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运动对骨骼和肌肉的共调作用研究

作者:赵常红,李世昌,孙朋,徐帅,方幸,季浏 来源:首都体育学院学报 论文栏目:体育论文     更新时间:2019-07-10   浏览

原文标题:《运动对骨骼和肌肉的共调作用研究》,作者:赵常红,李世昌,孙朋,徐帅,方幸,季浏,该学术论文发表于:首都体育学院学报,2017年6期 ,由论文网在线小编整理。

赵常红,,李世昌,,孙朋,,徐帅,,方幸,,季浏

摘 要:骨骼是一种由肌肉和重力共同作用的生物力学组织。年龄的增加、疾病的产生、神经肌肉营养不良、内分泌不足等会导致骨骼和肌肉同时出现质量衰减及功能障碍。通过肌肉组织和骨组织代谢的相互作用,提出运动可能是骨和肌肉共调解的有效方式。方法:采用文献资料法回顾近年来有关骨骼和肌肉相互作用共调节的研究成果。结果:发现骨骼和肌肉是一个关系紧密的整体,通过共享机制,在细胞和分子水平相互作用,达到共调控的平衡发展状态。结论:运动锻炼是实现共调节作用的一种有效方式,在增加肌肉质量和肌肉力量的同时,阻止骨量流失。

关键词:骨骼;肌肉;共调节;运动

中图分类号:G 804.7 文章编号:1009-783X(2017)06-0565-06 文献标识码:A

Abstract: Bone is a kind of biomechanics which is composed of muscle and gravity. The increase of age, the generation of disease, the muscular dystrophy, the endocrine insufficiency and so on can result in simultaneous mass attenuation and the dysfunction of the bone and the muscle. Through the interaction between muscle tissue and bone metabolism, it is suggested that exercise may be an effective way to mediate bone and muscle. Methods: literature review on the regulation of bone and muscle interactions in recent years was reviewed. Results: through the review of the literature in recent years, it is found that the skeleton and muscle are closely related to each other, and they can interact with each other at the cellular and molecular level through the sharing mechanism to achieve the balance. Conclusion: exercise training is an effective way to achieve inter-regulation, which can prevent bone loss while increasing muscle mass and muscle strength.

Keywords: skeleton; muscle; interaction; movement

近年研究發现,在生长过程中,骨骼和肌肉都可以作为与内分泌共同发挥作用的器官[1-3]。随着机体的不断衰老和疾病引起的肌肉衰减,肌肉力量或运动能力也会大受损失[4]。此外,缺乏运动或神经肌肉功能障碍,例如慢性阻塞性肺疾病、心脏衰竭、中风、癌症、帕金森病或糖皮质激素治疗等引起的肌肉废用会导致骨量流失,继发骨质疏松症。近年来发现,骨质疏松症同样也会伴有肌肉减少症,而且会增加跌倒的风险[5],二者同属衰减性疾病;因此,得名为骨骼-肌肉衰减综合症,即骨质疏松症和肌肉衰减症[6]。对此,可以通过加强骨骼与肌肉的相互作用实现共同治疗。药物治疗无法降低肌肉衰减带来的虚弱,但是通过体育锻炼可以将骨骼-肌肉作为一个整体单位予以加强,可以提高肌肉力量和身体平衡性。骨的质量和强度与肌肉是相匹配的,由遗传因素和环境因素共同决定,也通过共享调控机制(如内分泌、神经系统调节)在肌肉、骨器官水平(生物力学导致的生理活动信号)、细胞水平(细胞间通信)或分子水平(肌肉因子、细胞因子或生长因子)等层面进行交流。肌肉和骨骼作为独立的运动器官,在运动对其单独的代谢及功能的影响方面,运动科学领域已有很多研究;但把二者作为一个整体来研究,还较为少见。运动对骨骼和肌肉的质量、功能方面的生物学整合作用,主要体现在:1)生物力学的作用,不仅直接作用于骨骼和肌肉,而且肌肉收缩的力也间接作用于骨骼;2)内分泌调节作用,例如生长激素(growth hormone,GH)、胰岛素样生长因子(insulin-like growth factors,IGFs)、结合蛋白、糖皮质激素、性激素及维生素D和营养信号的共享;3)中枢神经系统,对肌肉和骨代谢产生共调控;4)局部激素,生长因子和细胞因子可能通过旁分泌共同作用于骨骼和肌肉;5)骨骼与肌肉细胞间的通讯。

1 生物力学的作用

力学刺激对骨骼和肌肉的代谢平衡非常重要。有研究发现悬吊小鼠尾巴,后肢的地面反作用力被完全去除,3周骨量丢失达30%[7]。

骨骼是一种生物力学组织,用最少材料经受住尽可能大的应变力[8]。研究发现,动态负载相对于静态负载(例如跳跃相对于站立)更能有效提高骨代谢,在间歇时间里,使骨代谢逐渐达到一个新的应变平衡[9]。力有肌肉产生的力和重力2种,普遍认为,运动的力学刺激仍是一个局部现象,主要是由肌肉产生,这决定了骨与肌肉相依相存,不可分割[10]。

1.1 肌肉收缩和重力的重要性

骨骼的受力一方面来自肌肉收缩,另一方面来自克服重力产生的反作用力。从理论上讲,骨骼的最大受力来自于肌肉收缩,这可能是因为杠杆作用使力放大,例如单腿跳跃,小腿肌肉会对足骨产生3倍于地面的反作用力,以及14倍于体重的负荷[11];同样,在3 km/h走和12 km/h跑时,髋关节接触峰值力增加1~2.5倍的地面反作用力和4.4~10倍的体重负荷[12]。相比之下,骑自行车和游泳的运动员也有巨大的肌肉收缩力,但骨量不增加,这说明肌肉力量对骨骼的影响主要通过克服重力起作用,在低重力环境中这种影响作用很小[13-14]。

实验发现,肉毒素注射引起肌肉萎缩,导致持续性骨丢失,同时再结合后肢悬吊导致失重,两者共同作用,使得骨量丢失最为显著,表明肌肉收缩和重力加载对于维持骨量的重要性[15],但造成以上现象的原因还不清楚,有待进一步研究。

1.2 骨骼与肌肉在衰老过程中机械响应的变化

肌肉卫星细胞数量和密度的降低是肌肉衰老的标志[16],同时还伴随着关键的肌肉细胞信号通路(AKT/mTOR)、细胞外信号调节激酶(extracellular regulated kinase1/2,ERK1/2)和IGF-1减少,氧化应激增加,Notch信号通路也可能同时发挥作用[17-18]。运动锻炼后,有效减缓因机体衰老而导致的蛋白质合成和骨骼肌肥大的下降速率,因此,运动锻炼对中老年人抗衰老效果明显[19-20]。

目前,人类衰老使骨骼对机械性刺激不敏感的机制还不是很清楚,但能明确的是,在细胞水平上,细胞凋亡是一种老化的重要标志[21];在分子水平上,衰老可能涉及内质网应激机制。随着人的衰老,骨細胞内质网应激增加,使原发性骨细胞环氧化酶(cyclooxygenase-2,COX-2)的反应减少[22]。机械负荷无论在体内或体外,COX-2均迅速上调,确认了前列腺素在体内骨骼机械响应中的重要性[23]。研究发现,老龄鼠中肌肉和骨骼合成反应的阈值都有所提高,但生物力学对其的刺激仍然非常有效[24]。

1.3 运动防止骨骼、肌肉衰减

越来越多的研究表明,运动治疗骨质疏松症和肌肉衰减症,但运动对骨骼和肌肉的刺激效果不尽相同。运动作为一种安全简便的防治肌肉萎缩的手段,能够提高肌肉力量,改善身体平衡,同时研究发现肌肉力量的提高还能降低肌肉和骨量下降的风险[25]。

运动使骨骼和肌肉质量获得的峰值,其影响能一直持续到老年[26]。低骨峰值(peak bone mass,PBM)会增加骨质疏松症风险,因此,增加PBM可以推迟骨质疏松的发生。有实验证明,在儿童期的运动(如跳跃)可能会增加骨密度及皮质骨的面积和厚度,持续的体育锻炼具有长期的效果,能防止老年期肌肉衰减,避免骨质疏松症发生[27]。

同样有研究报道,人年轻的时候,跑步锻炼增加的骨密度或皮质骨厚度容易消失[28],而外部负重锻炼增加的皮质骨横截面面积,更能抵制衰老过程中激素下降导致的骨量下降。毕竟,骨膜扩张是不可逆转的[29]。棒球运动员训练表现出的高皮质骨骨量,在退役后,仍能保持很长时间。这些结果都表明,高强度负重运动获得的皮质骨PBM增强可以延续到老年,但低强度、非负重运动的影响可随时间的延长而消失[30]。研究发现体育锻炼对60岁及以上健康受试者的肌肉质量和肌肉功能影响比单独饮食补充效果更好[31]。

