Biological role of myonectin and its correlation with exercise

doi:10.3969/j.issn.2095-4344.0266

Abstract

Abstract:

BACKGROUND: Myonectin (C1q tumor necrosis factor-α-related protein isoform 15) is a novel bioactivator secreted by skeletal muscle and is the 15th member of CTRP family. Myonectin is specially expressed in skeletal muscle and its expression is affected by the type of skeletal muscle fiber, nutritional conditions, other hormones, and cytokines.
OBJECTIVE: To explore the relationship between myonectin and exercise so as to provide the basis for the treatment of chronic diseases.
METHODS: A computer-based search of CNKI and PubMed databases was performed for relevant articles published from 1999 to 2017 using the keywords of “myokine, myonectin, erythroferrone” in Chinese and English, respectively. Finally 32 eligible articles were included in result analysis in accordance with the inclusion and exclusion criteria.
RESULTS AND CONCLUSION: Myonectin is released into bloodstream through endocrine or paracrine and works on adipose tissue and liver, involved in adipose tissue and liver lipid metabolism regulation. Nevertheless, myonectin can increase the expression of fatty acid uptake protein gene, promote the uptake of fatty acids and reduce the level of free fatty acids in serum. Notably, myonectin participates in obesity and insulin resistance and correlates with skeletal muscle energy metabolism. It is also involved in erythropoiesis during the regulation of iron metabolism, and therefore, myonectin is closely related to metabolic diseases.

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: Sports Medicine, Muscle, Skeletal, Tissue Engineering

CLC Number:

R318

Li Lin, Yu Liang. Biological role of myonectin and its correlation with exercise[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(28): 4566-4573.

Figures/Tables 2

2.1 Myonectin概况 Myonectin是新发现的肌肉因子，是CTRP家族的第15位成员，即CTRP15。CTRP家族是通过使用脂联素的cDNA序列询问小鼠及人类表达序列标签(expressed sequence tags，ESTs)和基因组数据库所得到的与脂联素(adiponectin)同源的高度保守的蛋白家族，该家族成员都具有与脂联素相似的模块化组织，并且包含4个不同的结构域：N末端的信号肽、短的可变区、胶原结构域和与补体蛋白C1q同源的C-末端球状结构域，由于球形的补体 C1q样结构域的晶体结构与肿瘤坏死因子( tumor necrosis factor，TNF)非常类似，因而将该家族命名为补体 C1q /肿瘤坏死因子相关蛋白(C1q /tumor necrosis factor-related protein，CTRP)[3]。 Myonectin由位于人染色体2q37.3上的基因编码，全长9 883 bp，由8个外显子和7个内含子组成，编码2 911 bp的mRNA；小鼠myonectin的基因位于第1号染色体上，全长8 057 bp，由9个外显子和8个内含子组成，编码2 835 bp的mRNA。利用免疫印迹的方法对小鼠骨骼肌组织myonectin的蛋白表达进行测定，发现在相对分子质量 40 000-50 000分布着多个被不同程度糖基化的myonectin特异性条带。利用同样的方法对12周龄的小鼠血清中myonectin水平进行测定发现特异性条带出现在45 000左右[4]。其蛋白包括5个结构域：用于分泌的信号肽(signal peptide，SP)结构域、N-末端结构域-1(N-terminal domain 1，NTD1)、具有6个Gly-X-Y重复的胶原结构域、N-末端结构域-2(NTD2)和补体C1q/TNF样结构域，其中C1q/TNF样结构域是CTRP 15发挥生物学作用的主要功能结构域[4]。 2.2 Myonectin的生物学作用 Seldin等[4]对小鼠myonectin的组织分布及表达进行了测定，发现myonectin主要存在于血液循环中，主要表达于骨骼肌组织中，其次极少量表达于肺、眼、平滑肌、心脏和脑、肾、胎盘、肝脏、胃及胸腺等，并且其在骨骼肌中的表达量是肺、眼、平滑肌等组织的5倍，是心肌、脑组织的10倍左右，除此以外的其余组织几乎没有myonectin mRNA的表达。此外，myonectin在小鼠分化的C2C12肌管细胞中表达显著升高，而在未分化的成肌细胞中其几乎不表达[4]，不是由卫星细胞分泌，所以，骨骼肌而非骨骼肌卫星细胞是myonectin特异性表达的组织，因此认定myonectin为典型的 “肌肉因子”，Myonectin以内分泌或旁分泌的方式释放入血，主要是作用于脂肪组织和肝脏，也有学者发现myonectin是红细胞生成过程中调节铁代谢的重要因子(见表1)。"

