Mechanism and clinical research advance of muscle atrophy: thinking based on the 65th Annual Meeting of American College of Sports Medicine

doi:10.3969/j.issn.2095-4344.1134

Abstract

Abstract:

BACKGROUND: The purpose of this study was to introduce the mechanism and clinical application of muscular atrophy that is a hotspot in the 65th Annual Meeting of American College of Sports Medicine and the 9th World Conference on Exercise Is Medicine and the World Conference of Basic Science of Muscle Hypertrophy and Atrophy.
OBJECTIVE: To summarize and analyze the frontiers and hotspots of research findings on muscular atrophy, in order to provide new ideas for further research of exercise improving muscle function and the mechanism and application in this field, and provide a reference for the study on sports science, sports medicine, and sports rehabilitation in China.
METHODS: Related reports and cutting-edge research findings in 65th Annual Meeting of American College of Sports Medicine were collected. Meanwhile, PubMed database between January 1993 and August 2018 was retrieved. The keywords were “skeletal muscle, muscle atrophy, movement and muscle, resistance movement”. Thirty-five articles related to the molecular mechanism and clinical application of muscle atrophy were included for analysis and discussion.
RESULTS AND CONCLUSION: The World Congress is a unique opportunity to bring together interdisciplinary investigators for the most comprehensive meeting ever held on this topic. The program will include a keynote lecture, tutorials, and symposia from leading experts. The meeting focused on the intrinsic and extrinsic variables that regulate skeletal muscle hypertrophy and atrophy. How exercise brings about skeletal muscle atrophy and its application in clinical problems such as aging, disease, injury, chronic diseases, and how these changes may relate to chronic disease were discussed as well. The research on muscle hypertrophy is mostly concentrated in the field of competitive sports.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Muscle, Skeletal, Muscular Disorders, Atrophic Disorders, Sports Medicine, Tissue Engineering

CLC Number:

R496

Wang Minjia1, Qi Ziyi2, Zhu Weihua1, Sun Junzhi1. Mechanism and clinical research advance of muscle atrophy: thinking based on the 65th Annual Meeting of American College of Sports Medicine[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(15): 2421-2426.

Figures/Tables 3

E1酶激活ATP裂解后的泛素蛋白，之后泛素从E1转移到E2酶类的成员，最终的泛素化反应是由E3酶类的成员催化的。E3与E2和蛋白底物结合，诱导泛素从E2转移到底物，一旦底物是聚泛素化的，它被停靠在蛋白酶体上降解，注意，聚泛素链可以通过去泛素化酶泛素特异性加工蛋白酶(USPS)除去。该系统的组成部分，有助于肌肉萎缩的描述。ZNF216参与了肌肉萎缩过程中泛素化蛋白蛋白酶体的识别和传递。AtROGNI-1调节MyoD转录因子和eIF3F的半衰期，这是蛋白质合成的关键。Fbxo40调节IRS1的半衰期，IRS1是IGF1/胰岛素信号传导的重要因子，而MuRF1调节几种肌节蛋白的半衰期。E3泛素连接酶被描绘成绿色，箭头指向它们的底物。注意泛素连接酶可以具有不同的细胞定位并能穿梭到细胞核中。另外，Alfred L.Goldberg和David J.Glass等发现的开创性基因表达谱分析，比较不同肌肉萎缩模型中的基因表达，可以识别萎缩的肌肉中通常出现上调或下调的一组基因[2]。在不同的疾病模型(包括糖尿病、癌症恶病质、慢性肾功能衰竭、禁食和去神经)均发现肌肉萎缩共同点，通常表达下调的基因被认为调节肌肉成分的损失被称为“萎缩相关(atrophy-related)基因”或“萎缩基因”(atrogenes)[3]。此外，有研究发现编码最强烈诱导的基因是2种特异性泛素连接酶atrogin1(也被称为MAFbx)和MuRF1[4]，值得注意的是，至少在去神经支配过程中，这2种基因的最大激活需要转录因子肌原蛋白(myogenin，肌肉发育的重要调控因子)[4]。同时推测,一些其他 E3s在萎缩期间激活,促进可溶性细胞蛋白的清除和限制同化过程[5-6]。 (2)自噬溶酶体通路：细胞自噬是广泛存在于真核细胞内的一种溶酶体介导的蛋白质降解途径。细胞在应答环境胁迫压力下(如细胞应激、营养缺乏、氨基酸饥饿和细胞因子)，将胞内物质包裹，送入溶酶体中消化并释放小分子重新循环用于细胞生理活动，从而维持细胞的正常代谢和生存[7]。根据细胞物质运到溶酶体内的途径不同，通常分为3类：巨自噬(mac-roautophagy)、微自噬(microautophagy)和分子伴侣介导的自噬(chaperone-mediated autophagy)。巨自噬的特征是有独特的双层膜结构，包裹胞质成分与溶酶体融合[5]，见图3。溶酶体能通过分解大量蛋白和细胞器来保证细胞在营养不足情况下存活，这一过程被称为自噬作用。研究发现，FoxO3转录因子引起了骨骼肌细胞的自噬过程。FoxO3控制着与自噬相关的基因的转录，其中包括LC3和Bnip3，而Bnip3能调节FoxO3在自噬过程中所起的作用，以上过程不受蛋白酶体抑制剂的影响。巨自噬在维持骨骼肌内环境稳态中起着相当重要的作用。自噬缺陷与多种骨骼肌疾病相关[8]，过高或过低的巨自噬水平均对骨骼肌正常生理功能有负面影响，自噬过低会引起骨骼肌纤维虚弱无力，而自噬过度激活则会引起骨骼肌质量下降。巨自噬缺陷还会引起骨骼肌糖、脂代谢异常，胰岛素抵抗，造成耐力运动能力下降等[9]。 2.1.2 调整肌肉量的信号通路有部分研究揭示了肌肉萎缩是一个由特定的信号通路和转录程序控制从而调节肌肉量的活跃过程。 (1)insulin/IGF-1-PI3K-Akt(PKB)/mTOR途径：胰岛素(insulin)或胰岛素样因子1与受体结合，其可以激活PI3K-Akt/FoxO及骨骼肌中特殊的泛素连接酶，通过胰岛素受体底物1(IRS-1)相关的PI3K-Akt-mTOR激活途径，进而促进蛋白的合成。但胰岛素样因子1对泛素蛋白酶体途径也起反向调节作用[10]。当处于胰岛素抵抗或者胰岛素样因子1缺乏的状态下，PI3K-Akt 通路受限，蛋白水解系统启动，导致肌肉蛋白的降解[11]。故Akt 下游的FoxO、Atrogin-1/MAFbx和MuRF1在该种情况下也能诱发肌肉分解致肌萎缩[12]。"