2 骨骼—肌肉的共享内分泌调节机制

骨骼和肌肉有各自的内分泌、旁分泌和自分泌信号途径,同时还共享许多内分泌、旁分泌和自分泌信号途径。本文主要介绍生长激素/胰岛素样生长因子(GH/IGF)、维生素D受体(vitamin D receptor,VDR)、糖皮质激素受体(glucocorticoid receptor,GR)和性激素信号,这些内分泌调节器与骨质疏松症及肌肉减少症相关[4]。运动可调控这些内分泌机制调节肌肉和骨代谢。

2.1 生长激素/胰岛素样生长因子信号

生长激素不敏感的人类疾病(Laron综合征)及被破坏GH/IGF转基因的小鼠均显示出骨骼和肌肉的获得性受损[32]。近年研究发现,肝脏IGF-1缺乏模型显示出肌肉的氧化应激增加及老化小鼠的骨丢失加速[33]。

研究还发现,条件敲除小鼠IGF-1受体对于运动性肌肉肥大并非必需[34],相反,IGF-1抵抗可能参与了废用性骨质疏松的形成。无创性胫骨负荷模型表明,IGF-1在成骨细胞中的表达增加[35,]。非负荷大鼠一方面是在IGF-1作用下阻碍骨形成[36],另一方面,局部IGF-1的表达造成骨骼和肌肉的损失[37]。在大鼠动物模型中,GH治疗增加IGF-1,减轻了肌肉和骨膜的损失[38]。总的来说,这些研究表明,GH和IGF-1的缺乏参与肌肉萎缩和废用性骨质的丢失。

2.2 骨骼和肌肉的钙调节轴

维生素D信号通过增加肠钙吸收有益于骨骼健康[39]。许多研究已经证明,维生素D缺乏与骨质疏松症和肌肉衰减症相关,如佝偻病或骨软化症会出现严重的肌无力,这可能是由于维生素D和钙缺乏,或甲状旁腺激素(parathyroid hormone,PTH)水平增加[40]。有研究表明,高PTH和低1,25-(OH)2 -维生素D会加速中老年男性的肌肉损失[41]。荟萃分析表明,钙和维生素D补充一般不会增加骨密度和降低骨折风险[42]。也有分析显示维生素D增加老年人肌肉力量,但不会增加肌肉质量[43]。对社区老年妇女2×2析因试验表明,缺乏维生素D和钙不会增加跌倒的风险,运动和平衡训练会减少跌伤风险[44]。也有研究发现,补充高剂量的维生素D与跌倒风险的增加呈正相关[45],所以我们推测,体育锻炼结合适量维生素D和钙补充可能有益于骨骼与肌肉的健康,但有待进一步验证。

2.3 糖皮质激素受体信号

衰老使内源性糖皮质激素亢进,增加了肌肉与骨骼对糖皮质激素的敏感性,包括对成骨细胞、骨细胞、破骨细胞和肌细胞产生直接作用,对肠钙吸收和性激素产生间接作用[46]。肌肉GR特异性基因敲除(GRKO)小鼠显示出肌肉质量增加以及良好的代谢改变[47],防止外源性和内源性糖皮质激素过量诱导的肌肉萎缩[48];然而,这些特定GRKO小鼠通过肌肉骨骼相互作用能否抵制糖皮质激素诱导的骨质疏松,目前尚无定论。

2.4 雄激素和雌激素受体信号

雄激素不仅影响肌肉的合成代谢,而且会通过雄激素受体芳构化成雌激素,刺激雌激素受体(estrogen receptor,ERa和ERb)来调节骨代谢[49]。

研究发现:雄激素受体(androgen receptor,AR)基因敲除小鼠不仅肌肉质量减少,而且运动能力也降低;但肌肉中缺失雄激素没有影响骨峰值[50]。这表明AR条件敲除小鼠模型中,雄激素对骨骼的影响不完全归因于肌肉质量。雄性雄激素受体-雌激素受体双敲小鼠ARKO-ERaKO的肌肉损失比单敲ARKO高, ERaKO小鼠骨骼机械响应减少[51]。在最近的成骨细胞和骨细胞特异性EraKO研究中,雌性小鼠表现出加载响应的增强[52]。相反,ERaKO DMP1 Cre雌性小鼠骨小梁的敏感性增加,却阻止了悬吊后肢皮质骨骨密度(bone mass density,BMD)的损失[53]。睾酮可以阻止肌肉萎缩,增加瘦体重和年轻男性的力量,因此,运动训练后两者能够协同增加;但在老年男性训练中没有出现协同性的增加,可能是因为试验中虚弱的老年男性出现心血管安全问题,无法进行高体能训练[54]。

