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 V(max) and K(m) (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.
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
Luis A
LA
Gómez
Shi-Hua D
SH
Heath
Tory M
TM
Hagen
D000108:Acetylcarnitine / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D002331:Carnitine / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics* / Q000378:metabolism*; D019587:Dietary Supplements; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D010171:Palmitoyl Coenzyme A; D000108:Acetylcarnitine; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine