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Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGMENTS
FOOTNOTES
LITERATURE CITED
ABSTRACT 
The fatty acid composition of the diet has been found to influence the activity and sensitivity of mitochondrial carnitine palmitoyltransferase I (CPT I; EC 2.3.1.21) to inhibition by malonyl CoA in rat heart and skeletal muscle. The nutritional state of rats has been shown to have less influence on the activity and metabolic control of mitochondrial CPT I in heart and skeletal muscle tissue than in the liver, a tissue in which CPT I activity and sensitivity to inhibition by malonyl CoA can be shown to be regulated acutely under different nutritional conditions. However, because manipulation of the nutritional state in these previous studies was restricted mainly to examining the effect of starvation, this study was undertaken to determine whether, as in liver, the fatty acid content and composition of the diet can regulate the activity and metabolic control of CPT I in heart and skeletal muscle. Rats were fed for up to 10 wk either a nonpurified low fat diet (30 g fat/kg) or a high fat diet (200 g fat/kg) containing one of the following five oil types: hydrogenated coconut oil (HCO), olive oil (OO), safflower oil (SO), evening primrose oil (EPO) or menhaden (fish) oil (MO). Feeding a diet enriched in MO had the most pronounced effect. Rats fed MO had a significantly greater skeletal muscle CPT I specific activity and tissue capacity, and a lower sensitivity of CPT I to malonyl CoA inhibition compared with rats fed a low fat diet, but the duration of feeding required to modulate this sensitivity was longer than that observed previously for the liver enzyme. Progressively greater sensitivity of heart CPT I to malonyl CoA occurred with feeding duration in all groups. These studies indicate that the fatty acid composition of the diet is involved in the regulation of mitochondrial CPT I activity in heart and skeletal muscle.
KEY WORDS: carnitine palmitoyltransferase I · fatty acid composition · skeletal muscle · heart · ratsINTRODUCTION
Extrahepatic tissues such as heart and skeletal muscle have high mitochondrial carnitine palmitoyltransferase I (CPT I; EC 2.3.1.21)4activity, which performs a function analogous to its role in the liver, namely, the exchange of coenzyme A for carnitine to facilitate the transfer of acyl groups into the mitochondria for 
-oxidation. The enzyme in each of these extrahepatic tissues also likely exerts control over the rate of -oxidation by virtue of its inhibition by malonyl CoA. However, the CPT I in both heart and skeletal muscle is much more sensitive to inhibition by malonyl CoA. McGarry et al. (1983)
found that the malonyl CoA concentration at which CPT I is inhibited by 50% ([I50]) is ~0.03 µmol/L in skeletal muscle, compared with a value of ~2.7 µmol/L for liver mitochondria. The [I50] for the enzyme from heart is between that of liver and skeletal muscle (0.10 µmol/L, as measured by McGarry et al. 1983).
More recent work by McGarry's group has revealed that the different sensitivities to malonyl CoA may be due to the presence of different isoforms of CPT I in these extrahepatic tissues (Weis et al. 1994). Thus, it has been shown that liver and skeletal muscle each express single, distinct forms of CPT I of ~88 and 82 kDa, respectively, whereas heart expresses both isoforms, the majority being the smaller skeletal muscle CPT I isoform, but also some (<10%) liver CPT I isoform (Weis et al. 1994).
The sensitivity of the inhibition of CPT I by malonyl CoA in the heart does not change in response to starvation (Mynatt et al. 1992), which contrasts with the increased [I50] of liver CPT I (Grantham and Zammit 1986). A decrease in the concentration of malonyl CoA in both heart and skeletal muscle has been reported during starvation (McGarry et al. 1983); this may be due to inhibition of the activity of acetyl CoA carboxylase. [Acetyl CoA carboxylase has now been identified in heart and skeletal muscle (Bianchi et al. 1990, Trumble et al. 1991).] If the CPT I of these tissues demonstrates an [I50] that is inversely related to the concentration of malonyl CoA within the intracellular milieu (Robinson and Zammit 1982), then the enzyme would be expected to become less sensitive to inhibition by malonyl CoA as the level declined during food deprivation. Decreased sensitivity to malonyl CoA due to starvation apparently does not occur in the heart (Mynatt et al. 1992) and is also unlikely to occur in the skeletal muscle, given that Veerkamp and Van Moerkerk (1982) found no differences in the ability of malonyl CoA to inhibit palmitate oxidation by rat muscle mitochondria obtained from starved and fed rats.
