Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism

Objective: Glycogen is a major energy reserve in liver and skeletal muscle. The master metabolic regulator AMP-activated protein kinase (AMPK) associates with glycogen via its regulatory beta subunit carbohydrate-binding module (CBM). However, the physiological role of AMPK-glycogen binding in energy homeostasis has not been investigated in vivo. This study aimed to determine the physiological consequences of disrupting AMPK-glycogen interactions. Methods: Glycogen binding was disrupted in mice via whole-body knock-in (KI) mutation of either the AMPK beta 1 (W100A) or beta 2 (W98A) isoform CBM. Systematic whole-body, tissue and molecular phenotyping was performed in KI and respective wild-type (WT) mice. Results: While beta 1 W100A KI did not affect whole-body metabolism or exercise capacity, beta 2 W98A KI mice displayed increased adiposity and impairments in whole-body glucose handling and maximal exercise capacity relative to WT. These KI mutations resulted in reduced total AMPK protein and kinase activity in liver and skeletal muscle of beta 1 W100A and beta 2 W98A, respectively, versus WT mice. beta 1 W100A mice also displayed loss of fasting-induced liver AMPK total and alpha-specific kinase activation relative to WT. Destabilisation of AMPK was associated with increased fat deposition in beta 1 W100A liver and beta 2 W98A skeletal muscle versus WT. Conclusions: These results demonstrate that glycogen binding plays critical roles in stabilising AMPK and maintaining cellular, tissue and whole-body energy homeostasis. (C) 2020 The Authors. Published by Elsevier GmbH.