Physiological and Molecular Mechanisms of Methionine Restriction

Abstract

Methionine restriction (MR) has been studied extensively over the last 25 years for its role in altering metabolic hallmarks of disease. Animals subjected to MR, display changes in metabolic flexibility demonstrated by increases in energy expenditure, glucose tolerance, and lifespan. These changes have been well characterized in a number of model systems and significant progress has been made in understanding how hepatic fibroblast growth factor 21 links MR to several components of its metabolic phenotype. Despite these advances, a complete understanding of mechanisms engaged by dietary MR remains elusive. In this review, we offer a brief history of MR and its known mechanisms associated with stress, metabolism, and lifespan extension. We consider the role of epigenetics in the response of animals to MR and propose a novel epigenetic pathway involving the regulation of microRNAs during MR.

Keywords: caloric restriction; mechanisms; methionine restriction; microRNA; physiological; stress.

Figure 1

Dietary methionine restriction has been shown to occur through two distinct pathways in the cell. In the endoplasmic reticulum, a reduction of Glutathione (GSH) causes an activation of the PKR-like endoplasmic reticulum kinase (PERK), which activates eukaryotic translation initiation factor 2a (elF2a). In the cytoplasm, a buildup of unchanged tRNAs activates general control non-derepressible 2 (GCN2) which in turn also activates elF2a. Both of these pathways converge in the activation of activating transcription factor 4 (ATF4) and activation of genes that respond to stress.

Figure 2

Our review suggests that a third pathway should be added to the already known mechanisms of methionine restriction (MR). Changes in chromatin methylation or methylation status of DNA promoters due to dietary MR has the ability to activate or repress microRNAs (miRNAs) involved in the cells response to MR. These distinct changes could then be related to MRs phenotype characterized by increased lifespan, glucose tolerance, and metabolic rate.