Hearts utilize fatty acids as a primary source of energy. hLPL0 mice had systolic dysfunction with a reduction in fractional shortening compared with age-matched controls (Fig. 1and = 5-7. … DZNep Lipid analysis. DGAT1 and -2 were reduced by the MHC-GLUT1 transgene; this would suggest that these hearts have reduced TG synthesis from FFA. However even on chow MHC-GLUT1 mice had an increase in heart TG and FFA content (Fig. 3 c-Raf and < 0.05 vs. littermate control mice; male mice = 5-9. MHC-GLUT1/hLPL0 hearts have increased ATP. We postulated that greater glucose uptake improved heart function by increasing energy production. Although hLPL0 mice had a reduced level of ATP after acute afterload (5) under nonstressed conditions ATP levels were not reduced. Surprisingly ATP was increased DZNep in MHC-GLUT1 hearts and also in the MHC-GLUT1/hLPL0 hearts (Fig. 4< 0.05 and §< 0.01 vs. control mice *< 0.05 ... We assessed directly the reasons for greater ATP production by assessing glucose uptake. As noted previously glucose uptake is usually increased in hLPL0 hearts; in this group of mice that increase was approximately threefold (Fig. 4B). MHC-GLUT1 increased 2-deoxyglucose (2-DG) uptake ～4.2-fold and led to a significant increase above that in the hLPL0 mice (Fig. 4B). Lactate levels in the heart were increased in hLPL0 hearts (see below) but not with MHC-GLUT1 expression (Fig. 4C). Exercise training improves cardiac function in mice with defective cardiac FA uptake. Exercise-mediated improvements in cardiac function are associated with alterations in energy substrate utilization. To investigate the effect of exercise training around the DZNep cardiac structure and function of hLPL0 mice a 6-wk swim training protocol was begun at 3 mo of age. Both control and hLPL0 mice had greater HW/TL ratios which was consistent with the development of DZNep exercise-induced cardiac hypertrophy (Fig. 5A). Trained hLPL0 mice exhibited significantly greater fractional shortening compared with their sedentary counterparts and led to a fractional shortening percentage identical to that DZNep seen in controls (Fig. 5B).There was no difference in cardiac contractility between trained hLPL0 and control mice reflecting normalization of cardiac function (Fig. 5C). Fig. 5. Effects of training on cardiac hypertrophy and function in 5-mo-old control (ctrl) and hLPL0 mice. Mice were randomly assigned to either a sedentary or training group that underwent swim training for 6 wk. Cardiac hypertrophy was determined by heart weight/tiba … Exercise training does not further increase cardiac glucose uptake in hLPL0 mice. We speculated that this improvements in cardiac function observed in trained hLPL0 mice might be due to an increase in the myocardial uptake of an alternate substrate. Since the hearts of these mice use more glucose than controls we theorized that this improvements in cardiac function were due to the increased uptake of glucose by trained hearts a process similar to that in MHC-GLUT1/hLPL0 mice. Although hLPL0 mice had increased cardiac 2-DG uptake compared with controls exercise training did not increase glucose further (Fig. 6A). Plasma glucose did not significantly change immediately after exercise in any of the mice (Table 2). Fig. 6. Cardiac glucose uptake lactate uptake and MCT-1 gene expression. A: control and hLPL0 mice fasted for 5 h; cardiac 2-deoxy-d-[1-3H]glucose uptake was determined by measuring cardiac radioactivity and normalized to 2-min plasma DZNep counts. B: [14C]lactate … Table 2. Plasma lipids and glucose at rest and immediately after exercise Lactate uptake is usually increased in the hearts of hLPL0 mice. Lactate becomes an important fuel for cardiac energy metabolism during exercise (24 46 when plasma lactate concentrations rise. Using radiolabeled [14C]lactate we specifically assessed myocardial lactate uptake. Plasma lactate levels and [14C]lactate clearance curves were not different between groups. Similar to monocarboxylate transporter-1 (MCT-1) mRNA expression sedentary hLPL0 mice exhibited an increase in radiolabeled lactate uptake compared with controls (Fig. 6B). Training did not further increase [14C]lactate uptake. MCT-1 the major lactate transporter in the heart increases with training and.