Proceedings of The Physiological Society
University of Cambridge (2008) Proc Physiol Soc 11, C31
Cortisol suppresses the anabolic signalling proteins, p-mTOR and p-S6 kinase, in skeletal muscle of fetal sheep near term
A. J. Forhead1, Q. W. Shen2, M. Du2, A. L. Fowden1
1. Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. 2. Animal Science, University of Wyoming, Laramie, Wyoming, USA.
Glucocorticoids retard growth in utero although the effects of endogenous and exogenous cortisol on metabolic signalling proteins in fetal skeletal muscle are unknown. This study investigated the effects of (a) the developmental change in plasma cortisol concentration near term and (b) a premature elevation in plasma cortisol induced by exogenous hormone infusion on signalling proteins in skeletal muscle of fetal sheep. After maternal euthanasia (200 mg/kg pentobarbitone iv), hind limb skeletal muscle samples were collected from sheep fetuses at 130 (n=13) and 144 days of gestation (n=7, term 145±2 days). In 11 of the fetuses sampled at 130 days, indwelling catheters were implanted under general anaesthesia (1.5% halothane in O2-N2O) at 115-120 days and the fetuses were infused iv with either saline (0.9% sodium chloride, n=6) or cortisol (2-3 mg/kg/day, n=5) for 5 days from 125 days of gestation. All surgical and experimental procedures were carried out in accordance with the UK Animals (Scientific Procedures) Act 1986. Plasma cortisol concentration was determined by RIA and the muscle signalling proteins, p-mTOR (mammalian target of rapamyosin), p-S6 kinase and calpastatin, were measured by Western blot. Between 130 and 144 days of gestation, the prepartum cortisol surge was associated with significant reductions in the protein levels of p-mTOR, p-S6 kinase and calpastatin in fetal skeletal muscle (Table 1). In the cortisol-infused fetuses, p-mTOR and p-S6 kinase levels were significantly lower than those infused with saline (Table 1). When values from all fetuses were considered, significant inverse relationships were observed between plasma cortisol and p-mTOR (r=-0.46, n=20, p<0.05), p-S6 kinase (r=-0.63, n=20, p<0.05) and calpastatin (r=-0.48, n=20, p<0.05). Therefore, in fetal sheep, the growth-retarding actions of cortisol may be mediated, in part, by suppression of anabolic signalling proteins, such as p-mTOR and p-S6 kinase, in skeletal muscle.
Where applicable, experiments conform with Society ethical requirements