Postnatal ontogeny of skeletal muscle protein synthesis in pigs

Abstract

The neonatal period is characterized by rapid growth and elevated rates of synthesis and accretion of skeletal muscle proteins. The fractional rate of muscle protein synthesis is very high at birth and declines rapidly with age. The elevated capacity for muscle protein synthesis in the neonatal pig is driven by the high ribosome content and, together with an increased efficiency of the translation process, promotes accelerated protein synthesis rates. Feeding profoundly stimulates muscle protein synthesis in neonatal pigs and the response decreases with age. The feeding-induced stimulation of muscle protein synthesis is modulated by an enhanced sensitivity to the postprandial increase in insulin and amino acids. The developmental decline in the response to insulin and amino acids parallels a marked decrease in the feeding-induced activation of translation initiation factors that regulate the binding of mRNA to the 40S ribosomal complex. The abundance and activation of many known positive regulators of the nutrient- and insulin-signaling pathways that are involved in translation initiation are high, whereas those of many negative regulators are low in skeletal muscle of younger pigs. Thus, the activation and(or) abundance of the positive regulators, such as the insulin receptor, insulin receptor-substrate-1, phosphoinositide-3 kinase, phosphoinositide-dependent kinase-1, protein kinase B, mammalian target of rapamycin, raptor, ribosomal protein S6 kinase-1, eukaryotic initiation factor (eIF) 4E-binding protein 1, and eIF4E associated with eIF4G, are greater in 7-d-old pigs than in 26-d-old pigs. The activation of negative regulators, including protein tyrosine phosphatase-1B, phosphatase and tensin homologue deleted on chromosome 10, protein phosphatase 2A, and tuberous sclerosis complex 1/2, are lower in 7-d-old pigs than in 26-d-old pigs. Thus, the developmental decline in the stimulation of skeletal muscle protein synthesis by insulin and amino acids is due in part to the developmentally related decrease in the activation of the signaling pathways that lead to translation initiation.

Figure 1

Insulin and amino acid signaling pathway leading to the stimulation of translation initiation. Activation of the insulin signaling pathway is initiated by the binding of insulin to its receptor. This activates the insulin receptor and insulin receptor substrate-1 (IRS-1), followed by the activation of phosphoinositide-3 kinase (PI 3-K). Activated PI 3-K then stimulates the activation of phosphoinositide-dependent kinase 1 (PDK-1) and protein kinase B (PKB). Phosphorylation of PKB inactivates tuberous sclerosis complex 1/2 (TSC1/2), thereby inducing the activation of mammalian target of rapamycin (mTOR). Amino acids as well as insulin can 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 eIF4E·4EBP1 complex, allowing the formation of the active eIF4G·eIF4E complex, which mediates the binding of mRNA to the 43S ribosomal complex. Insulin signaling can be attenuated by protein tyrosine phosphatase-1B (PTP-1B), which dephosphorylates the insulin receptor and IRS-1; phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which inactivates PI 3-K; and protein phosphatase 2A (PP2A), which acts on PKB and S6K1. An increase in adenosine monophosphate (AMP) levels enhances AMP kinase activation, resulting in the activation of TSC1/2 complex and the decreased activation of mTOR.