研究发现,AR和ER对肌肉和骨骼单独发挥作用,雄激素缺乏可能会减弱训练后肌肉的响应;但研究发现性激素基因剔除小鼠中,运动仍是防止性激素缺乏引起肌肉与骨骼退化的有效方法。雌激素直接作用于骨骼,而雄激素通过影响肌肉来作用于骨骼[50]。目前,关于性激素受体与运动调节骨骼和肌肉代謝相互作用有待进一步研究。

综上所述,骨骼和肌肉紧密相连,两者共享内分泌调节机制,在老年人低GH/IGF-1、维生素D或性激素水平下,运动是有效的刺激方式。以前单独论述运动与肌肉,运动与骨骼的关系,但近年来研究发现:骨骼和肌肉存在共享机制,运动作为一种有效的调节方式能对他们共同调节[8]。

3 骨骼与肌肉间的神经调节

在哺乳动物自然废用模型中,如熊的冬眠,在长达4~5个月的时间里,骨量却没有发生显著性损失,其原因可能是熊会通过自主神经系统或循环同化激素来减少骨转换,保持骨形成和骨吸收的平衡[55]。神经不仅调控肌肉代谢,而且调节骨代谢。肌肉的功能依赖运动神经的输入,去神经、脊髓损伤、神经肌肉疾病(包括中风、帕金森病等)必然会导致肌肉衰减和骨量丢失。注射肉毒杆菌毒素,干扰突触前囊泡结合神经递质乙酰胆碱的释放,在大鼠、小鼠和斑马鱼体内产生快速的骨丢失[56]。这种对肌肉神经的封锁最终会影响破骨细胞的活性[57]。 这为运动调节骨代谢和肌肉代谢相互作用提供理论依据。

肾上腺素受体(adrenergic receptor,ADRP)可以间接调节骨量,交感神经系统通过成骨细胞的肾上腺素受体减少骨形成,增加骨吸收[58]。ADRP激动剂克伦特罗(兴奋剂)能导致骨骼肌肥大,对骨骼非常有害,这可能是由于减少了脂肪,降低了瘦素水平而导致的[59-60]。

感觉神经的抑制会导致小鼠骨小梁丢失,但这是否是由于加载模式或改变局部介质,如降钙素基因相关肽(calcitonin gene related peptide,CGRP)导致的,仍不清楚。最近发现,脑信号蛋白3A神经元特异性缺失能解释感觉神经支配的低骨形成[61],而感觉神经参与的骨骼载荷自适应响应还需要进一步确认[62]。由上可见,骨骼和肌肉可能部分依赖于共同的中枢神经调节系统。两者作为运动器官,其相互作用的紧密性是必然的。

