Ontogeny of sensitivity to growth hormone in rat diaphragm muscle

In order to delineate the ages of onset and decline in sensitivity to growth hormone (GH) in rats, the ability of ovine GH in vitro to stimulate amino acid uptake and protein synthesis was studied in diaphragm muscle. GH (25 mug/ml) produced a significant, but small (12-17%), stimulation of alpha-aminoisobutyric acid (AIB, 1 mM) uptake in diaphragms from fed intact rats 7-24 days old, but not from 21-day fetuses or from fed rats 4, 30, 50, 100, or 130 days old. When intact rats were fasted for 24 h, both the magnitude and consistency of the responses to GH increased considerably. In fasted rats, GH significantly stimulated AIB transport by 10,29, 77,111, and 58% at ages 4, 7, 11, 15, and 23 days, respectively; GH was not effective at age 3 or 30 days. At age 15 days, 0.5 mug/ml GH stimulated AIB transport by 96%. GH (25 or 0.5 mug/ml) significantly increased leucine incorporation into protein at age 15 days in fasted intact rats. When rats were hypophysectomized at age 28, 47, or 98 days and tested 2-3 days later, the basal rate of protein synthesis fell, but the basal rate of AIB transport did not; however, GH now stimulated both AIB uptake and amino acid incorporation into protein. These results suggest that rat diaphragm muscle first becomes sensitive to GH at about age 4-7 days (AIB transport), but that further development may be necessary for the anabolic action of the hormone (protein synthesis) to be seen. Stimulation of AIB uptake is maximal about 15 days after birth. Thereafter, diaphragm muscles from normal rats becomes progressively more refractory to the acute stimulatory effects of GH on transport processes. Hypphysectomy of rats 30 days old or more leads to the re-establishment of GH-responsiveness by the AIB transport system. This cannot be attributed merely to a lowering of the basal transport rate; rather hypophysectomy appears to result in the loss of an inhibitor of growth hormone's acute stimulatory actions on transport processes. Previous work suggests that this refractory state is produced in normal rats by occasional surges of endogenous growth hormone. The dominance of the refractory state appears about the time of weaning. This may protect the weaned rat, whose diet is more variable than it is during the suckling period, from periodic depletion of amino acids and glucose from the plasma in response to intermittent surges of GH, thereby allowing GH to produce a sustained stimulation of protein synthesis and growth.