Myostatin基因及其与动物双肌性状间关系的研究进展  

Myostatin and Its Double-Muscling Phenotype in Animals

作　　者：王建起[1] 曹文广[1] 

机构地区：[1]中国农业科学院北京畜牧兽医研究所,北京100193

出　　处：《中国农业科学》2014年第8期1577-1587,共11页Scientia Agricultura Sinica

基　　金：国家转基因重大专项(2013ZX08008-003;2014ZX08008-003)

摘　　要：肌肉生长抑制素(myostatin,MSTN)又称生长分化因子8(growth differentiation factor 8,GDF-8),属于转化生长因子β(transforming growth factorβ,TGF-β)超家族成员,由McPherron等在1997年筛选小鼠肌肉cDNA文库时首次发现。目前已研究过的不同哺乳物种间的MSTN基因结构均含3个外显子和2个内含子,且成熟肽氨基酸序列的差异均在3个以内。MSTN在多个组织中表达,包括心肌、脂肪、胎盘、乳腺、子宫、嗅觉神经细胞、肝、脾、肺和肾等,主要在骨骼肌中高水平表达。MSTN的成熟包括由信号肽酶、前蛋白转化酶Furin和金属蛋白酶BMP-1/tolloid家族的酶解和加工,成熟的MSTN为同质二聚体化。MSTN的最显著作用是作为骨骼肌的强有力的负调控因子,可通过自分泌或旁分泌的方式激活TGF-β、p38 MAPK、ERK1/2、和JNK等信号途径及抑制IGF-AKT和Wnt信号途径,协同抑制成肌细胞的增殖和分化。MSTN基因敲除小鼠的肌肉重量显著增加而表现为双肌性状,并可通过增强肌肉再生和降低纤维化的方式提高肌肉愈伤能力;糖的消耗和糖摄入加强,且对胰岛素的敏感性加强;心脏增大且压力应激增强;脂肪重量减轻,脂肪发生受到抑制,且白色脂肪组织的黄化加强而能够促进生热作用;骨密度和骨矿物质含量增强,并可增加骨折骨痂的尺寸和强度而促进骨折的愈合。MSTN还可通过调控胎盘的建立和葡萄糖的摄入、调控子宫平滑肌细胞和内膜上皮细胞的增殖及乳腺的发育,参与雌性哺乳动物的生殖调控。自然发生的MSTN基因功能缺失型纯合突变也能够引起动物表现双肌性状,已知的这些突变包括牛的p.D273RfsX13(也称nt821(del11))、p.C313Y、p.F140X(也称nt419(del7ins10))、p.Q204X、p.E226X和p.E291X突变,绵羊的c.960delG(也称p.K320NfsX39)和c.120insA(也称p.N40MfsX9)突变,狗的c.939-940delTG突变和人类的c.373+5G>A突变;此外在绵羊中还存在一个靶向MSTN基因的miRNA功能�Myostatin （MSTN）, also known as growth differentiation factor 8（GDF-8）, is a member of the transforming growth factor β（TGF-β） superfamily, which was first obtained from screening a murine skeletal muscle complementary DNA library in 1997. The gene of MSTN consists of three exons and two introns, the gene is very conservative as only three or fewer differences exist among the amino acid sequences of mature peptide in all studied species. High levels of expression of MSTN has been found mainly in skeletal muscle although it is expressed in multiple tissues, including the cardia, adipose, placenta, mammary gland, uterus, olfactory neuron, liver, spleen, lung, and kidney, etc. The mature MSTN is liberated as a homogeneous dimer from prepromyostatin through proteolytic processing of signal peptidase, furin and BMP-1/tolloid family. MSTN acts as a strong autocrine/paracrine negative regulator of muscle growth. It inhibits the proliferation and differentiation of myoblast cells through activating TGF-β, p38 MAPK, ERK1/2 and JNK signal pathway, and inhibiting IGF-AKT and Wnt signal pathway. MSTN also regulates glucose uptake and metabolism in the muscle cell. Myostatin-null animals showed significant increased muscle mass, that is double-muscling phenotype, improved muscle healing through enhancing regeneration and reducing fibrosis, etc; reduced adipogenesis and consequently decreased leptin secretion, and enhanced thermogenesis through driving browning of white adipose tissue; increased bone density and bone mineral content, and increased fracture callus size and strength for fracture healing. Naturally occurred loss-of-function mutations in the MSTN gene have also been shown to underlie the double-muscling phenotype in mammals. Such known mutations are found in several species including p.D273RfsX13（nt821（del11））, p.C313Y, p.F140X（nt419（del7-ins10））, p.Q204X, p.E226X and p.E291X in cattle, c.960delG（p.K320NfsX39） and c.120insA（p.N40MfsX9）in sheep, c.939-940delTG in dogs and c.37

关 键 词：肌肉生长抑制素 生长分化因子8 双肌性状 哺乳动物 功能缺失型突变 

分 类 号：Q75[生物学—分子生物学]