Mitochondrial metabolism and substrate competition in the aging fischer rat heart

Objective: The objective was to examine mitochondrial oxidative metabolism of long chain fatty acids and to compare it with glucose uptake and the generation of pressure-volume work in hearts from mature and aged rats. Methods: Hearts from mature (8 to 15 months of age) and old (28 to 30 months) Fischer 344 rats were perfused as working hearts with either 10 mM glucose or glucose plus 1 mM oleic acid (2% bovine serum albumin) and rates of glucose extraction were determined. Hearts were subjected to a stepwise increase in work load. In separate experiments, mitochondria were isolated from mature and old rat hearts and assayed for respiratory function, carnitine exchange, carnitine palmitoyltransferase activities, and phospholipid content. Results: Although there were no differences in peak work attained between the mature and old rats in the presence of either glucose alone or glucose plus oleic acid, glucose utilisation was significantly decreased by oleate in the mature animals only. No significant changes in either glutamate or succinate (+rotenone) supported respiration were found in heart mitochondria isolated from old rats compared with mature animals. In agreement with prior studies with the Wistar rat model of aging, significant decrements in the rates of palmitoylcarnitine oxidation and carnitine exchange were apparent in the old Fischer animals. A significant lowering of heart mitochondrial carnitine palmitoyltransferase I activity was also found in the old animals. A decrease in the amounts of carnitine loaded in mitochondria from old animals is consistent with reduced carnitine content in both mitochondria and whole hearts from aged Wistar and Fischer rats. A significant (23%) reduction in heart mitochondrial cardiolipin content from 30 month old Fischer rats suggests that this phospholipid may also contribute to the lower rates of carnitine and acylcarnitine transport across the mitochondrial inner membrane. Conclusion: The limitation in the delivery of fatty acyl units to β oxidation as measured in isolated heart mitochondria from old rats has a physiological correlate in the intact heart. The well documented suppression of glucose oxidation by fatty acids seen in the adult rat heart is not seen in old hearts, supporting the in vitro finding of decreased oxidation of palmitoylcarnitine with senescence.Cardiovascular Research 1993;27:2222-2228.