Mechanisms for increased glycolysis in the hypertrophied rat heart.
Glycolysis increases in hypertrophied hearts but the mechanisms are unknown. We studied the regulation of glycolysis in hearts with pressure-overload LV hypertrophy (LVH), a model that showed marked increases in the rates of glycolysis (by 2-fold) and insulin-independent glucose uptake (by 3-fold). Although the V(max) of the key glycolytic enzymes was unchanged in this model, concentrations of free ADP, free AMP, inorganic phosphate (P(i)), and fructose-2,6-bisphosphate (F-2,6-P2), all activators of the rate-limiting enzyme phosphofructokinase (PFK), were increased (up to 10-fold). Concentrations of the inhibitors of PFK, ATP, citrate, and H+ were unaltered in LVH. Thus, our findings show that increased glucose entry and activation of the rate-limiting enzyme PFK both contribute to increased flux through the glycolytic pathway in hypertrophied hearts. Moreover, our results also suggest that these changes can be explained by increased intracellular free [ADP] and [AMP], due to decreased energy reserve in LVH, activating the AMP-activated protein kinase cascade. This, in turn, results in enhanced synthesis of F-2,6-P2 and increased sarcolemma localization of glucose transporters, leading to coordinated increases in glucose transport and activation of PFK.
NMR Laboratory for Physiological Chemistry, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Room 252, Boston, MA 02115, USA. lnascimben@partners.org.bwh.harvard.edu
Luigino
L
Nascimben
Joanne S
JS
Ingwall
Beverly H
BH
Lorell
Ilka
I
Pinz
Vera
V
Schultz
Keith
K
Tornheim
Rong
R
Tian
D055372:AMP-Activated Protein Kinases; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D010101:Oxygen Consumption; D025221:Phosphofructokinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D009097:Multienzyme Complexes; D007770:L-Lactate Dehydrogenase; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D025221:Phosphofructokinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose