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Title: In utero glucocorticoid exposure reduced fetal skeletal muscle mass in rats independent of effects on maternal nutrition

Author
item GOKULAKRISHNAN, GANGA - Children'S Nutrition Research Center (CNRC)
item ESTRADA, IRMA - Children'S Nutrition Research Center (CNRC)
item SOSA, HORACIO - Children'S Nutrition Research Center (CNRC)
item FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC)

Submitted to: American Journal of Physiology - Regulatory Integrative & Comparative Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/7/2012
Publication Date: 3/14/2012
Citation: Gokulakrishnan, G., Estrada, I.J., Sosahoracio, A., Fiorotto, M.L. 2012. In utero glucocorticoid exposure reduced fetal skeletal muscle mass in rats independent of effects on maternal nutrition. American Journal of Physiology - Regulatory Integrative & Comparative Physiology. 302 (10):R1143-R1152.

Interpretive Summary: Babies of malnourished mothers often weigh too little at birth which means that their growth in utero was inadequate. We wanted to know how much of the poor growth occurs because the fetus does not get enough nutrients from the mother, and how much is due to the baby receiving too much of a stress hormone, a glucocorticoid, that malnourished mothers sometimes produce. Too much of this hormone prevents normal growth even when nutrients are sufficient. To answer this question, we studied 3 groups of rat mothers: one group of rat mothers was fed 85% of the amount of food they would normally eat; this is a mild form of undernutrition nutrition that is not sufficient to cause stress. A second group was given the same amount of food and dexamethasone (a form of the stress hormone that can be given by mouth). A third group was a control group that was allowed to eat as much as they wanted and received no hormone. We found that the mild undernutrition by itself did not alter overall weight gain of the fetus compared to control mothers; their muscles, however, were smaller. When dexamethasone was given, body weight gain was less and the muscles were more severely affected. We determined that the mechanism by which insufficient nutrition prevents normal muscle growth is different from how dexamethasone prevents growth. Thus, when the two are combined, the effect is much worse. These results are significant because they have shown us that during fetal life, the muscles are very sensitive to maternal food intake. If the mother is also stressed, the effect is significantly worse. This information will help doctors understand how nutrition and stress of pregnant mothers should be managed so that the growth of their baby is not compromised.

Technical Abstract: Maternal stress and undernutrition can occur together and expose the fetus to high glucocorticoid (GLC) levels during this vulnerable period. To determine the consequences of GLC exposure on fetal skeletal muscle independently of maternal food intake, groups of timed-pregnant Sprague-Dawley rats (n = 7/group) were studied: ad libitum food intake (control, CON); ad libitum food intake with 1 mg dexamethasone/l drinking water from embryonic day (ED)13 to ED21 (DEX); pair-fed (PF) to DEX from ED13 to ED21. On ED22, dams were injected with [(3)H]phenylalanine for measurements of fetal leg muscle and diaphragm fractional protein synthesis rates (FSR). Fetal muscles were analyzed for protein and RNA contents, [(3)H]phenylalanine incorporation, and MuRF1 and atrogin-1 (MAFbx) mRNA expression. Fetal liver tyrosine aminotransferase (TAT) expression was quantified to assess fetal exposure to GLCs. DEX treatment reduced maternal food intake by 13% (P < 0.001) and significantly reduced placental mass relative to CON and PF dams. Liver TAT expression was elevated only in DEX fetuses (P < 0.01). DEX muscle protein masses were 56% and 70% than those of CON (P < 0.01) and PF (P < 0.05) fetuses, respectively; PF muscles were 80% of CON (P < 0.01). Muscle FSR decreased by 35% in DEX fetuses (P < 0.001) but were not different between PF and CON. Only atrogin-1 expression was increased in DEX fetus muscles. We conclude that high maternal GLC levels and inadequate maternal food intake impair fetal skeletal muscle growth, most likely through different mechanisms. When combined, the effects of decreased maternal intake and maternal GLC intake on fetal muscle growth are additive.