Sensitivity of CPT I to malonyl-CoA in trained and untrained human skeletal muscle.
The present study examined the sensitivity of carnitine palmitoyltransferase I (CPT I) activity to its inhibitor malonyl-CoA (M-CoA), and simulated metabolic conditions of rest and exercise, in aerobically trained and untrained humans. Maximal CPT I activity was measured in mitochondria isolated from resting human skeletal muscle. Mean CPT I activity was 492.8 +/- 72.8 and 260.8 +/- 33.6 micromol. min(-1). kg wet muscle(-1) in trained and untrained subjects, respectively (pH 7.0, 37 degrees C). The sensitivity to M-CoA was greater in trained muscle; the IC(50) for M-CoA was 0.17 +/- 0.04 and 0.49 +/- 0.17 microM in trained and untrained muscle, respectively. The presence of acetyl-CoA, free coenzyme A (CoASH), and acetylcarnitine, in concentrations simulating rest and exercise conditions did not release the M-CoA-induced inhibition of CPT I activity. However, CPT I activity was reduced at pH 6.8 vs. pH 7.0 in both trained and untrained muscle in the presence of physiological concentrations of M-CoA. The results of this study indicate that aerobic training is associated with an increase in the sensitivity of CPT I to M-CoA. Accumulations of acetyl-CoA, CoASH, and acetylcarnitine do not counteract the M-CoA-induced inhibition of CPT I activity. However, small decreases in pH produce large reductions in the activity of CPT I and may contribute to the decrease in fat metabolism that occurs during moderate and intense aerobic exercise intensities.
Starritt
E C
EC
Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario N1G 2W1, Canada.
Howlett
R A
RA
Heigenhauser
G J
GJ
Spriet
L L
LL
D000105:Acetyl Coenzyme A / Q000494:pharmacology; D000108:Acetylcarnitine / Q000494:pharmacology; D000328:Adult; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D003065:Coenzyme A / Q000494:pharmacology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008316:Malonyl Coenzyme A / Q000494:pharmacology*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology*; D010806:Physical Education and Training; D012016:Reference Values
D008316:Malonyl Coenzyme A; D000108:Acetylcarnitine; D000105:Acetyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D003065:Coenzyme A