Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/30/2001
Publication Date: 10/30/2001
Citation: Kimball, S.R., Farrell, P.A., Nguyen, H.V., Jefferson, L.S., Davis, T.A. 2002. Developmental decline in components of signal transduction pathways regulating protein synthesis in pig muscle. American Journal of Physiology Endocrinology and Metabolism. 282(3):E585-E592.
Interpretive Summary: The muscles of newborns grow at a very rapid rate. We have previously demonstrated that this is due to an enhanced response of the skeletal muscle to feeding, which stimulates protein synthesis. We identified the cellular processes that regulate that response, and demonstrated that insulin and amino acids are involved. In this study, involving newborn pigs as a model for the human, we further identified and delineated the developmentally related behavior of the cellular signaling pathways that communicate stimuli triggered by insulin and amino acids. Ultimately, the findings of this study indicate that the developmental decline in the stimulation of muscle protein synthesis by feeding during the period prior to weaning is due to a reduction in certain specific cellular signaling component capabilities with regard to the stimuli provided by insulin and/or amino acids. These study findings in baby pigs are important early steps in the progression of scientific understanding of the mechanisms of muscle growth in newborn infants, and how we might be able to optimize and best nurture this aspect of human development.
Technical Abstract: Our previous studies showed that the feeding-induced stimulation of protein synthesis in skeletal muscle of neonatal pigs is accompanied by enhanced phosphorylation of the eukaryotic initiation factor (eIF)4E-binding protein (4E-BP1) and the ribosomal protein S6 kinase (S6K1). These effects of feeding are substantially reduced with development. The goal of the present investigation was to delineate the basis for the reduced responsiveness to feeding observed in the older animals. In these studies, the content and activity of protein kinases located upstream of S6K1 and 4E-BP1 in signal transduction pathways activated by amino acids, insulin, and insulin-like growth factor I were examined in 7- and 26-day-old pigs that were either fasted overnight or fed porcine milk after an overnight fast. Feeding stimulated phosphatidylinositol (PI) 3-kinase activity to the same extent in muscle of 7- and 26-day-old pigs, suggesting that PI 3-kinase is not limiting in muscle of older animals. In contrast, protein kinase B (PKB) activity was significantly less in muscle from 26- vs. 7-day-old pigs, regardless of nutritional status, suggesting that its activity is regulated by mechanisms distinct from PI 3-kinase. In part, the reduced PKB responsiveness can be attributed to a developmental decline in PKB content. Likewise, muscle content of the protein kinase termed mammalian target of rapamycin (mTOR) in 26-day-old pigs was <25% of that in 7-day-old animals. Finally, in agreement with our earlier work showing that S6K1 phosphorylation is reduced in older animals, S6K1 activity was stimulated to a lesser extent in 26- compared with 7-day-old pigs. Overall, the results suggest that the blunted protein synthetic response observed in 26- vs. 7-day-old neonatal pigs is due in part to decreased content and/or activity of signaling components downstream of PI 3-kinase, e.g., PKB, mTOR, and S6K1.