Mitochondrial Carnitine Palmitoyltransferase I Isoform Switching in the Developing Rat Heart

The expression pattern of mitochondrial carnitine palmitoyltransferase (CPT) enzymes was examined in the developing rat heart. Whereas the specific activity of CPT II increased ∼3-fold during the first month of life, the profile for CPT I, which is composed of both liver (L) and muscle (M) isoforms, was more complex. Exposure of mitochondria to 3Hetomoxir (a covalent ligand for CPT I), followed by fluorographic analysis of the membrane proteins, established that while in the adult heart L-CPT I represents a very minor constituent, its contribution is much greater in the newborn animal. Use of the related inhibitor, 2-6-(2,4-dinitrophenoxy)hexyloxirane-2-carboxylic acid (specific for L-CPT I), allowed the activities of the two CPT I variants to be quantified separately. The results showed that in the neonatal heart, L-CPT I contributes ∼25% to total CPT I activity (in Vmax terms), the value falling during growth of the pups (with concomitant increasing expression of the M isoform) to its adult level of 2-3%.Because the myocardial carnitine content is very low at birth and rises dramatically over the next several weeks, it can be estimated that L-CPT I (Km for carnitine of only 30 μM compared with a value of 500 μM for M-CPT I) is responsible for some 60% of total cardiac fatty acid oxidation in the newborn rat; the value falls to ∼4% in adult animals. Should these findings have a parallel in humans, they could have important implications for understanding the pathophysiological consequences of inherited L-CPT I deficiency syndromes. The expression pattern of mitochondrial carnitine palmitoyltransferase (CPT) enzymes was examined in the developing rat heart. Whereas the specific activity of CPT II increased ∼3-fold during the first month of life, the profile for CPT I, which is composed of both liver (L) and muscle (M) isoforms, was more complex. Exposure of mitochondria to 3Hetomoxir (a covalent ligand for CPT I), followed by fluorographic analysis of the membrane proteins, established that while in the adult heart L-CPT I represents a very minor constituent, its contribution is much greater in the newborn animal. Use of the related inhibitor, 2-6-(2,4-dinitrophenoxy)hexyloxirane-2-carboxylic acid (specific for L-CPT I), allowed the activities of the two CPT I variants to be quantified separately. The results showed that in the neonatal heart, L-CPT I contributes ∼25% to total CPT I activity (in Vmax terms), the value falling during growth of the pups (with concomitant increasing expression of the M isoform) to its adult level of 2-3%. Because the myocardial carnitine content is very low at birth and rises dramatically over the next several weeks, it can be estimated that L-CPT I (Km for carnitine of only 30 μM compared with a value of 500 μM for M-CPT I) is responsible for some 60% of total cardiac fatty acid oxidation in the newborn rat; the value falls to ∼4% in adult animals. Should these findings have a parallel in humans, they could have important implications for understanding the pathophysiological consequences of inherited L-CPT I deficiency syndromes. The carnitine palmitoyltransferase (CPT) 1The abbreviations used are:CPTcarnitine palmitoyltransferaseL-CPT Iliver-type CPT IM-CPT Imuscle-type CPT Ietomoxir2-6-(4-chlorophenoxy)hexyloxirane-2-carboxylic acidDNP-etomoxir2-6-(2,4-dinitrophenoxy)hexyloxirane-2-carboxylic acid. 1The abbreviations used are:CPTcarnitine palmitoyltransferaseL-CPT Iliver-type CPT IM-CPT Imuscle-type CPT Ietomoxir2-6-(4-chlorophenoxy)hexyloxirane-2-carboxylic acidDNP-etomoxir2-6-(2,4-dinitrophenoxy)hexyloxirane-2-carboxylic acid. enzyme system effects the entry of long chain fatty acids into the mitochondrial matrix for β-oxidation. CPT I, located on the outer membrane, catalyzes the transfer of acyl groups from coenzyme A to carnitine, the acylcarnitine so formed then traversing the inner membrane by means of a specific transporter. CPT II, on the matrix side of the inner membrane, reverses the transacylation reaction, regenerating acyl-CoA (1McGarry J.D. Woeltje K.F. Kuwajima M. Foster D.W. Diabetes Metab. Rev. 1989; 5: 271-284Crossref PubMed Scopus (285) Google Scholar). Overall control of fatty acid transport, and thus of β-oxidation, is exerted at the level of CPT I by virtue of its unique inhibitability by malonyl-CoA, the product of the acetyl-CoA carboxylase reaction (1McGarry J.D. Woeltje K.F. Kuwajima M. Foster D.W. Diabetes Metab. Rev. 1989; 5: 271-284Crossref PubMed Scopus (285) Google Scholar). Although first recognized in the context of hepatic ketogenesis and its regulation (2McGarry J.D. Mannaerts G.P. Foster D.W. J. Clin. Invest. 