HORMONAL REGULATION OF NEONATAL MUSCLE PROTEIN SYNTHESIS

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DESCRIPTION (Adapted from applicant's abstract): Net protein accretion is essential for the growth of neonates. The long-term objective is to determine the mechanisms which enable nutrients, hormones, and growth factors to regulate the high rate of accretion of skeletal muscle proteins during early postnatal life. This elevated muscle protein accretion is associated with an enhanced stimulation of muscle protein synthesis by nutrient intake. Muscle protein accretion, ribosomal concentration, and nutrient-stimulated muscle protein synthesis decline in parallel over the suckling period. The investigators hypothesize that the postnatal decline in the response of muscle protein synthesis to nutrient intake is due to a decline in the sensitivity of muscle protein synthesis to insulin, and that a decline in insulin-like growth factor-I (IGF-I) abundance in muscle is responsible for this decline in insulin sensitivity. AIM 1 is to determine the early postnatal changes in the sensitivity of skeletal muscle protein synthesis to acute increases in insulin. To achieve this, the in vivo insulin does-response of muscle protein synthesis and ribosomal RNA (rRNA) abundance will be determined in 7- and 26-day-old suckling pigs during hyperinsulinemic euglycemic clamps while using a novel amino acid clamp which the investigators have developed. AIM 2 is to determine the direct effect of amino acid supply on muscle protein synthesis during the early postnatal period, and its influence on insulin-stimulated muscle protein synthesis. To achieve this, the response of muscle protein synthesis and rRNA abundance to elevated plasma amino acid levels during amino acid infusion alone and during hyperinsulinemic euglycemic clamps will be determined in 7- and 26-day-old pigs. AIM 3 is to determine the early postnatal changes in the response of muscle protein synthesis to acute increases in IGF-I. To achieve this, the response of muscle protein synthesis and rRNA abundance to acute infusions of IGF-I, while basal fasting plasma insulin, glucose, and amino acids are maintained, will be determined in 7- and 26-day-old pigs. AIM 4 is to determine whether prolonged elevations in IGF-I enhance the insulin sensitivity of muscle protein synthesis. To achieve this, the effect of a chronic infusion of IGF-I on the insulin sensitivity of muscle protein synthesis and rRNA abundance will be determined during hyperinsulinemic euglycemic euaminoacidemic clamps in 26-day-old pigs. The importance of this work is that identification of the mechanisms that regulate muscle protein accretion in the neonate will reveal new strategies to optimize the use of amino acids for muscle protein deposition in neonates with growth failure, and it will establish the physiological basis for the use of IGF-I in the treatment of both low-birth-weight and growth-retarded infants.