Zhu Mei-Jun, Ford Stephen P, Nathanielsz Peter W, Du Min
Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071, USA.
Biol Reprod. 2004 Dec;71(6):1968-73. doi: 10.1095/biolreprod.104.034561. Epub 2004 Aug 18.
The effect of maternal nutrient restriction on mTOR (mammalian target of rapamyosin) signaling and the ubiquitin system as well as their possible relation to growth of fetal muscle was determined. Ewes were fed to 50% (nutrient-restricted) or 100% (control-fed) of total digestible nutrients (National Research Council requirement) from Days 28 to 78 of gestation. Ewes were killed at Day 78 of gestation, and the fetal longissimus dorsi muscle was sampled for the measurement of mTOR, ribosomal protein S6, AMP-activated protein kinase (AMPK), calpastatin, and protein ubiquitylation. No difference was observed in the content of mTOR and ribosomal protein S6, but the phosphorylation of mTOR at Ser2448 and ribosomal protein S6 at Ser235/336 were reduced (P <0.05) in muscle from nutrient-restricted fetuses. Because phosphorylation of mTOR and ribosomal protein S6 up-regulates protein translation, these results show that nutrient restriction down-regulates protein synthesis in fetal muscle. No difference in AMPK activity was detected. The lack of difference in calpastatin and ubiquitylized protein content shows that nutrient restriction did not affect degradation of myofibrillar proteins in fetal muscle. Fetuses of nutrient-restricted ewes showed retarded development of muscles and skeleton. Muscle from nutrient-restricted fetuses contained fewer secondary myofibers than muscle from control fetuses, and the average area of fasciculi was smaller (P <0.05). The decreased number of secondary myofibers in nutrient-restricted fetuses may result from the decreased mTOR signaling. Lower activation of mTOR signaling in nutrient-restricted fetuses may reduce the proliferation of myoblasts and, thus, reduce the formation of secondary myofibers. This decrease in secondary myofibers in fetuses may predispose fetuses to metabolic diseases, such as diabetes and obesity, in their postnatal lives.
确定了母体营养限制对雷帕霉素哺乳动物靶点（mTOR）信号传导和泛素系统的影响，以及它们与胎儿肌肉生长的可能关系。在妊娠第28天至78天，母羊分别按总可消化营养素（符合美国国家研究委员会要求）的50%（营养限制组）或100%（对照饲喂组）进行饲喂。在妊娠第78天处死母羊，采集胎儿背最长肌样本，用于检测mTOR、核糖体蛋白S6、AMP激活的蛋白激酶（AMPK）、钙蛋白酶抑制蛋白和蛋白质泛素化。mTOR和核糖体蛋白S6的含量未观察到差异，但营养限制胎儿的肌肉中，mTOR在Ser2448位点的磷酸化以及核糖体蛋白S6在Ser235/336位点的磷酸化降低（P<0.05）。由于mTOR和核糖体蛋白S6的磷酸化上调蛋白质翻译，这些结果表明营养限制下调了胎儿肌肉中的蛋白质合成。未检测到AMPK活性的差异。钙蛋白酶抑制蛋白和泛素化蛋白含量没有差异，表明营养限制不影响胎儿肌肉中肌原纤维蛋白的降解。营养限制母羊的胎儿肌肉和骨骼发育迟缓。营养限制胎儿的肌肉中次生肌纤维比对照胎儿的肌肉少，束状肌的平均面积更小（P<0.05）。营养限制胎儿次生肌纤维数量减少可能是由于mTOR信号传导降低所致。营养限制胎儿中mTOR信号传导的较低激活可能会减少成肌细胞的增殖，从而减少次生肌纤维的形成。胎儿次生肌纤维的这种减少可能使胎儿在出生后易患代谢性疾病，如糖尿病和肥胖症。