1977; 60: 265-270Crossref PubMed Scopus (490) Google Scholar), the malonyl-CoA/CPT I interaction has since emerged as a key component of fuel “cross-talk” in a variety of non-hepatic tissues such as heart (3Saddik M. Gamble J. Witters L.A. Lopaschuk G.D. J. Biol. Chem. 1993; 268: 25836-25845Abstract Full Text PDF PubMed Google Scholar), skeletal muscle (4Duan C. Winder W.W. J. Appl. Physiol. 1992; 72: 901-904Crossref PubMed Scopus (27) Google Scholar), and the pancreatic β-cell (5Prentki M. Vischer S. Glennon M.C. Regazzi R. Deeney J.T. Corkey B.E. J. Biol. Chem. 1992; 267: 5802-5810Abstract Full Text PDF PubMed Google Scholar, 6Chen S. Ogawa A. Ohneda M. Unger R.H. Foster D.W. McGarry J.D. Diabetes. 1994; 43: 878-883Crossref PubMed Scopus (166) Google Scholar). In addition, CPT I has attracted attention as a potential site of pharmacological intervention in poorly controlled diabetes mellitus where fatty acid oxidation is excessive and has a detrimental effect on glucose homeostasis (7Foley J.E. Diabetes Care. 1992; 15: 773-784Crossref PubMed Scopus (164) Google Scholar, 8McGarry J.D. Science. 1992; 258: 766-770Crossref PubMed Scopus (562) Google Scholar). carnitine palmitoyltransferase liver-type CPT I muscle-type CPT I 2-6-(4-chlorophenoxy)hexyloxirane-2-carboxylic acid 2-6-(2,4-dinitrophenoxy)hexyloxirane-2-carboxylic acid. carnitine palmitoyltransferase liver-type CPT I muscle-type CPT I 2-6-(4-chlorophenoxy)hexyloxirane-2-carboxylic acid 2-6-(2,4-dinitrophenoxy)hexyloxirane-2-carboxylic acid. Efforts to dissect the mitochondrial CPT system 2In this article the terms CPT I and CPT II refer exclusively to the mitochondrial enzymes, although it is recognized that proteins with CPT activity are also associated with peroxisomes and microsomes (9Murthy M.S.R. Pande S.V. J. Biol. Chem. 1994; 269: 18283-18286Abstract Full Text PDF PubMed Google Scholar). 2In this article the terms CPT I and CPT II refer exclusively to the mitochondrial enzymes, although it is recognized that proteins with CPT activity are also associated with peroxisomes and microsomes (9Murthy M.S.R. Pande S.V. J. Biol. Chem. 1994; 269: 18283-18286Abstract Full Text PDF PubMed Google Scholar). in terms of its structure/function/regulatory characteristics have been greatly enhanced by the recent isolation of cDNAs corresponding to the rat and human CPT II proteins (10Woeltje K.F. Esser V. Weis B.C. Sen A. Cox W.F. McPhaul M.J. Slaughter C.A. Foster D.W. McGarry J.D. J. Biol. Chem. 1990; 265: 10720-10725Abstract Full Text PDF PubMed Google Scholar, 11Finocchiaro G. Taroni F. Rocchi M. Martin A.L. Colombo I. Tarelli G.T. DiDonato S. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 661-665Crossref PubMed Scopus (107) Google Scholar, 12McGarry J.D. Sen A. Brown N.F. Esser V. Weis B.C. Foster D.W. Carter A.L. Current Concepts in Carnitine Research. CRC Press, Boca Raton, FL1992: 137-151Google Scholar) as well as those encoding rat and human liver CPT I (13Esser V. Britton C.H. Weis B.C. Foster D.W. McGarry J.D. J. Biol. Chem. 1993; 268: 5817-5822Abstract Full Text PDF PubMed Google Scholar, 14Britton C.H. Schultz R.A. Zhang B. Esser V. Foster D.W. McGarry J.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1984-1988Crossref PubMed Scopus (123) Google Scholar). Available evidence indicates that in both species CPT II (∼71 kDa) is expressed as the same protein throughout the entire body (12McGarry J.D. Sen A. Brown N.F. Esser V. Weis B.C. Foster D.W. Carter A.L. Current Concepts in Carnitine Research. CRC Press, Boca Raton, FL1992: 137-151Google Scholar, 15Woeltje K.F. Esser V. Weis B.C. Cox W.F. Schroeder J.G. Liao S.-T. Foster D.W. McGarry J.D. J. Biol. Chem. 1990; 265: 10714-10719Abstract Full Text PDF PubMed Google Scholar). By contrast, the regulated enzyme, CPT I, exists in at least two isoforms. These have been designated L-CPT I and M-CPT I, indicating their association with liver and skeletal muscle, respectively (16Weis B.C. Esser V. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 18712-18715Abstract Full Text PDF PubMed Google Scholar, 17Weis B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google Scholar). The two proteins differ not only in monomeric size (∼88 and 82 kDa, respectively) but also in their profoundly different kinetic characteristics (Km for carnitine, ∼30 and 500 μM, respectively; I50 3The term I50 refers to the concentration of malonyl-CoA required to inhibit CPT I activity by 50% under defined assay conditions. 3The term I50 refers to the concentration of malonyl-CoA required to inhibit CPT I activity by 50% under defined assay conditions. for malonyl-CoA, ∼2.7 and 0.03 μM, respectively (18McGarry J.D. Mills S.E. Long C.S. Foster D.W. Biochem. J. 1983; 214: 21-28Crossref PubMed Scopus (461) Google Scholar)). In examining the features of CPT I in adult rat heart mitochondria we made the unexpected observation that this tissue expresses both the M- and L-type enzymes (16Weis B.C. Esser V. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 18712-18715Abstract Full Text PDF PubMed Google Scholar, 17Weis B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google Scholar). The fact that the L variant contributed only ∼2-3% to total CPT I activity was puzzling and difficult to rationalize teleologically. In the present study, therefore, we asked the following question: is the 98:2 ratio of M- to L-CPT I activity a fixed property of rat cardiac tissue, or is it possible that the L isoform (low Km for carnitine) makes a more significant contribution in the newborn period when the carnitine content of the heart is known to be low (19Robles-Valdes C. McGarry J.D. Foster D.W. J. Biol. Chem. 1976; 251: 6007-6012Abstract Full Text PDF PubMed Google Scholar)? As outlined below, it that birth L-CPT I is responsible for a of fatty acid oxidation in rat heart and that its during growth of the pups represents of isoform in heart The findings have pathophysiological in of inherited CPT I deficiency syndromes. on with from to was and with the of birth designated as and at The by adult first by of tissue, and The by of to from of used for analysis in the and of used for adult of and in of M M as in A of J.D. Mills S.E. Long C.S. Foster D.W. Biochem. J. 1983; 214: 21-28Crossref PubMed Scopus (461) Google and in M M at of the was with of M M M M M μM and of 3Hetomoxir or to a concentration of or μM, only the The then for at this the to their and it is in this that they with CPT I, the mitochondria at for at in the same of and with or the was to of tissue in A for assay of CPT I. The mitochondrial to of tissue in M and in and then at for 30 at The to of in and for and of of of the was to followed by Kuwajima M. Foster D.W. McGarry J.D. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of CPT II activity mitochondria by and at not established that CPT II is for under these the of the in A of was to a concentration of and the on for 30 of CPT I and of CPT II in K.F. Kuwajima M. Foster D.W. McGarry J.D. J. Biol. Chem. Full Text PDF PubMed Google Scholar). CPT activity was at in the of (18McGarry J.D. Mills S.E. Long C.S. Foster D.W. Biochem. J. 1983; 214: 21-28Crossref PubMed Scopus (461) Google Scholar) in the of μM and the of over the period the assay only CPT I, the activity of which is by was by the of A.L. J. Biol. Chem. Full Text PDF PubMed Google Scholar). from or adult by of heart tissue and of by as (16Weis B.C. Esser V. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 18712-18715Abstract Full Text PDF PubMed Google Scholar, Biochem. PubMed Scopus Google Scholar) for the of I during as by The in A at a concentration of of of a The was then in the or of and for CPT I as for heart in and at the that of tissue under and the was in of acid. the was with and used for the of and total carnitine chain assay J.D. Foster D.W. of Scholar). have been in B.C. Esser V. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 18712-18715Abstract Full Text PDF PubMed Google Scholar, 17Weis B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google J.D. Mills S.E. Long C.S. Foster D.W. Biochem. J. 1983; 214: 21-28Crossref PubMed Scopus (461) Google and the profile of CPT I and CPT II activities in heart mitochondria from at of These in which carnitine was present at a concentration of is that the activity of CPT I in at its level the next the value by and to the By contrast, CPT II in increased throughout the of a value at that was that at The of both enzymes and activities of CPT I and CPT II be compared in since the was in the of which its kinetic The CPT II component is not The for CPT I in not the two of the enzyme, M and to be expressed in adult rat heart (16Weis B.C. Esser V. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 18712-18715Abstract Full Text PDF PubMed Google Scholar, 17Weis B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google Scholar). into the ratio of these during we made of the inhibitor, in its with both proteins and thus as a (16Weis B.C. Esser V. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 18712-18715Abstract Full Text PDF PubMed Google Scholar, 17Weis B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google Scholar). heart mitochondria from and adult to 3Hetomoxir in the of and which the to followed by As from both and M-CPT I present at of was also in tissue not The important is that the of the I compared with the M-CPT I can be to with increasing of the In to in the activities of the two CPT I isoforms, mitochondria in the or of with and a that L-CPT I while the M variant B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google Scholar). Because the Km of L-CPT I for carnitine is that of M-CPT I 500 J.D. Mills S.E. Long C.S. Foster D.W. Biochem. J. 1983; 214: 21-28Crossref PubMed Scopus (461) Google the of the is more in at low of this B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google Scholar). a concentration of μM was for the in As in while of CPT I activity in adult this value was in the of in and newborn and with The activity of CPT I isoform under these assay is in which their the first month the level of M-CPT I rises and L-CPT I the of the in the of μM results as the of of CPT I activity by at was more not on the activity of the two CPT I at and μM carnitine and on the known Km value of adult enzyme for this it is the to the into a Vmax it is that throughout the Km of enzyme The is in is that the of L-CPT I M-CPT I rises from to of during the period and falls to ∼30 of in adult animals. is by a in the contribution of L-CPT I to enzyme the value in the and to ∼2-3% in the adult heart. in the of cardiac muscle are also in the neonatal period Physiol. Rev. PubMed Scopus Google Scholar), the that the level of L-CPT I during this from to be that in from and adult The then that mitochondrial with and and for CPT I at μM In two the of of enzyme activity by the was and in and and in adult These are very to those with mitochondria from heart tissue that the ratio of to M-CPT I in the of in the cardiac In of the fact that the and of CPT I have such different for carnitine Km for S.E. Foster D.W. McGarry J.D. Biochem. J. PubMed Scopus Google it that the contribution of enzyme to the of fatty acid oxidation in the developing heart be a not only of its but also of the tissue carnitine concentration at this we both the total term not long chain These are during acid of the tissue in only a of the total carnitine and carnitine content of the heart throughout the of The for total carnitine are very to those by (19Robles-Valdes C. McGarry J.D. Foster D.W. J. Biol. Chem. 1976; 251: 6007-6012Abstract Full Text PDF PubMed Google Scholar) and the fact that this is low in the heart and rises in the A profile was with to carnitine, although at and it of the total and total carnitine increased the and adult of By the for carnitine in of tissue by of the carnitine concentration in and these with the of the of contribution of CPT I isoform to total enzyme it is the to the contribution of L-CPT I to cardiac fatty acid oxidation in the developing The are in The key is that in the newborn period the of total fatty acid the of heart mitochondria that is by L-CPT I value falls during as the expression of L-CPT I and the tissue carnitine content the of to the Km M-CPT I, which is increasing in expression over this In the adult of CPT I be to the muscle contribution of L-CPT I to CPT I in the developing rat heart. are expressed as the of CPT I estimated to L-CPT I. of is under The present was by recent observation that the adult rat heart expresses both liver and muscle of mitochondrial CPT I (16Weis B.C. Esser V. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 18712-18715Abstract Full Text PDF PubMed Google Scholar, 17Weis B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google Scholar). we have the of the cardiac CPT enzymes with on the of the two CPT I a in CPT activity in rat heart during the period B. R. J. Clin. Invest. PubMed Scopus Google Scholar, Biol. PubMed Scopus Google Scholar). at the of those the of the CPT system not as well they are and the assay not the CPT I and CPT II By the CPT in and mitochondria it is possible to this K.F. Kuwajima M. Foster D.W. McGarry J.D. J. Biol. Chem. Full Text PDF PubMed Google Scholar). this it is that while the specific activity of both CPT I and CPT II the of birth and is a greater for CPT II compared with CPT I be that the mitochondrial content of the heart is also increasing during this period Physiol. Rev. PubMed Scopus Google Scholar), which the in CPT I and CPT II when are expressed on a of tissue The of the in is the in the ratio of CPT II to CPT I when are at carnitine concentration of The of not the since the activity for CPT I represents the of two different the L and M of the two to examining the CPT I profile more by the contribution of variant to total CPT I 3Hetomoxir to both proteins, fluorographic analysis that they not of The results with adult heart (16Weis B.C. Esser V. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 18712-18715Abstract Full Text PDF PubMed Google Scholar, 17Weis B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google Scholar) that both and M-CPT I are present but that the is a very minor In contrast, the of the L-CPT I was to be in the of the activity of isoform was by the of which the liver enzyme B.C. Cowan A.T. Brown N. Foster D.W. McGarry J.D. J. Biol. Chem. 1994; 269: 26443-26448Abstract Full Text PDF PubMed Google Scholar). important it could been that the of the Vmax for total CPT I increased only and to value in the adult the Vmax of L-CPT I from the of birth to and then by a of as the in with the fluorographic to the contribution of L-CPT I to total enzyme activity in Vmax terms was as as in the falling during and to its low of ∼2-3% in the adult this in the ratio of to M-CPT I in the developing heart was to be a of the cardiac and not of some of these findings as the contribution of L-CPT I to cardiac fatty acid oxidation in the developing the be in the context of the carnitine content of the heart at of that total carnitine in rat heart are low at birth and during the period (19Robles-Valdes C. McGarry J.D. Foster D.W. J. Biol. Chem. 1976; 251: 6007-6012Abstract Full Text PDF PubMed Google Scholar). we this and it to the of the carnitine which is also to be very low at some during and by a in adult animals. the in carnitine concentration are with the ratio of to M-CPT I, it can be estimated that the contribution of L-CPT I to cardiac CPT while only ∼4% in the adult is 60% in Whereas in the adult carnitine is in liver and from from skeletal the of this for the newborn rat is the (19Robles-Valdes C. McGarry J.D. Foster D.W. J. Biol. Chem. 1976; 251: 6007-6012Abstract Full Text PDF PubMed Google Scholar). a for the expression of L-CPT I in the neonatal heart. the is in from and fatty with important for heart (19Robles-Valdes C. McGarry J.D. Foster D.W. J. Biol. Chem. 1976; 251: 6007-6012Abstract Full Text PDF PubMed Google Scholar). the M isoform of CPT I be to at this since carnitine has not in the A expression of the low Km L-CPT I a for fatty acylcarnitine the low tissue content of As and the heart carnitine the L of CPT I with concomitant increased expression of the Km M which then the for the fatty acid oxidation In we have a of the contribution of L-CPT I to cardiac fatty acid oxidation as the rat be that kinetic of the CPT I with to as well as of the the but the is The of L-CPT I in rat heart also have to the puzzling of fatty acid oxidation can in cardiac tissue the fact that its content of malonyl-CoA has been to and under (18McGarry J.D. Mills S.E. Long C.S. Foster D.W. Biochem. J. 1983; 214: 21-28Crossref PubMed Scopus (461) Google Scholar, Biochem. J. 1993; PubMed Scopus Google Scholar, G.D. Witters L.A. R. A. J. Biol. 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