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 β subunit carbohydrate-binding module (CBM). However, the physiological role of AMPK-glycogen binding in energy h...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-11-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820301228 |
| _version_ | 1811324747855691776 |
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| author | Nolan J. Hoffman Jamie Whitfield Natalie R. Janzen Mehdi R. Belhaj Sandra Galic Lisa Murray-Segal William J. Smiles Naomi X.Y. Ling Toby A. Dite John W. Scott Jonathan S. Oakhill Robert Brink Bruce E. Kemp John A. Hawley |
| author_facet | Nolan J. Hoffman Jamie Whitfield Natalie R. Janzen Mehdi R. Belhaj Sandra Galic Lisa Murray-Segal William J. Smiles Naomi X.Y. Ling Toby A. Dite John W. Scott Jonathan S. Oakhill Robert Brink Bruce E. Kemp John A. Hawley |
| author_sort | Nolan J. Hoffman |
| collection | DOAJ |
| description | 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 β 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 β1 (W100A) or β2 (W98A) isoform CBM. Systematic whole-body, tissue and molecular phenotyping was performed in KI and respective wild-type (WT) mice. Results: While β1 W100A KI did not affect whole-body metabolism or exercise capacity, β2 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 β1 W100A and β2 W98A, respectively, versus WT mice. β1 W100A mice also displayed loss of fasting-induced liver AMPK total and α-specific kinase activation relative to WT. Destabilisation of AMPK was associated with increased fat deposition in β1 W100A liver and β2 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. |
| first_indexed | 2024-04-13T14:19:55Z |
| format | Article |
| id | doaj.art-87aacaf855cb400a99375db49d1f3201 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-13T14:19:55Z |
| publishDate | 2020-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-87aacaf855cb400a99375db49d1f32012022-12-22T02:43:30ZengElsevierMolecular Metabolism2212-87782020-11-0141101048Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolismNolan J. Hoffman0Jamie Whitfield1Natalie R. Janzen2Mehdi R. Belhaj3Sandra Galic4Lisa Murray-Segal5William J. Smiles6Naomi X.Y. Ling7Toby A. Dite8John W. Scott9Jonathan S. Oakhill10Robert Brink11Bruce E. Kemp12John A. Hawley13Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Level 5, 215 Spring Street, Melbourne, Victoria 3000, Australia; Corresponding author.Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Level 5, 215 Spring Street, Melbourne, Victoria 3000, AustraliaExercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Level 5, 215 Spring Street, Melbourne, Victoria 3000, AustraliaExercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Level 5, 215 Spring Street, Melbourne, Victoria 3000, AustraliaSt. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, AustraliaSt. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, AustraliaSt. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, AustraliaSt. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, AustraliaSt. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, AustraliaExercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Level 5, 215 Spring Street, Melbourne, Victoria 3000, Australia; St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, Australia; The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria 3052, AustraliaExercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Level 5, 215 Spring Street, Melbourne, Victoria 3000, Australia; St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, AustraliaImmunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, UNSW Sydney, Level 5 deLacy Building, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, AustraliaExercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Level 5, 215 Spring Street, Melbourne, Victoria 3000, Australia; St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, Australia; Corresponding author. St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, Australia.Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Level 5, 215 Spring Street, Melbourne, Victoria 3000, Australia; Corresponding author.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 β 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 β1 (W100A) or β2 (W98A) isoform CBM. Systematic whole-body, tissue and molecular phenotyping was performed in KI and respective wild-type (WT) mice. Results: While β1 W100A KI did not affect whole-body metabolism or exercise capacity, β2 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 β1 W100A and β2 W98A, respectively, versus WT mice. β1 W100A mice also displayed loss of fasting-induced liver AMPK total and α-specific kinase activation relative to WT. Destabilisation of AMPK was associated with increased fat deposition in β1 W100A liver and β2 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.http://www.sciencedirect.com/science/article/pii/S2212877820301228AMP-activated protein kinaseCarbohydrate-binding moduleCellular energy sensingExerciseLiverSkeletal muscle |
| spellingShingle | Nolan J. Hoffman Jamie Whitfield Natalie R. Janzen Mehdi R. Belhaj Sandra Galic Lisa Murray-Segal William J. Smiles Naomi X.Y. Ling Toby A. Dite John W. Scott Jonathan S. Oakhill Robert Brink Bruce E. Kemp John A. Hawley Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism Molecular Metabolism AMP-activated protein kinase Carbohydrate-binding module Cellular energy sensing Exercise Liver Skeletal muscle |
| title | Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism |
| title_full | Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism |
| title_fullStr | Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism |
| title_full_unstemmed | Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism |
| title_short | Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism |
| title_sort | genetic loss of ampk glycogen binding destabilises ampk and disrupts metabolism |
| topic | AMP-activated protein kinase Carbohydrate-binding module Cellular energy sensing Exercise Liver Skeletal muscle |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820301228 |
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