Alterations in key gluconeogenic regulators with age and endurance training.

The purpose of the present investigation was to examine changes in six potential regulators of hepatic gluconeogenesis with normal aging and endurance training: fructose 2,6-bisphosphate (F 2,6-P2), mitochondrial and cytosolic phosphoenolpyruvate carboxykinase (PEPCK) activity, PEPCK mRNA, and pyruvate carboxylase and malate dehydrogenase activity. Young (4 months), middle-aged (12 months), and old (22 months) male-Fischer 344 rats (N = 66) were divided into trained and sedentary groups. Trained animals were run 1 h/d, 5 d/wk for 10 weeks at treadmill speeds of 75% age-specific maximal running capacity. Animals were killed at rest, and the right main lobe of the liver was removed. F 2,6-P2 levels were significantly greater in old compared with young animals regardless of training condition (119% and 80% increase in old trained and untrained animals, respectively). No changes were found with training. Rates of cytosolic PEPCK activity declined significantly with age in both trained (1.3 +/- 0.1, 1.0 +/- 0.1, and 0.7 +/- 0.1 mumol/g/min in young, middle-aged, and old, respectively) and untrained (1.3 +/- 0.1, 1.1 +/- 0.1, and 0.8 +/- 0.2 mumol/g/min) groups. Training did not result in any significant differences between age groups. PEPCK gene expression (mRNA) determined by Northern blot analysis decreased 30% in trained and untrained old animals compared to the young counterparts; again, training had no effect in any age group. No significant differences were found in pyruvate carboxylase, mitochondrial PEPCK, or malate dehydrogenase activity with either age or training. These results suggest that previous age-related declines found in hepatic gluconeogenic capacity can be attributed, in part, to changes in F 2,6-P2, cytosolic PEPCK activity, and PEPCK mRNA, but not to alterations in the activities of mitochondrial PEPCK, malate dehydrogenase, or pyruvate carboxylase. Since training had no effect on any regulator studied, the factors responsible for attenuation in the age-related decline in gluconeogenesis with training remain to be determined.