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The primary objective of our application is to study the effect of chronic ethanol treatment on the neuroendocrine regulation of protein synthesis in skeletal muscle. Our working hypothesis is that chronic ethanol decreases plasma somatomedin-C levels and inhibits skeletal muscle protein synthesis. We believe that this effect is mediated by a decline in the amplitude of growth hormone pulses in ethanol treated rats. Initially, we will test whether alterations in the brain/neuroendocrine system (via decreased amplitude of growth hormone pulses) induced by 1 or 5 months of chronic ethanol are correlated with declines in somatomedin-C levels and skeletal muscle protein snythesis and whether the decreases in growth hormone result from an enhanced metabolic clearance rate for this hormone. Once the relationship between ethanol induced changes in growth hormone and protein synthesis are established, the capacity of bovine growth hormone to restore skeletal muscle protein synthesis in ethanol treated rats will be assessed.

The neuroendocrine mechanisms responsible for the decline in growth hormone will be investigated by (1) comparing the ability of ethanol treated and pair-fed control rats to synthesize growth hormone in vitro (incorporation of 3H-leucine into growth hormone, separation by polyacrylamide gel electrophoresis, and analysis of growth hormone and free leucine specific activity), (2) determining the biological activity of growth hormone in ethanol treated and pair-fed control rats using the classical tibial bioassay, (3) assessing ethanol induced alterations in the mechanism of hypothalamic hormone action on pituitary somatotrophs by testing the ability of somatostatin-14 and -28 to inhibit growth hormone and rhGRF to stimulate growth hormone release in vivo and in vitro, (4) measuring the release of somatostatin directly from superfused hypothalamic fragments of ethanol treated rats in response to growth hormone, somatomedin-C, and 55mMK+ (samples are fractionated to determine relative and absolute concentrations of somatostatin-14 and -28).

These results are clinically relevant since a decline in growth hormone pulse amplitude in chronic ethanol treated rats may be responsible for a reduced capacity to synthesize protein and may contribute to a decline in tissue and organ function.
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