The accretion of skeletal muscle mass is a dominant component of neonatal growth. The long-term objective is to define the mechanisms by which nutrients and hormones mediate the high rate of skeletal muscle protein deposition in neonates, with the goal of identifying new strategies to optimize the nutritional management of low birth weight infants. Previous work showed that the feeding-induced stimulation of muscle protein synthesis is mediated independently by insulin and amino acids and is effected by enhanced activation of translation initiation. The insulin response is associated with a heightened responsiveness of the insulin signaling pathway in immature muscle. However, neither the contribution of individual amino acids and glucose to the feeding response, nor the cellular mechanisms responsible for the loss in the insulin and nutrient sensitivity of muscle protein synthesis with development have been elucidated. This proposal tests the hypotheses that: 1) The postprandial rise in leucine alone can stimulate muscle protein synthesis in neonates by modulating translation initiation factor activity; 2) The postprandial rise in glucose enhances the feeding-induced stimulation of muscle protein synthesis in neonates by activating the insulin/nutrient signaling pathway, independently of insulin; and 3) Down-regulation in the activity of the insulin/nutrient signaling pathway with development blunts the nutrient and insulin sensitivity of muscle protein synthesis. The following aims are proposed to address these hypotheses.
In Aim 1, the effect of a physiological rise in leucine on muscle protein synthesis and translation initiation factor activity will be determined using in vivo kinetic measurement of muscle protein synthesis and determination of the activity of the translation initiation factors required for mRNA binding to the 40S ribosomal subunit.
In Aim 2, the effect of a physiological rise in glucose on muscle protein synthesis and the activity of the insulin/nutrient signaling pathway that regulates translation initiation will be assessed from measurements of muscle protein synthesis and the activities of insulin/nutrient signaling proteins and translation initiation factors.
In Aim 3, the relative contributions of positive versus negative signaling regulators in effecting the developmental decline in the sensitivity of muscle protein synthesis to insulin and nutrients will be determined. All studies will use pancreatic-substrate clamps and will be performed in 7- and 26-day-old pigs.
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