Acetyl-l-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the l-carnitine content in the rat heart

The aging heart displays a loss of bioenergetic reserve capacity partially mediated through lower fatty acid utilization. We investigated whether the age-related impairment of cardiac fatty acid catabolism occurs, at least partially, through diminished levels of l-carnitine, which would adversely affect carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme for fatty acyl-CoA uptake into mitochondria for β-oxidation. Old (24–28 mos) Fischer 344 rats were fed ± acetyl-l-carnitine (ALCAR; 1.5% [w/v]) for up to four weeks prior to sacrifice and isolation of cardiac interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria. IFM displayed a 28% (p < 0.05) age-related loss of CPT1 activity, which correlated with a decline (41%, p < 0.05) in palmitoyl-CoA-driven state 3 respiration. Interestingly, SSM had preserved enzyme function and efficiently utilized palmitate. Analysis of IFM CPT1 kinetics showed both diminished Vmax and Km (60% and 49% respectively, p < 0.05) when palmitoyl-CoA was the substrate. However, no age-related changes in enzyme kinetics were evident with respect to l-carnitine. ALCAR supplementation restored CPT1 activity in heart IFM, but not apparently through remediation of l-carnitine levels. Rather, ALCAR influenced enzyme activity over time, potentially by modulating conditions in the aging heart that ultimately affect palmitoyl-CoA binding and CPT1 kinetics.

► Aging decreases cardiac CPT1 catalytic activity for palmitoyl-CoA utilization.
► CPT1 activity loss is localized to a specific mitochondrial subpopulation (IFM).
► CPT1 catalysis declines without a significant change in affinity for l-carnitine.
► ALCAR feeding to old rats remediates overall IFM CPT1 activity loss.
► ALCAR supplementation does not remediate the loss of myocardial carnitine content.