malonyl-CoA in the heart and skeletal muscle: does control analysis help to explain the paradox?

Carnitine palmitoyl transferase I (CPT I), a transmembrane enzyme of the mitochondrial outer membrane, catalyses the transfer of an acyl moiety from a longchain acyl-CoA ester to carnitine to form a long-chain acyl-carnitine ester, which can then enter the mitochondrion and undergo β-oxidation. The enzyme is a potential site for regulation of β-oxidation flux via its physiological inibitor, malonylCoA [1, 2] and is widely assumed to be the rate-limiting step in the β-oxidation of long-chain fatty acids in the heart [1] and other tissues. It has been found to have significant control over β-oxidation flux in hepatocytes [3–5], liver mitochondria [6] and astrocytes [7]. However, the concentration of malonyl-CoA in the heart is estimated to be in the range of 1-10 μM [2]. This greatly exceeds the IC50 of heart CPT I for malonyl-CoA [8] so it is difficult to see how β-oxidation proceeds in cardiac tissue if CPT I activity is rate-limiting for β-oxidation, unless most of the malonyl-CoA is intramitochondrial or bound and therefore not available to inhibit CPT I. There are two isoforms (liver and muscle) of carnitine palmitoyl transferase I (CPT I) in the heart [9, 10]. Inborn errors of carnitine palmitoyl transferase II are well-known to present with myopathy and cardiomyopathy; defects in the liver isoform of CPT I have also been diagnosed but to date no patients defective in the muscle form of CPT I have been diagnosed. We wished to investigate the role of the two isoforms in control of β-oxidation in the heart and in skeletal muscle.