Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage
Open Access
- 1 May 2007
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 117 (5), 1432-1439
- https://doi.org/10.1172/JCI30658
Abstract
AMP-activated protein kinase (AMPK) responds to impaired cellular energy status by stimulating substrate metabolism for ATP generation. Mutation of the gamma2 regulatory subunit of AMPK in humans renders the kinase insensitive to energy status and causes glycogen storage cardiomyopathy via unknown mechanisms. Using transgenic mice expressing one of the mutant gamma2 subunits (N488I) in the heart, we found that aberrant high activity of AMPK in the absence of energy deficit caused extensive remodeling of the substrate metabolism pathways to accommodate increases in both glucose uptake and fatty acid oxidation in the hearts of gamma2 mutant mice via distinct, yet synergistic mechanisms resulting in selective fuel storage as glycogen. Increased glucose entry in the gamma2 mutant mouse hearts was directed through the remodeled metabolic network toward glycogen synthesis and, at a substantially higher glycogen level, recycled through the glycogen pool to enter glycolysis. Thus, the metabolic consequences of chronic activation of AMPK in the absence of energy deficiency is distinct from those previously reported during stress conditions. These findings are of particular importance in considering AMPK as a target for the treatment of metabolic diseases.Keywords
This publication has 53 references indexed in Scilit:
- Genetic model for the chronic activation of skeletal muscle AMP-activated protein kinase leads to glycogen accumulationAmerican Journal of Physiology-Endocrinology and Metabolism, 2007
- Muscle-specific overexpression of wild type and R225Q mutant AMP-activated protein kinase γ3-subunit differentially regulates glycogen accumulationAmerican Journal of Physiology-Endocrinology and Metabolism, 2006
- Increased α2 Subunit–Associated AMPK Activity and PRKAG2 CardiomyopathyCirculation, 2005
- Decreased Contractile and Metabolic Reserve in Peroxisome Proliferator–Activated Receptor-α–Null Hearts Can Be Rescued by Increasing Glucose Transport and UtilizationCirculation, 2005
- Mechanisms for Increased Glycolysis in the Hypertrophied Rat HeartHypertension, 2004
- UDP‐Glucose pyrophosphorylase is upregulated in carriers of the porcine RN− mutation in the AMP‐activated protein kinaseProteomics, 2004
- Glycogen synthase localization and activity in rat skeletal muscle is strongly dependent on glycogen contentThe Journal of Physiology, 2001
- Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heartJCI Insight, 1999
- Role of the AMP-activated protein kinase in the cellular stress responseCurrent Biology, 1994
- Uridine diphosphate glucose synthase from calf liver. Determinants of enzyme activity in vitroBiochemistry, 1975