Effect of Maternal Nutrient Restriction in Sheep on the Development of Fetal Skeletal Muscle1
Effect of Maternal Nutrient Restriction in Sheep on the Development of Fetal Skeletal Muscle1
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DOI：
10.1095/biolreprod.104.034561
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发表时间：
2004-12
期刊：
影响因子：
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通讯作者：
Mei J. Zhu;S. Ford;P. Nathanielsz;M. Du
中科院分区：
文献类型：
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作者：
Mei J. Zhu;S. Ford;P. Nathanielsz;M. Du
摘要研究了母体营养限制对哺乳动物雷帕肌球蛋白靶蛋白（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。从妊娠第28天到第78天，母羊被饲喂50%（营养限制）或100%（对照饲喂）的总可消化营养素（国家研究理事会要求）。在妊娠第78天处死母羊，并对胎儿背最长肌进行取样，用于测量mTOR、核糖体蛋白S6、AMP活化蛋白激酶（AMPK）、钙蛋白酶抑制蛋白和蛋白泛素化。营养限制胎儿肌肉中mTOR和核糖体蛋白S6的含量无差异，但mTOR Ser2448和核糖体蛋白S6 Ser235/336磷酸化水平降低（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胎儿肌肉中的蛋白质合成。AMPK活性无差异。钙蛋白酶抑制蛋白和泛素化蛋白含量的差异表明，营养限制并没有影响胎儿肌肉肌原纤维蛋白的降解。营养限制母羊的胎儿表现出肌肉和骨骼发育迟缓。营养限制组胎儿肌肉中次级肌纤维的数量少于对照组，肌纤维束的平均面积也小于对照组（P <0.05）。在营养受限的胎儿中，次级肌纤维的数量减少可能是由于mTOR信号传导减少。在营养受限的胎儿中，mTOR信号的较低激活可能会减少成肌细胞的增殖，从而减少次级肌纤维的形成。胎儿中次级肌纤维的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。
Abstract 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.