Myocardial NEFA Uptake is Enhanced to a Greater Extent Than NEFA Oxidation in Conscious Senescent Beagles with Myocardial Insulin Resistance

Background : Prior studies have demonstrated that aging is associated with myocardial insulin resistance, mitochondrial ultra-structural changes and decreased UCP-3 protein. We sought to determine the relationship between these metabolic limitations and myocardial NEFA uptake and oxidation in senescent beagles. Methods : Eight young (age 3– 4 years) and 8 senescent (age 11–12 years) beagles underwent chronic instrumentation for measurement of hemodymics and myocardial substrate balance. All dogs were subjected to an 8 week exercise training program prior to instrumentation to control for activity level. In the fasting, conscious state, myocardial NEFA uptake and oxidation was measured using 3 H-oleate, and insulin resistance was assessed via hyperinsulinemic-euglycemic clamps. Samples of LV myocardium were harvested at euthanasia to measure components of NEFA transport. Results : There was no difference in body weight or adiposity between groups. Older beagles had marked (p<0.01) increases in plasma NEFA (Y:426± 65; O:902±78 μMol/min) and increased cardiac NE spillover (Y:21±4; O: 221±36 pmol/min). However, myocardial external efficiency was reduced (p<0.05) in older dogs (Y:15±3; O: 9±3 g·m 2 /ml O 2 /min). Hearts from older beagles demonstrated significant increases (p<0.01) in NEFA uptake (Y: 5.2±0.9; O: 9.3±0.8 μMol/min/100g), and only modest increases in oxidation (Y: 4.9±0.6; O: 7.0±1.1 μMol/min/ 100g). In sarcolemmal membranes, expression of Fatty Acid Transport Protein-1 (FATP-1) was upregulated (Y:72 11 DU; O: 235 21 DU, p<0.05), whereas that of FAT/CD36 was markedly reduced (Y: 1,312±123; O: 387±12 DU, p<0.001). There was no difference in PPARα (Y: 425±25; O: 475±116 DU) or PGC-1α (Y: 637±53; O: 633±14 DU) expression. The cumulative result of these changes was an accumulation of neutral lipids within older hearts and significant (p<0.02) insulin resistance (Y: 8.3 ±0.6; O: 4.3±0.8 μMol/min/100g). Conclusion : In older beagles, myocardial NEFA uptake exceeds oxidation, resulting in intramyocardial lipid accumulation. Increased FA uptake occurs despite decreased FAT/CD36 expression, and may be mediated by an upreguation of FATP-1 expression. These changes are seen in association with progressive myocardial insulin resistance.