Comparatively little work has been conducted on the influence of lipid nutrition on the regulation of skeletal muscle CPT I, in spite of the fact that fatty acids are an important fuel for sustained muscular activity. A greater dependency on the utilization of fat as a fuel source arises both during and after depletion of carbohydrate reserves by sustained exercise (Newsholme et al. 1992). It has been recently shown that the muscles of endurance-trained athletes contain much higher total CPT activity (i.e., CPT activity per gram of muscle), and it was suggested that this may determine the rate of utilization of fatty acids available during extended bouts of exercise (Arenas et al. 1994). Elevated CPT I specific activity (i.e., CPT I activity per milligram of mitochondrial protein) has also been reported in the slow- and fast-twitch skeletal muscles and heart of rats trained by prolonged physical exercise, an enzymatic adaptation that may sustain the increased rates of fatty acid oxidation that appear in these tissues after long-term physical exercise (Guzmán and Castro 1988). The ability of elevated levels of fatty acid oxidation enzymes to enable sparing of muscle glycogen has also been outlined by Henrikkson (1992). Newsholme and Leech (1983) proposed that if the rate of fatty acid oxidation limits the provision of energy during endurance exercise, then even small increases (e.g., 5%) in the capacity of enzymes such as CPT I may be of considerable value to athletes who compete in events that require the oxidation of fat for fuel. The influence that the lipid components of the diet have on CPT I activity in the liver has been discussed elsewhere (see Power et al. 1994). However, in view of the above, an investigation of the relationship between the fatty acid content and composition of the diet and the activity of CPT I in heart and skeletal muscle would be particularly worthwhile if it enabled the identification of the components of the diet that could potentially increase the CPT I activity of these other tissues.
Some of the factors that would potentially influence CPT I activity have been studied in detail in the muscle. For instance, the malonyl CoA content of rat skeletal muscle increases with carbohydrate intake (Elayan and Winder 1991), a situation that should suppress the activity of CPT I if regulation of CPT I activity is the same as in the liver. In addition, the feeding of a high fat diet increases the total pool of long-chain acyl CoA in skeletal muscle (Chen et al. 1992), to levels that may saturate CPT I with pathway substrate. Although the feeding of high fat diets increases the activity of the -oxidation enzyme hydroxyacyl CoA dehydrogenase in skeletal muscle (Fisher et al. 1983), the specific effect on CPT I in this tissue is unknown. The recent finding that total CPT activity is higher in the muscle of rats fed high vs. low fat (nonpurified) diets (Cheng et al. 1994), suggests that the total CPT enzyme activity in muscle is regulated to some extent by the fat content of the diet. In that study, however, no attempt was made to discriminate between the activities of CPT I and II. The influence of the fatty acid composition of the diet on CPT I in muscle also remains to be established.
In view of the previous inability to observe changes in the sensitivity of heart and skeletal muscle CPT I to malonyl CoA after starvation, the malonyl CoA content of these tissues may not impose an "inherent" change in susceptibility to inhibition to the same extent as in the liver (see Zammit 1994 for a discussion of this phenomenon). However, because turnover of the fatty acids of the phospholipids of rat skeletal muscle can occur within a few days of feeding lipid-modified diets (Ayre and Hulbert 1996), changes to the physical characteristics of the outer mitochondrial membrane by dietary manipulation may still be a plausible mechanism for imposing a change in the conformation of CPT I that would result in different sensitivity to inhibition by malonyl CoA.
This research was undertaken to examine the influence of the fatty acid composition of the diet on the activity of heart and skeletal muscle CPT I and to establish whether the sensitivity to inhibition by malonyl CoA of the CPT I of these tissues can be modulated by feeding lipid-modified diets. The results indicate that the fatty acid composition of the diet can markedly affect both the malonyl CoA sensitivity of CPT I and also the CPT I activity in each of these extrahepatic tissues.
MATERIALS AND METHODS
Table 1.
The compositions and energy densities of the experimental diets1
Table 2.
