其他介质可能包括各种代谢物[21]、非编码RNA[22]等。运动对海马体的影响比大脑其他部位更大。对啮齿动物和人类的研究证实，运动可以增加海马体的体积和大脑血供[23]。脑源性神经营养因子(BDNF)是海马体的生长因子，参与细胞生长和学习[24]，在调节运动对海马体的影响方面起主导作用[25]。此前，BDNF已被证明与运动诱导的认知功能改善有关联[26-27]。人有氧运动训练3个月后，健康者的海马体体积增加12%，精神分裂症病人增加16%[28]。
在运动过程中，人类骨骼肌中也可以产生BDNF，但目前并未发现肌肉来源的BDNF释放到血液中，即并未发现BDNF可以直接进入循环介导肌肉与大脑的相互作用[29]。然而，有研究表明，组织蛋白酶-B和鸢尾素可以通过血脑屏障，提高BDNF水平。组织蛋白酶-B是一种新发现的肌因子，MOON等[30]研究发现，运动导致循环中组织蛋白酶-B水平升高，从而促进海马体中BDNF表达。跑步导致小鼠肌肉中组织蛋白酶-B基因的表达增加，运动4个月后小鼠血浆中组织蛋白酶基因的表达增加。但组织蛋白酶-B是否参与人类运动后的认知功能的增强尚不明确。鸢尾素也是一种新近发现的肌因子，WRANN等[24]研究报道，鸢尾素参与身体活动对大脑的中介作用。当鸢尾素过表达时会导致BDNF增加，而Ⅲ型纤连蛋白域蛋白5(FNDC5)的下调则会导致BDNF减少。但鸢尾素是否参与肌肉与大脑的内分泌循环有一定争议[31-32]。
IL-6通常与代谢综合征有关，IL-6水平升高常伴随肥胖和2型糖尿病的发生[33]。然而，IL-6对代谢活动也有有益影响，缺乏IL-6的小鼠体质量增加，并出现全身胰岛素抵抗[34]。ELLIINGSGAARD等[35]研究显示，在肥胖状态下IL-6触发胰腺α细胞增殖，并刺激胰高血糖素样肽-1(GLP-1)产生，进而产生胰岛素分泌。IL-6的积极作用还包括增强胰岛素刺激的葡萄糖摄取和脂肪氧化，也可通过延迟胃排空从而影响餐后血糖。TIMPER等[36]研究发现，给小鼠中枢应用IL-6，可以抑制小鼠食欲并改善葡萄糖耐量。然而，外周应用更高浓度的IL-6显著减少了食物摄入量。这一发现表明，全身高浓度的IL-6可以通过血脑屏障对食欲产生影响。因此，通过运动诱导产生IL-6可能抑制食欲。
3 肌因子对脂肪的作用运动诱导骨骼肌产生的IL-6可参与调节脂质代谢。另外，IL-6作用于脂肪组织还可以增加瘦素分泌和增加饱腹感[37]。最近的研究表明，一些肌因子可能同时具有诱导白色脂肪组织棕色化的能力。PEDERSEN等[38]研究发现，IL-6可以通过调控AMP激活蛋白激酶(AMPK)信号通路增强脂肪分解和脂肪氧化。
白色脂肪棕色化能明显促进机体能量的消耗，同时改善机体糖脂代谢[39]。因此，这可能成为针对肥胖症及其相关代谢异常疾病治疗的新靶点。肌肉表达过氧化物酶体增殖物激活受体γ共激活因子-1(PGC-1)刺激FNDC5的表达增加，FNDC5是一种膜蛋白，它可被裂解为鸢尾素[40]。鸢尾素作用于白色脂肪细胞，进而刺激解偶联蛋白(UCP1)表达和白色脂肪棕色化[41]。在小鼠和人类的运动中，血液中鸢尾素水平的轻度增加会导致小鼠的能量消耗增加，而运动或食物摄入量没有变化[41]。尽管肌肉释放鸢尾素可诱导白色脂肪棕色化，但运动是否可以导致鸢尾素水平增加还存在争议。IL-6同样可诱导白色脂肪组织棕色化，例如，给小鼠腹腔注射1周IL-6，小鼠腹股沟白色脂肪组织中UCP1 mRNA水平明显增加[42]。
4 肌因子对骨骼的作用肌肉和骨骼在生长发育过程中密切相关，肌肉减少症会导致骨质疏松症[43]。骨骼肌通过分泌肌因子调节骨代谢，这些肌因子分别包括IL-6、肌肉生长抑制素、胰岛素样生长因子-1(IGF-1)等。IL-6从促进成骨细胞分化[44]和破骨细胞生成[45]两方面影响骨代谢。在转基因小鼠实验中，肌肉生长抑制素可以干扰破骨细胞形成，抑制肌肉生长抑制素通路可导致骨量增加[46]。肌肉来源的IGF-1可以作用于表达相应受体的成骨细胞，从而促进骨形成[47]。
5 肌因子对肝脏的作用运动中常伴随肝糖原分解，内源性葡萄糖产生的介质包括胰高血糖素与胰岛素、肾上腺素和去甲肾上腺素。此外，肌肉同样产生肌因子以促进体内葡萄糖快速增加，肌肉来源的IL-6在人类运动中刺激肝脏葡萄糖输出[48]。PEPPLER等[49]发现，IL-6可增强蛋白激酶B(AKT)信号通路，从而降低小鼠肝脏中糖异生基因表达，表明肥胖状态下IL-6对维持葡萄糖和胰岛素的稳态有积极作用。运动是非乙醇性脂肪性肝病的一线治疗方法，有氧运动和抗阻力运动都能减轻非乙醇性脂肪性肝病的肝脏脂肪变性。研究发现，非乙醇性脂肪性肝病病人血清鸢尾素水平低于健康个体[50]，而抗阻力运动可升高循环中鸢尾素水平[51]。
6 肌因子对肿瘤的作用流行病学研究表明，体育活动可以降低至少13种不同类型癌症的发生风险[52]。在前列腺癌、结直肠癌和乳癌病人中，进行体育锻炼的人相对于不锻炼者生存率更高[53]。许多癌症伴有慢性低度系统性炎症，这种炎症可能会加速肿瘤进展。因此，体育锻炼可能是通过抗炎作用而发挥抗肿瘤作用。自然杀伤细胞(NK细胞)可被肾上腺素动员，阻断β肾上腺素能信号减弱了训练依赖性肿瘤抑制。PEDERSEN等[54]发现，运动的小鼠肿瘤体积和发病率都显著降低。运动可引起肾上腺素分泌增多，而肾上腺素特异性向肿瘤招募IL-6敏感性NK细胞，从而影响肿瘤生长，而阻断IL-6信号通路使训练诱导的肿瘤内NK细胞浸润和活化减少，从而促进肿瘤生长。因此，IL-6可能在介导抗癌过程中发挥作用。有证据表明，富含半胱氨酸的酸性分泌蛋白(SPARC)、鸢尾素等肌因子在抑制乳癌和结肠癌中发挥作用，其具体机制尚未明确。
7 结语缺乏体育运动与大量的慢性疾病发生相关，包括2型糖尿病、心血管疾病、癌症、痴呆症和骨质疏松症等[53]。其机制可能与缺乏某种肌因子有关。但目前运动改善慢性疾病症状的具体机制还尚未明确，有待进一步的研究和探讨。对运动相关肌因子的研究可能为慢性病病人的生活方式提供指导，为慢性疾病的防治提供新的思路。
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