(2)炎症因子-核因子κB途径：有研究发现，核因子κB转录因子在免疫和炎症介质中起重要作用，在骨骼肌中也有表达，它们介导炎症因子。的确，肌萎缩时存在许多因子，但其中只有肿瘤坏死因子α能激活核因子κB并对肌肉萎缩和恶病质产生影响，见图3。即在非活性状态下，核因子κB通过一系列被称为IkB的抑制性蛋白在细胞质中被隔离，在肿瘤坏死因子α的作用下，IkB激酶复合物使IkB磷酸化，导致其泛素化和蛋白酶体降解。这造成了核因子κB的核转位和核因子κB介导的基因转录的激活[13]，使其迅速进入细胞核并使转录因子FoxO 启动，导致MuRF1表达，进而引起肌肉蛋白的降解[14-15]，发生肌萎缩。同样，肿瘤坏死因子α还可通过核因子κB途径，抑制MyoD等肌肉分化生长因子mRNA水平，导致骨骼肌分化中断，影响受损肌肉组织的修复[16]。 2.1.3 肠道-肌肉轴——骨骼肌质量调控的新途径肠道菌群是近年来医学界研究的热点，其中“肠-脑轴”是学者研究的着重发力点。而和运动紧密相关的骨骼肌的关系，最近的研究发现：①体育锻炼影响肠道菌群组成，益生菌的干预影响肌肉的功能。机体中可能存在“肠道-肌肉轴(Gut-Muscle Axis)”，肠道菌群可作为营养对肌肉细胞作用的中介；②“肠道-肌肉轴”联通了肠道微生物群与骨骼肌健康之间的交叉对话，该轴对于调节衰老骨骼肌质量，组成和功能的变化起着重要的作用。 Gregory[17]报道机体衰老与肌肉质量和功能(肌肉减少症)的减少有关，肠道菌群正在成为与年龄相关的肌肉衰退的潜在因素。随年龄增长，肠道通透性增加，导致肠道微生物群的生态失调，促进内毒素和其他微生物产物进入循环；进入循环后，脂多糖和其他微生物因子促进炎症信号传导和骨骼肌变化，这是衰老肌肉表型的标志；研究指出营养不良和活动不足是老年人原发性肌少症的主要病理生理因素；肠道菌群通过代谢营养物质产生叶酸、甜菜碱、色氨酸、短链脂肪酸等，影响骨骼肌功能；粪便菌群的组成、物种丰度、多样性与老年人的虚弱及残疾相关，粪便菌群组成变化可能与肌肉功能及肌肉量的下降相关；锻炼影响肠道菌群组成，益生菌的干预影响肌肉功能，见图4。这些都提示在机体中可能存在“肠道-肌肉轴”，肠道菌群可作为营养对肌肉细胞作用的中介；Owen等[19]提出专业运动员的肠道菌群多样性比普通人丰富，因此更有利的促进了生理和代谢健康。但需要排除专业运动员或者专业健身人员饮食的特殊性，以确定是否是运动本身在菌群改变中发挥了核心作用。"

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