The fatty acid composition of the experimental diets1,2
), are given in Table 2. The weight gain and food intake of all rats were monitored throughout the experimental period (see Yaqoob et al. 1995). For samples of heart, groups of 12-18 rats were provided with each diet, and 4-6 animals removed at random after 2, 4 or 10 wk of consuming the modified diets; for skeletal muscle, tissue was taken only from rats fed for 4 and 10 wk. Rats were housed under temperature-controlled conditions with a 12-h light:dark cycle and given unlimited access to food and water. Rats were killed by CO2 asphyxiation.
). Palmitoyl CoA and all other biochemicals were purchased from Sigma Chemical (St. Louis, MO), and the sucrose and butanol were supplied by BDH Chemicals (Poole, UK).
Preparation of mitochondria.
Heart mitochondria were prepared by the method of McGarry et al. (1983) by isolating them from the low speed nuclear pellet, rather than from the low speed supernatant as is the case for preparing liver mitochondria. Weis et al. (1994) have recently indicated that the above method yields heart mitochondria with only minimal contamination from other subcellular organelles. Briefly, hearts were excised and rinsed free of blood in 10 volumes of an isolation medium containing 225 mmol/L mannitol, 75 mmol/L sucrose, 10 mmol/L Tris-HCl (pH 7.4 at 0°C) and 1 mmol/L EGTA, trimmed of atria and adipose tissue, then minced with scissors. The isolation medium was decanted, and the tissue was resuspended in 20 volumes of fresh medium and homogenized with a Kinematica Polytron (Kinematica, Luzern, Switzerland; 10 s at setting 6). The resulting homogenate was centrifuged at 1000 × g for 15 min. The supernatant thus produced was used as the source for mitochondria, and these were pelleted by centrifugation at 15,000 × g for 15 min. The pellet was finally resuspended in 1.0-2.0 mL of a mannitol-free medium containing 150 mmol/L KCl, 5 mmol/L Tris-HCl and 1 mmol/L EGTA (pH 7.4 at 0°C) at a concentration of ~20 g mitochondrial protein/L. The mitochondrial yield from heart tissue was lower (~30% as estimated from the cytochrome oxidase activity recovery; results not shown) with the use of this method compared with other methods such as the protease treatment procedure of Idell-Wegner et al. (1982). Minimizing the effect of the isolation method on the malonyl CoA sensitivity was especially important in this investigation. Because Kashfi and Cook (1992) found that proteases differentially affected the inhibition of CPT I by malonyl CoA, the protease treatments prescribed by Idell-Wegner et al. (1982) were avoided. The protein content was determined by the biuret method of Gornall et al. (1949) by using bovine serum albumin (BSA) as a standard, with the modification that all mitochondria were preincubated for 30 min with 2.0 mol/L NaOH to ensure complete solubilization of protein before assay.
with some modifications. Hind leg muscle (soleus) was dissected, and excess fat and connective tissue discarded. The muscle (~3.0-5.0 g) was weighed and placed immediately in ice-cold medium containing 120 mmol/L KCl, 5 mmol/L tris-HCl and 1 mmol/L EGTA, pH 7.4, at 0°C. The muscle was then chopped finely with scissors, rinsed twice in ~30 mL of the same medium, then homogenized by a Kinematica Polytron (10 s at setting 6) in 10 volumes of medium. The homogenate was centrifuged at 600 × g for 10 min to remove cellular debris. The supernatant was filtered through two layers of gauze, then centrifuged at 17,000 × g for 10 min in a Sorvall RC5B centrifuge (Dupont, Wilmington, DE) fitted with an SS34 rotor. The pellet was resuspended in 10 volumes of the isolation medium and recentrifuged at 7000 × g for 10 min. The resultant pellet was then resuspended in 0.5-1.0 mL of isolation medium to give a final protein concentration of 10-20 mg/mL. The mean mitochondrial recovery per gram of tissue was ~22%, on the basis of the cytochrome oxidase content of the whole homogenate as measured by the method of Darley-Usmar (1987) (results not shown). The protein concentration of the final resuspension was determined as described above for heart mitochondria.
