Connecting the Dots: Linking Sirtuins and AMPK in Metabolism and Aging

The paper “Glucose Restriction Inhibits Skeletal Myoblast Differentiation by Activating SIRT1 through AMPK-Mediated Regulation of Nampt” by Fulco et al. is remarkably integrative. If you think about it, there are only two small molecules in cells most important in providing an indication of energy status: ATP and NAD. These molecules can be sensed by regulatory proteins, such as AMP-kinase (which senses the AMP/ATP ratio) and sirtuins (which require NAD to deacetylate protein substrates). The paper by Fulco shows that AMPK and SIRT1 can be connected in a linear pathway in which glucose restriction triggers AMPK activity, and this activates the gene encoding the NAD synthetic enzyme, Nampt, providing the crucial link to the activation of the sirtuin SIRT1. The net effect of this signaling by ATP and NAD is to activate SIRT1 during energy limitation and restrain differentiation of skeletal myoblasts. This pathway thus elegantly links two critical metabolic regulators AMPK and sirtuins and provides a framework for how calorie restriction exerts its effects in a particular tissue.This PaperPick refers to “Glucose Restriction Inhibits Skeletal Myoblast Differentiation by Activating SIRT1 through AMPK-Mediated Regulation of Nampt,” by M. Fulco, Y. Cen, P. Zhao, E.P. Hoffman, M.W. McBurney, A.A. Sauve, and V. Sartorelli, published in May 2008.Video AbstractVittorio Sartorelli and Marcella Fulco discuss their identification of a nutrient-sensing pathway that governs the differentiation of skeletal muscle cells