Amino acids and insulin are regulators of muscle protein synthesis in neonatal pigs

Abstract

The stage of development between birth and weaning in mammals is a period of very rapid growth that is crucial for the long-term well-being of the animal. The rate of protein deposition in neonatal animals is very high because dietary protein is efficiently utilized to increase body protein mass. Our studies in neonatal pigs have shown that this high efficiency of protein deposition is largely due to the marked increase in protein synthesis after feeding, and this response is particularly profound in the skeletal muscle. The enhanced stimulation of muscle protein synthesis in neonates after feeding is independently mediated by the rise in insulin and amino acids and this response declines with age. Intracellular signaling components that respond to the postprandial rise in amino acids and insulin have been identified and their activation has been shown to be elevated in skeletal muscle of neonatal pigs after a meal and to decrease with development. The enhanced activation of these components in the amino acid and insulin signaling pathways in neonatal muscle contributes to the high rate of muscle protein synthesis and rapid gain in skeletal muscle mass in newborn pigs, which are essential determinants of efficient growth during development.

Figure 1

Insulin and amino acid signaling pathways that lead to the stimulation of translation initiation. The binding of insulin to its receptor activates the insulin receptor and insulin receptor substrate-1 (IRS-1), followed by the activation of phosphoinositide-3 kinase (PI 3-kinase). Activated PI3 kinase stimulates phosphoinositide-dependent kinase 1 (PDK-1) and protein kinase B (PKB) activation. Phosphorylation of PKB inactivates tuberous sclerosis complex 1 and 2 (TSC1/2), inducing the activation of Rheb and mammalian target of rapamycin (mTOR). Both amino acids and insulin activate mTOR, which exists in a complex with raptor and G protein β-subunit-like protein (GβL). Activated mTOR phosphorylates ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor (eIF) 4E-binding protein-1 (4EBP1). Phosphorylation of S6K1 enhances the activation of ribosomal subunit S6 (rpS6), which increases the translation of specific mRNA. Phosphorylated 4EBP1 releases eIF4E from an inactive complex with 4EBP1, enabling the formation of the active eIF4E-eIF4G complex that mediates mRNA binding to the ribosome. Insulin signaling can be attenuated by a number of signaling proteins. These include protein tyrosine phosphatase-1B (PTP-1B), which dephosphorylates the insulin receptor and IRS-1; phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which inactivates PI 3-kinase; and protein phosphatase 2A (PP2A), which decreases activation of PKB and S6K1. An increase in adenosine monophosphate (AMP) levels enhances AMP kinase activation, increasing TSC1/2 complex activation and decreasing mTOR activation.