Sensitivity of CPT I to malonyl-CoA in trained and untrained human skeletal muscle

The present study examined the sensitivity of carnitine palmitoyltransferas e I (CPT I) activity to its inhibitor malonyl-CoA (M-CoA), and simulated me tabolic conditions of rest and exercise, in aerobically trained and untrain ed humans. Maximal CPT I activity was measured in mitochondria isolated fro m resting human skeletal muscle. Mean CPT I activity was 492.8 +/- 72.8 and 260.8 +/- 33.6 mu mol.min(-1).kg wet muscle(-1) in trained and untrained s ubjects, respectively (pH 7.0, 37 degrees C). The sensitivity to M-CoA was greater in trained muscle; the IC50 for M-CoA was 0.17 +/- 0.04 and 0.49 +/ - 0.17 mu M 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 physiol ogical concentrations of M-CoA. The results of this study indicate that aer obic training is associated with an increase in the sensitivity of CPT I to M-CoA. Accumulations of acetyl-CoA, CoASH, and acetylcarnitine do not coun teract the M-CoA-induced inhibition of CPT I activity. However, small decre ases in pH produce large reductions in the activity of CPT I and may contri bute to the decrease in fat metabolism that occurs during moderate and inte nse aerobic exercise intensities.