, Saddick et al. 1993). The mitochondria were added to an aliquot of this incubation medium and preincubated for 6 min at 37°C. In the assays in which malonyl CoA sensitivity was assessed, the concentration of defatted BSA was raised to 10 g/L to provide conditions under which the sensitivity of CPT I to inhibition by malonyl CoA was low, thereby allowing relatively high concentrations of malonyl CoA to be used. This may minimize the influence on the kinetic data of the loss of malonyl CoA through the activity of mitochondrial deacylase (Grantham and Zammit 1988). High albumin concentrations may also stabilize the outer mitochondrial membrane by reducing the detergent-like properties of palmitoyl CoA, thus minimizing the contribution of CPT II to the assay (Harano et al. 1972). In these particular assays, malonyl CoA was added to the incubation mixture in varying volumes to achieve the final concentrations shown in Figures 1 and 2. The mitochondria were preincubated with or without malonyl CoA for 2 min before the initiation of the reaction with a 0.050-mL aliquot of L-carnitine (0.5 µmol/L) containing 18.5 GBq/mol [3H]-carnitine. The reactions were terminated after 6 min by the addition of a 0.3-mL aliquot of 6.0 mol/L HCl, and the product (palmitoyl-[3H]-carnitine) was extracted and counted as described previously (Power et al. 1994).
) were routinely evident in the mitochondrial preparations of this study, suggesting minimal cross-contamination from peroxisomes. The inhibition of CPT I by malonyl CoA is given as the activity of the enzyme in the presence of a given concentration of malonyl CoA divided by that obtained in the absence of exogenous malonyl CoA (i.e., the "control" activity) and expressed as a percentage (Zammit 1984). The control activity in the absence of malonyl CoA is thus 100% in each of the inhibition sensitivity assays, and under the higher albumin assay conditions used to assess malonyl CoA sensitivity, the uninhibited control activity was usually substantially lower (i.e., ~50%) than that observed when the enzyme was assayed under conditions that yielded maximal activity (i.e., at 1.3 g/L defatted BSA).
) was used to test differences among the different groups of rats, with P < 0.05 taken to indicate significant differences.
RESULTS
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Table 3. The influence of feeding duration and dietary oil type on the specific activity of heart and skeletal muscle mitochondrial carnitine palmitoyltransferase I (CPTI) in rats1 |
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Table 4. The influence of feeding duration and dietary oil type on the heart and skeletal muscle mitochondrial carnitine palmitoyltransferase I (CPTI) tissue capacity of rats1 |
). Briefly, we found ranges of [I50] from 0.010-0.022 µmol/L for skeletal muscle CPT I and from 0.020-0.101 µmol/L for heart CPT I (Table 5), which are similar to those reported by others using similar techniques (see e.g., Weis et al. 1994).
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Table 5. The influence of dietary oil type and feeding duration on the sensitivity of heart and skeletal muscle mitochondrial carnitine palmitoyltransferase I (CPTI) to inhibition by malonyl CoA ([I50])1 |
DISCUSSION
-oxidation (and thus higher CPT I activity) may occur because there is less risk of losing too much linoleic acid through catabolism and developing essential fatty acid deficiency as a result. A case for the "sparing" from oxidation of linoleic acid has recently been proposed from observations of the kinetic behavior of the hepatic CPT I of rats fed diets containing different fatty acid compositions (Power et al. 1997).
. Because it has been demonstrated that the feeding of high fat diets to rats (Thumelin et al. 1994) and the presence of long-chain fatty acids in rat hepatocyte cultures (Chatelain et al. 1996) increase the concentration of CPT I mRNA, it is possible that the increased enzyme activity seen in this investigation may have been due to an enhancement of CPT I gene expression. Alternatively, these changes could have been due either to an influence of some of the dietary fatty acids on the composition of the mitochondrial outer membrane lipids that are associated with CPT I (see Zammit 1994) or to an effect on enzyme degradation.
, Mynatt et al. 1992, Paulson et al. 1984) and skeletal muscle (Veerkamp and Van Moerkerk 1982). This study demonstrates, for the first time, that "qualitative" changes to the dietary lipid components can markedly affect the sensitivity of CPT I in extrahepatic tissues.
) and the extent of unsaturation of the fatty acids of membrane phospholipids (Power et al. 1994), appears to correlate positively with the activity of CPT I in the liver (see Kolodziej and Zammit 1990). Thus, the highly unsaturated fatty acid diets that led to greater CPT I activity in this investigation (SO, EPO and MO) may have increased the fluidity of the mitochondrial outer membranes. An elevated concentration of docosahexaenoic acid [22:6(n-3)] in mitochondrial outer membranes (Niot et al. 1994) and whole mitochondria (Power et al. 1994) after the feeding of a fish oil-containing diet has previously been observed to correlate with increased CPT I activity and decreased sensitivity to malonyl CoA relative to the activities of rats fed diets containing higher (n-6)/(n-3) ratios.
