|Burrin, Douglas - Doug|
Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/24/2002
Publication Date: 10/1/2002
Citation: Davis,T.A., Fiorotto,M.L., Burrin,D.G., Vann,R.C., Reed,P.J., Nguyen,H.V., Beckett,P.R., Bush,J.A. 2002. Acute IGF-I infusion stimulates protein synthesis in skeletal muscle and other tissues of neonatal pigs. American Journal of Physiology - Endocrinology and Metabolism. 283(4):E638-E647. Interpretive Summary: At birth and shortly afterward, the rates of growth and protein deposition are very high and remain high because of high rates of protein synthesis. During this rapid growth period, skeletal muscle synthesis is very sensitive to insulin and amino acids. Feeding stimulates the synthesis of protein, a response which is regulated in skeletal tissues by the increase in insulin and amino acids that occurs after feeding, based on our previous findings. Because insulin and insulin-like growth factor (IGF-I) have commonalities in structure, and both insulin and IGF-I act on some of the same signalling pathways in cells, we wanted to find out whether muscle protein synthesis was also extremely sensitive to stimulation by IGF-I, and whether the response was regulated in conjunction with development. So we took 7-day-old pigs and 28-day-old pigs that had been on a fast overnight and infused them the next morning with low or high doses of IGF-I while we kept amino acids and glucose at fasting levels. These infusions were at doses representing levels in the fed state. In 7-day-old pigs, the infusions stimulated various skeletal muscles, cardiac muscle, skin and spleen, and there was no difference in response between dose levels. Insulin replacement did not alter the response. The induced changes declined over time with development. We found that the magnitude, tissue specificity and developmental change in the response of protein synthesis to IGF-I were similar to those we previously reported for insulin. We think that both IGF-I and insulin act on the same signaling components that stimulate protein synthesis, and this pathway is highly sensitive to stimulation in the newborn animal. Although this suggests both IGF-I and insulin play a role in the feeding-induced stimulation of muscle protein synthesis, we think this is unlikely because unlike insulin, IGF-I levels don't rise immediately after feeding, and while circulating IGF-I levels increase with development, skeletal muscle protein synthesis rates decline. However, IGF-I may play a role as a long-term growth regulator, or further research may unveil a role in clinical conditions requiring a boost in protein deposition, such as muscle wasting.
Technical Abstract: Studies have shown that protein synthesis in skeletal muscle of neonatal pigs is uniquely sensitive to a physiological rise in both insulin and amino acids. Protein synthesis in cardiac muscle, skin, and spleen is responsive to insulin but not amino acid stimulation, whereas in the liver, protein synthesis responds to amino acids but not insulin. To determine the response of protein synthesis to insulin-like growth factor I (IGF-I) in this model, overnight-fasted 7- and 26-day-old pigs were infused with physiological levels of IGF-I (0, 20, or 50 micrograms/kg/hr, while amino acids and glucose were clamped at fasting levels. Because IGF-I infusion lowers circulating insulin levels, an additional group of high-dose IGF-I-infused pigs was also provided replacement insulin (10 ng/kg 0.66/min). Tissue protein synthesis was measured using a flooding dose of L-[4-3H]phenylalanine. In 7-day-old pigs, low-dose IGF-I increased protein synthesis in various skeletal muscles (from +25% to +60%), cardiac muscle (+38%), skin (+24%), and spleen (+32%). High-dose IGF-I also increased protein synthesis in skeletal muscles (from +45% to +79%), cardiac muscle (+37%), skin (+32%), and spleen (+47%) and these responses did not differ between IGF-I doses. Insulin replacement did not alter the response of protein synthesis to IGF-I in any tissue. The IGF-I-induced increases in tissue protein synthesis decreased with development. IGF-I infusion, with or without insulin replacement, had no effect on protein synthesis in liver, jejunum, pancreas, or kidney. Thus, the magnitude, tissue specificity, and developmental change in the response of protein synthesis to the infusion of physiological levels of IGF-I in the neonatal pig are similar to those previously reported for insulin. We postulate that IGF-I and insulin act on many of the same signaling components that stimulate protein synthesis and that this pathway is highly sensitive to stimulation in the neonate.