Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage.
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.
Luptak
Ivan
I
NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.
Shen
Mei
M
He
Huamei
H
Hirshman
Michael F
MF
Musi
Nicolas
N
Goodyear
Laurie J
LJ
Yan
Jie
J
Wakimoto
Hiroko
H
Morita
Hiroyuki
H
Arad
Michael
M
Seidman
Christine E
CE
Seidman
J G
JG
Ingwall
Joanne S
JS
Balschi
James A
JA
Tian
Rong
R
D055372:AMP-Activated Protein Kinases; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D006003:Glycogen / Q000378:metabolism*; D006008:Glycogen Storage Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015219:Substrate Cycling / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D009097:Multienzyme Complexes; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases