Interactive Roles for AMPK and Glycogen from Cellular Energy Sensing to Exercise Metabolism

Abstract

The AMP-activated protein kinase (AMPK) is a heterotrimeric complex with central roles in cellular energy sensing and the regulation of metabolism and exercise adaptations. AMPK regulatory β subunits contain a conserved carbohydrate-binding module (CBM) that binds glycogen, the major tissue storage form of glucose. Research over the past two decades has revealed that the regulation of AMPK is impacted by glycogen availability, and glycogen storage dynamics are concurrently regulated by AMPK activity. This growing body of research has uncovered new evidence of physical and functional interactive roles for AMPK and glycogen ranging from cellular energy sensing to the regulation of whole-body metabolism and exercise-induced adaptations. In this review, we discuss recent advancements in the understanding of molecular, cellular, and physiological processes impacted by AMPK-glycogen interactions. In addition, we appraise how novel research technologies and experimental models will continue to expand the repertoire of biological processes known to be regulated by AMPK and glycogen. These multidisciplinary research advances will aid the discovery of novel pathways and regulatory mechanisms that are central to the AMPK signaling network, beneficial effects of exercise and maintenance of metabolic homeostasis in health and disease.

Keywords: AMP-activated protein kinase; cellular energy sensing; energy utilization; exercise; glycogen; glycogen storage disease; liver; metabolic disease; metabolism; skeletal muscle.

Figure 1

The AMPK is a heterotrimeric protein, consisting of a catalytic α subunit and regulatory β and γ subunits. The β subunit (β1 and β2 isoforms) possesses a glycogen-binding domain (CBM) that mediates AMPK’s interaction with glycogen, an N-terminal myristoylation site (myr) and an αγ subunit binding sequence (αγ-SBS) involved in the heterotrimeric complex formation. Tissue expression of the β1 and β2 isoforms varies between humans and mice, as the β2 isoform is predominately expressed in both human liver and skeletal muscles, while mice predominately express the β1 isoform in the liver and the β2 isoform in the skeletal muscles.

Figure 2

There are several potential alterations in cellular metabolism and signaling as a consequence of dysregulated AMPK-glycogen physical and functional interactions that represent key knowledge gaps in our current understanding and warrant further investigation in future studies. These potential alterations include changes in AMPK localization, translocation, substrates, and signaling pathway crosstalk, and subsequently, alterations in gene expression, cellular metabolism and glycogen storage.