4 肌肉因子和胞间通信

运动有利于肌肉能量代谢,促进葡萄糖吸收[2],同时各种运动信号和功能的执行要求组织之间的紧密结合。研究表明,在营养(特别是葡萄糖)缺乏的情况下,白介素-6(interleukin-6,IL-6)水平的升高会促进破骨细胞生成,刺激骨吸收,IL-6的长期升高可导致全身骨丢失[63]。虽然,肌肉肥大和肌肉萎缩的恢复也需要IL-6,但长期IL-6升高会导致肌肉萎缩[64]。研究还确认肌源性IL-15也能够调节骨骼和脂肪质量。周期性肌管紧张也增加了其他细胞因子如IL-8、趋化因子配体1(CXCL1)和CCL7的表达,这些都会吸引破骨细胞前体细胞和成骨中其他炎症细胞的细胞因子[65]。重要的是,肌肉细胞表达核因子κB受体活化因子配体(receptor activator for nuclear factor-κB ligand,RANKL)的诱饵受体骨保护素(osteoprotegerin,OPG),被认为是原始的骨吸收调节器[66]。此外,负载训练在C2C12肌管中迅速降低RANKL/OPG mRNA比值,这提示运动对抗RANKL,对于防治骨质疏松有一定指导意义[67]。有研究还发现,鸢尾素作为一种运动性肌肉因子诱导白色脂肪向褐色脂肪转化,调节能量消耗[68]。虽然小鼠鸢尾素能够调节成骨细胞的分化,但在人身上还缺乏研究[69]。肌肉是肌肉因子增长的源泉,如IGF-1和成纤维细胞生长因子-2(fibroblast growth factor-2,FGF-2)2种肌源性生长因子,在骨中也有其受体,说明IGF和FGF可能是最丰富的肌源性生长因子,可以调节骨骼—肌肉间通信[70]。蛋白质组学研究已经确定了肌肉衍生的肽包括IGF-1、IGF-2和几种胰岛素样生长因子结合蛋白及其他生长因子(如转化生长因子)能够影响骨代谢,同时明确了几种基质蛋白(骨粘连蛋白、蛋白聚糖、胶原蛋白、基质蛋白)、钙等[71]在肌肉和骨骼中的共表达。研究发现,自主转轮运动训练能够提高老年小鼠血液中IGF-1的水平并诱导肌肉肥大,但未增加骨骼强度,说明肌肉与骨骼虽然有着密切的胞间交流,但运动方式对骨骼的影响更为重要[70]。

5 骨骼与肌肉间的交流

研究表明,骨骼也可以作为一种内分泌器官影响肌肉生成。小鼠或小鸡敲除印度刺猬蛋白(indian hedgehog,Ihh)?发现,其不仅在软骨中表达,并参与软骨细胞的分化和长骨发育,还会会影响肌肉的生长[72]。最近的一项研究发现,在受损骨骼-肌肉成骨细胞/骨细胞特定的Cx43基因敲除小鼠中,骨钙素的羧基化证明了骨骼-肌肉间的交流[73]。体外研究发现,成骨细胞样细胞系(如MLO-Y4)表达的肌肉合成和分解代谢的因子如IL-6、前列腺素E2(prostaglandin E2,PGE2)、血管内皮生长因子(vascular endothelial growth factor,VEGF)、肝细胞生长因子(hepatocyte growth factor,HGF)、IGF-1和机械生长因子(mechanical growth factor,MGF)等,都说明骨骼和肌肉间存在着千丝万缕的联系和交流[74]。最近研究发现,骨骼肌也产生瘦素,且受体在骨骼肌和骨间充质干细胞表达丰富。这些结果表明,瘦素在肌肉和骨骼中发挥重要作用。老化导致的瘦素抵抗可随年龄增长而增加,低水平的瘦素使得骨髓干细胞向脂肪细胞分化,从而导致骨量降低,最终导致骨质流失和肌肉萎缩,促进骨脆性和跌倒的发生。蛋白质和氨基酸补充,可以增加肌肉质量和肌肉来源的瘦素,降低老人跌倒和骨折的发生率[75],科学运动能促进肌肉和骨量的增加,能够预防骨质疏松症,相反骨衍生的因子也会影响肌肉功能[76],他们之间的内在联系,有待研究进行进一步的研究。

6 結论与展望

骨骼和肌肉不可分割,相互调节。骨骼、肌肉和脂肪细胞都来源于间充质干细胞,骨质疏松症和肌肉衰减症的部分原因是由于细胞机制涉及脂肪分化的过量和成肌、成骨分化的不足。运动可影响睾酮涉及这种机制,增加骨骼和肌肉质量,减少脂肪量,运动锻炼可导致肌肉肥大,肌腱和结缔组织强度增加,以及肌肉神经功能增强,同时增加骨形成、减少骨吸收,预防骨质疏松。研究发现,骨质疏松症会减少肌肉力量,增加跌倒和骨折的风险。运动作为两者有效的刺激方式,如何增加肌肉含量,提高骨密度与骨强度,促进肌肉和骨骼的相互作用势必成为运动科学下一个研究的热点。由于骨骼和肌肉关系紧密,二者相辅相成,科学运动会起到双重效果,且运动方式对二者的刺激非常重要,骨质疏松症和肌肉衰减症就像一对连体的孪生兄弟,在运动防治过程中必将引起运动科学领域的共同重视。

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