Simulating molecular mechanisms of protein synthetic control to explain classic amino acid nutrition behaviours

The nutritional concepts of a dietary amino acid imbalance or deficiency have classically been ascribed to a limiting amino acid phenomenon that has had no mechanistic explanation until the recent discovery of mRNA translational regulation by eukaryotic initiation factor 2 (eIF2) and eukaryotic initiation factor 4E (eIF4e) binding protein 1 (4E-BP1). This thesis represents an attempt to simulate the regulation of mRNA translation in liver and muscle of growing animals to predict growth responses to dietary amino acid imbalances and deficiencies. The research consists of three parts. Firstly, a mechanistic model was developed for prediction of global protein synthesis to nutritional stimuli in a generic tissue. The model included effects of amino acids and insulin on protein synthesis as an activation of eIF2 and 4E-BP 1. Uncharged tRNA inhibits GTP exchange on eIF2, and free amino acids and insulin inhibit reversible sequestration of eIF4e by 4E-BP 1. The model correctly predicts the direction of tissue responses to variations in extracellular amino acid and insulin concentration. Secondly, the model was calibrated to liver and muscle data from growing animals. The model was modified to facilitate parameter estimation, the sensitivity of predictions to changes in the main model parameters was evaluated, and then parameters exhibiting the greatest sensitivity were adjusted to optimize the fit between model predictions and observed responses of liver and muscle to a variety of AA and insulin levels. In most cases, the errors due to the deviation of the regression slope from 1 were minor, while random error was the major contributor to the mean square prediction error (> 90 %). Finally, a mechanistic model for predicting responses of protein accretion and amino acid catabolism in growing animals to amino acid imbalances and deficiencies was developed by combining muscle and liver models with blood amino acid pools. The whole-animal model considers stimulatory effects of amino acids and insulin on liver and muscle protein synthesis, and stimulatory effects of amino acids and glucagon on amino acid catabolism. Simulation results show the classical decrease in protein synthesis and limiting amino acid concentration in blood when all amino acids but one are added to a diet (imbalance), or when one essential amino acid is removed from the diet (deficiency). Furthermore, simulation results show that the decrease in limiting amino acid concentration is due to a more efficient clearance of the limiting amino acid from blood, stimulated by other amino acids, insulin, and glucagon. The reconciliation of molecular biology with nutrition provides a platform to optimize amino acid content of animal diets and explain many experimental phenomena such as indicator amino acid oxidation.