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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 beta1 (W100A) or beta2 (W98A) isoform CBM. Systematic whole-body, tissue and molecular phenotyping was performed in KI and respective wild-type (WT) mice. RESULTS: While beta1 W100A KI did not affect whole-body metabolism or exercise capacity, beta2 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 beta1 W100A and beta2 W98A, respectively, versus WT mice. beta1 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 beta1 W100A liver and beta2 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.

Type Journal
ISBN 2212-8778 (Electronic) 2212-8778 (Linking)
Authors Hoffman, N. J.; Whitfield, J.; Janzen, N. R.; Belhaj, M. R.; Galic, S.; Murray-Segal, L.; Smiles, W. J.; Ling, N. X. Y.; Dite, T. A.; Scott, J. W.; Oakhill, J. S.; Brink, R.; Kemp, B. E.; Hawley, J. A.
Responsible Garvan Author Prof Robert Brink
Publisher Name Molecular Metabolism
Published Date 2020-11-30
Published Volume 41
Published Pages 101048
Status Published in-print
DOI 10.1016/j.molmet.2020.101048
URL link to publisher's version