suggests that although the total levels of malonyl CoA in the heart are similar to those occurring in the liver (i.e., at least 5 µmol/L), the amount of malonyl CoA that is accessible to CPT I may be much lower because fatty acid oxidation continues to occur in the heart when the in vivo concentrations of malonyl CoA would otherwise predict almost complete abolition of flux through CPT I. McMillin et al. (1994) recently suggested that this is related to the fact that fatty acids are an important source of energy for the heart and must therefore be continually oxidized, even at the maximal concentrations of malonyl CoA that prevail in the heart. In related work, Awan and Saggerson (1993) proposed that the malonyl CoA within cardiac myocytes may be bound by the enzyme of a fatty acid elongation system that incorporates malonyl CoA into fatty acids. Substantial "elongation activity" was detected by these authors in a particulate fraction isolated from whole-heart homogenate. Because the Km of this enzyme for malonyl CoA was estimated to be 50 µmol/L, it was suggested that the capacity of this enzyme to bind malonyl CoA and act as a "sink" for this metabolite would be significant, thus presumably reducing the "free" concentration able to interact with CPT I. However, it should be noted that because of the extreme sensitivity of CPT I in heart tissue, a small proportional change in the amount of malonyl CoA that can access the enzyme may markedly affect the activity of CPT I. Thus, the extent to which the comparatively lower sensitivity of CPT I of MO-fed rats that was observed in this investigation would lead to increased flux through CPT I in vivo is difficult to estimate, due to the potentially greater influence that a change in the content of malonyl CoA that is accessible to the enzyme in the heart may have on the enzymes' activity in this tissue. In the absence of a clearer understanding of how malonyl CoA is sequestered within the heart, the potential that this nutritional adaptation offers to enhanced flux through CPT I is open to question and is thus the subject of ongoing research.
), suggests that if the expression of this form of the enzyme increased even slightly, it would greatly affect the overall sensitivity to malonyl CoA of the total heart mitochondrial CPT I. It would therefore be of interest to examine the relative proportion of each of these CPT I isoforms after feeding lipid-modified diets to determine whether different amounts of either isoform could influence overall sensitivity and account for the changes observed in this study. The age-related increase in the malonyl CoA sensitivity seen in hearts from the majority of rats in this investigation supports the recent report of McGarry (1995) that the contribution of the liver isoform is higher in newborn rats than in adults. If a progressive decline in abundance of the liver isoform occurs with age, a commensurate increase in the sensitivity of the total heart CPT I population would be expected.
could not detect any change in the sensitivity of fatty acid oxidation to malonyl CoA after rats were starved for periods of either 18 or 48 h. Skeletal muscle mitochondria may require longer periods for changes in lipid composition before this property influences the malonyl CoA sensitivity of CPT I, although no fatty acid analyses were conducted on skeletal muscle mitochondria in this investigation. Other work from this laboratory, however, found that the content of docosahexaenoic acid, a main constituent of MO, was severalfold higher in the soleus muscle phospholipids of rats fed MO, relative to the other diets used in this study, when the feeding duration was extended to 10 wk (E. Sherrington, personal communication). If the (n-3) fatty acids are involved in mediating changes to the major structural phospholipids or any other components that determine the conformation of the mitochondrial outer membrane (e.g., cholesterol esters), the slow progress of the transition of CPT I to a conformation that transmits the malonyl CoA effect less readily may be related to the longer term required for acyl substitution. In this connection, it may be relevant that Berger et al. (1992) found that docosahexaenoic acid appears to be selectively taken up from the plasma by heart and incorporated into mitochondrial phospholipids to a greater extent than in the liver, although the situation in skeletal muscle mitochondria remains to be resolved. Previous work from this laboratory implicated substitution of linoleic and arachidonic acids with (n-3) polyunsaturated fatty acids as being responsible for the decreases in sensitivity to malonyl CoA seen in liver mitochondrial CPT I after consumption of a MO diet similar to that used in this investigation (Power et al. 1994).
ACKNOWLEDGMENTS
FOOTNOTES
Manuscript received 17 July 1996. Initial reviews completed 6 September 1996. Revision accepted 18 June 1997.
LITERATURE CITED
-oxidation.
Biochem. J.
1988;
253:541-547
[Medline]
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