Exercise induces a decline in liver malonyl-CoA, an inhibitor of carnitine palmitoyltransferase-1. The purpose of these experiments was to determine whether this decrease in malonyl-CoA is accompanied by an activation of AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase (ACC). Rats were killed at rest, after 10 min of running at 32 m/min up a 15% grade or at 0, 15, or 60 min postexercise after 120 min of running at 16 m/min. There was no significant difference in AMPK and ACC activities after 120 min of exercise, although a trend toward a decrease in ACC and an increase in AMPK was noted 15 min postexercise. After 10 min at 32 m/min, however, maximal ACC activity decreased from 487 +/- 27 to 280 +/- 39 nmol. g-1. min-1, and the activation constant for citrate activation of ACC increased from 5.9 to 12.5 mM. AMPK activity increased from a resting value of 4.7 +/- 0.4 to 9.8 +/- 2.0 pmol. mg-1. min-1 after exercise. These data provide indirect evidence of phosphorylation and inactivation of liver ACC during heavy exercise. In contrast, the decrease in malonyl-CoA during long-term, low-intensity exercise may occur by mechanisms other than phosphorylation of ACC.

Background/Aims: Carnitine is essential for the transport of long-chain FAs (FA) into the mitochondria for energy production. During acute exercise, the increased demand for FAs results in a state of free carnitine deficiency in plasma. The role of kidney in carnitine homeostasis after exercise is not known. Methods: Swiss Webster mice were sacrificed immediately after a 1-hour moderate intensity treadmill run, and at 4-hours and 8-hours into recovery. Non-exercising mice served as controls. Plasma was analyzed for carnitine using acetyltransferase and [¹⁴C] acetyl-CoA. Kidney was removed for gene and protein expression of butyrobetaine hydroxylase (γ-BBH), organic cation transporter (OCTN2), and peroxisome proliferator-activated receptor (PPARα), a regulator of fatty acid oxidation activated by FAs. Results: Acute exercise caused a decrease in plasma free carnitine levels. Rapid return of free carnitine to control levels during recovery was associated with increased γ-BBH expression. Both mRNA and protein levels of OCTN2 were detected in kidney after exercise and during recovery, suggesting renal transport mechanisms were stimulated. These changes were accompanied with a reciprocal increase in PPARα protein expression. Conclusions: Our results show that the decrease in free carnitine after exercise rapidly activates carnitine biosynthesis and renal transport mechanism in kidney to establish carnitine homeostasis.

We determined whether one single bout of exercise stimulates carnitine biosynthesis and carnitine uptake in liver and heart. Free carnitine (FC) in plasma was assayed using acetyltransferase and [14C]acetyl-CoA in Swiss Webster mice after 1 hour of moderate-intensity treadmill running or 4 hours and 8 hours into recovery. Liver and heart were removed under the same conditions for measurement of carnitine biosynthesis enzymes (liver butyrobetaine hydroxylase, γ-BBH; heart trimethyllysine dioxygenase, TMLD), organic cation transporter-2 (OCTN2, carnitine transporter), and liver peroxisome proliferator-activated receptor-alpha (PPARα, transcription factor for γ-BBH and OCTN2 synthesis). In exercised mice, FC levels in plasma decreased while heart and liver OCTN2 protein expressed increased, reflecting active uptake of FC. During recovery, the rise in FC to control levels was associated with increased liver γ-BBH expression. Protein expression of PPARα was stimulated in liver after exercise and during recovery. Interestingly, heart TMLD protein was also detected after exercise. Acute exercise stimulates carnitine uptake in liver and heart. The rapid return of FC levels in plasma after exercise indicates carnitine biosynthesis by liver is stimulated to establish carnitine homeostasis. Our results suggest that exercise may benefit patients with carnitine deficiency syndromes.

The intrathecal penetration of N-formimidoyl thienamycin (MK0787) with or without coadministration of the renal dipeptidase enzyme inhibitor (MK791) in normal rabbits was studied immediately before and after the third dose of 40 mg/kg infused intravenously at daily 6-h intervals. Mean ± standard error peak concentrations in cerebrospinal fluid were 0.23 ± 0.02 and 0.53 ± 0.12 ,ug/ml without and with coadministration of MK791, respectively (P < 0.05, Student's t test). Penetration into cerebrospinal fluid (based on the ratio of cerebrospinal fluid to plasma area under the concentration-time curves) were 4.4 and 6.0%, respectively. N-Formimidoyl thienamycin penetrated uninflamed meninges, and peak concentrations were significantly augmented by coadministration of MK791.N-Formimidoyl thienamycin (MK0787) has potent activity against both gram-positive and gram-negative bacteria and might be useful for treatment of bacterial meningitis (5). N-Formimidoyl thienamycin is unique among 1-lactam antibiotics in that it is metabolized and inactivated in the brush border of the renal tubules by the dipeptidase enzyme, dehydropeptidase I, which hydrolyzes the P-lactam ring (4). The degradation of N-formimidoyl thienamycin in vivo can be halted and its concentration in urine and plasma augmented by the coadministration of a renal dipeptidase inhibitor (MK-791) in chimpanzees and humans (4). Accordingly, we studied the intrathecal penetration of N-formimidoyl thienamycin in rabbits with or without coadministration of MK791.Groups of New Zealand White female rabbits weighing 2 to 3 kg each were studied. Each rabbit was adapted in individual cages for 48 h before experimentation. Anesthesia was attained by intramuscular ketamine hydrochloride (100 mg/ml) admixed with acepromazine maleate (2.5 mg/ml). N-Formimidoyl thienamycin at a dose of 40 mg/kg alone or in combination with MK791 at a dose of 40 mg/kg was administered at 6-h intervals by intravenous bolus infusion through anterior marginal ear veins. N-Formimidoyl thienamycin (Merck Sharp search Laboratories, Rahway, N.J.) was prepared in sterile normal saline. Antibiotic solutions containing MK791 (Merck Sharp & Dohme Research Laboratories) were prepared by admixing stock solutions of N-formimidoyl thienamycin and MK791 in a water bath maintained at 80°C. Approximately 2.5 ml of plasma and 0.5 to 1 ml of cerebrospinal fluid (CSF) were obtained at each sampling from the anterior ear veins and cistemal space, respectively, immediately before and at 0.5, 1, 2, 4, and 6 h after the third dose of antibiotic. No bloody samples were accepted for analysis. All samples were immediately stabilized in MES (50%o [vol/vol]

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