BOR - Papers in Press, published online ahead of print
August 18, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.034561
BIOLOGY OF REPRODUCTION 71, 19681973 (2004)
DOI: 10.1095/biolreprod.104.034561
© 2004 by the Society for the Study of Reproduction, Inc.
Effect of Maternal Nutrient Restriction in Sheep on the Development of Fetal Skeletal Muscle1
Mei-Jun Zhu3,
Stephen P. Ford3,
Peter W. Nathanielsz4, and
Min Du2,3
Center for the Study of Fetal Programming,3 Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071
Center for Women's Health Research,4 New York University Medical School, New York, New York 10016
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.
1 Supported by National Research Initiative Competitive Grant 2003-35206-12814 from the U.S. Department of Agriculture Cooperative State Research, Education, and Extension Service and a grant from NIH-HD21350.
2 Correspondence: Min Du, Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071. FAX: 307 766 2355; mindu{at}uwyo.edu
Copyright © 2004 by the Society for the Study of Reproduction.