2.2.1 Myonectin在脂肪组织中的作用许多CTRP家族成员是由脂肪组织分泌并以自分泌、旁分泌和内分泌方式作用于附近或远处器官，所以被称为“脂肪因子”，它们可以调节脂肪组织的功能，进而调节全身胰岛素敏感性、能量代谢及心血管疾病[5-6]，例如CTRP 3可以抑制小鼠病理性心脏的重塑[7]、CTRP 5可以通过促进AMPK信号传导增加葡萄糖的摄取，改善肥胖小鼠的葡萄糖代谢[8]。Myonectin是CTRP家族成员之一，但不同的是它是由骨骼肌分泌并以内分泌方式调节体内脂质系统的平衡，并且实现骨骼肌和其他代谢组织(主要脂肪组织和肝脏)之间的“对话”[4]。为了探究myonectin的作用，用myonectin重组蛋白作用于小鼠后发现FFA(游离脂肪酸或非酯化脂肪酸)水平降低，而脂肪细胞脂解能力几乎没有改变，提示myonectin在脂肪细胞对脂肪酸的摄取中起到了一定的作用[4，9]。非酯化脂肪酸是血浆的成分之一，在正常情况下，脂肪组织的脂肪水解释放非酯化脂肪酸进入血液，被骨骼肌、肝脏等多种外周组织摄取利用，进行氧化供能。猜测Myonectin降低循环非酯化脂肪酸水平通过2种可能的机制：抑制脂肪组织脂肪分解或促进脂肪酸摄取进入细胞，于是用myonectin分别处理3T3-L1脂肪细胞和原代睾周脂肪组织，发现myonectin对常态下的脂解及肾上腺素诱导的脂解均没有抑制作用[4]，因此排除了第1种可能的机制；随后继续对myonectin是否促进了脂肪酸的摄取进行观察，用饱和剂量的胰岛素(50 nmol/L)和5 mg/L的myonectin处理脂肪细胞均能大幅度增加脂肪酸摄取，而同时用胰岛素和myonectin蛋白刺激脂肪细胞不会导致脂肪酸摄取的进一步增加，因此推测myonectin和胰岛素增强脂质摄取所激活的途径类似[4]。在脂肪酸摄入细胞中起重要作用的包括脂肪酸转运蛋白CD36、小窝蛋白1 ( caveolin-1，Cav1)、脂肪酸转运蛋白(fatty acid transport protein 1，FATP1)、脂肪酸结合蛋白(fatty acid bindin protein 4，FABP4)等蛋白，实验中利用RT-PCR分析显示在脂肪细胞中重组myonectin可以不同程度地上调这些基因的表达，在脂代谢过程中，FAT/CD36是骨骼肌主要的脂肪酸转运体之一，在敲除FAT/CD36基因的小鼠中[10]，脂肪酸摄入明显减少，而当FAT/CD36基因过表达时[11]，骨骼肌对脂肪酸的利用显著增加，提示FAT/CD36在骨骼肌脂肪酸摄入中起到关键作用，所以myonectin可以通过转录上调参与脂肪酸吸收的基因促进脂肪细胞的脂质摄入，通过刺激FAT/CD36的表达来促进脂肪酸的摄入[4]，而又有学者发现大鼠进行跑台训练下调了myonectin的水平，而同时非酯化脂肪酸水平降低，似乎myonectin不参与运动对血清非酯化脂肪酸的调节作用，结果相悖则需要进一步的实验探究。 2.2.2 Myonectin在肝脏中的作用为了证实myonectin在肝脏中的作用，采用RT-PCR技术分析小鼠H4IIE肝细胞发现，饥饿或禁食可分别引起H4IIE肝细胞和小鼠肝脏中自噬相关基因Atg7和Atg12的表达增加，而重组myonectin可以增加Cav1和Fabp1的表达，促进脂肪酸摄取的增加，所以myonectin可以通过转录上调参与脂肪酸吸收的基因促进肝细胞的脂质摄入[4]。另外，Seldin等[12]发现myonectin可激活细胞自噬抑制因子mTOR(雷帕霉素受体)，激活PI3K/Akt/mTOR途径从而抑制肝脏自噬。而自噬调节细胞物质的合成、降解和重新利用之间的代谢平衡起很大的作用，所以myonectin水平的异常也会影响到能量代谢的平衡，但是其机制还需要进一步的实验证明。为了研究myonectin和葡萄糖之间的关系，将重组myonectin蛋白注射到小鼠中发现没有降低葡萄糖的作用，所以myonectin主要与脂质代谢关系密切，根据Seldin等[4]的报道，在体外重组myonectin通过增加在脂肪酸吸收中起重要作用的CD36，FATP1水平、增强Fabp4 mRNA表达，促进小鼠脂肪细胞和大鼠肝细胞中的脂肪酸摄取(见图1)。此外，重组myonectin对脂肪组织脂解没有影响。因此可以推测myonectin蛋白血清长期保持高水平可以增加脂肪组织和肝脏中的脂肪酸摄取，并改善脂肪代谢和脂质处理，但是机制尚不清楚。"

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