Free Carnitine Concentrations Research Articles

Determination of Carnitine Ester Patterns During the Second Half of Pregnancy, at Delivery, and in Neonatal Cord Blood by Tandem Mass Spectrometry: Complex and Dynamic Involvement of Carnitine in the Intermediary Metabolism

We studied plasma concentrations of free carnitine and 30 carnitine esters by electron spray ionization (ESI) tandem mass spectrometry in 37 pregnant women at the 20th and 30th weeks of gestation and at delivery, and in their neonates at birth, and in 22 age-matched nonpregnant women. The plasma levels of acetylcarnitine and carnitine esters with more than five carbons were significantly higher, whereas the concentration of free carnitine was significantly lower at term than at the 20th week of pregnancy (16.75 +/- 0.89 versus 19.61 +/- 1.25). Almost all of C2- to C12-carnitine esters were significantly lower, whereas C16- and C18-carnitines with in-chain modifications were significantly higher in mothers at delivery compared with nonpregnant women. Plasma levels of free carnitine and C2-, C3-, C4-, C5-, C6-, and C16-carnitines were significantly lower, while concentrations of carnitine esters with 8, 10, 12 and 18 carbons in the acyl chain as well as C14:1-, C14:2-, and C16:1-OH-carnitines were significantly higher in mothers at term than in their neonates. The data of the present study clearly show dynamic features of plasma carnitine profile during pregnancy and indicate an extraordinarily active participation of the carnitine in the intermediary metabolism both in the pregnant woman and in the neonate.

Equine biochemical multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of rhabdomyolysis

Two horses (a 7-year-old Groninger warmblood gelding and a six-month-old Trakehner mare) with pathologically confirmed rhabdomyolysis were diagnosed as suffering from multiple acyl-CoA dehydrogenase deficiency (MADD). This disorder has not been recognised in animals before. Clinical signs of both horses were a stiff, insecure gait, myoglobinuria, and finally recumbency. Urine, plasma, and muscle tissues were investigated. Analysis of plasma showed hyperglycemia, lactic acidemia, increased activity of muscle enzymes (ASAT, LDH, CK), and impaired kidney function (increased urea and creatinine). The most remarkable findings of organic acids in urine of both horses were increased lactic acid, ethylmalonic acid (EMA), 2-methylsuccinic acid, butyrylglycine (iso)valerylglycine, and hexanoylglycine. EMA was also increased in plasma of both animals. Furthermore, the profile of acylcarnitines in plasma from both animals showed a substantial elevation of C4-, C5-, C6-, C8-, and C5-DC-carnitine. Concentrations of acylcarnitines in urine of both animals revealed increased excretions of C2-, C3-, C4-, C5-, C6-, C5-OH-, C8-, C10:1-, C10-, and C5-DC-carnitine. In addition, concentrations of free carnitine were also increased. Quantitative biochemical measurement of enzyme activities in muscle tissue showed deficiencies of short-chain acyl-CoA dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and isovaleryl-CoA dehydrogenase (IVD) also indicating MADD. Histology revealed extensive rhabdomyolysis with microvesicular lipidosis predominantly in type 1 muscle fibers and mitochondrial damage. However, the ETF and ETF-QO activities were within normal limits indicating the metabolic disorder to be acquired rather than inherited. To our knowledge, these are the first cases of biochemical MADD reported in equine medicine.

Effect of l-Carnitine Infusion and Feed Restriction on Carnitine Status in Lactating Holstein Cows

Previously we determined that abomasal infusion of l-carnitine increased in vitro hepatic fatty acid oxidation, decreased liver lipid accumulation, and supported higher fat-corrected milk yield in feed-restricted lactating cows. The objectives of this study were to examine the effects of supplemental l-carni-tine and amount of feed intake on free carnitine and carnitine ester concentrations in liver, muscle, milk, and plasma of lactating dairy cows. Eight lactating Holstein cows (132±36 d in milk) were used in a replicated 4×4 Latin square design with 14-d periods to test factorial combinations of water or l-carnitine infusion (20g/d; d 5 to 14) and ad libitum or restricted (50% of previous 5-d intake; d 10 to 14) dry matter intake. Plasma was obtained 3 times daily on d 4, 8, and 12; milk samples were collected on d 8, 9, 13, and 14. Liver and muscle were biopsied on d 14 of each period. Free carnitine, short-chain acylcarnitine, and long-chain acylcarnitine concentrations were determined using a radioenzymatic assay coupled with ion exchange chromatography. Abomasal l-carnitine infusion increased total carnitine in plasma on d 8 and d 12. All liver carnitine fractions were increased by carnitine infusion. Feed restriction elevated concentrations of free carnitine, long-chain acylcarnitine, and total carnitine in liver tissue from carnitine-infused cows but not in those infused with water. In muscle, acid-soluble carnitine, long-chain acylcarnitine, and total carnitine concentrations were increased by carnitine infusion and feed restriction without significant interaction. Feed restriction increased free carnitine concentrations in muscle from water-infused cows but not in carnitine-infused cows. Carnitine infusion increased the concentration of each milk carnitine fraction as well as milk carnitine output on d 8 to 9. On d 13 to 14, all carnitine fractions except short-chain acylcarnitine were increased in milk from water-infused, feed-restricted cows, whereas all fractions were increased in carnitine-infused, feed-restricted cows. Carnitine infusion increased total carnitine in plasma, liver, muscle, and milk during feed restriction, whereas feed restriction alone increased carnitine concentrations in muscle and milk but not in liver. Liver carnitine concentrations might limit hepatic fatty acid oxidation capacity in dairy cows during the periparturient period; therefore, supplemental l-carnitine might decrease liver lipid accumulation in periparturient cows.

Long-Term Stability of Amino Acids and Acylcarnitines in Dried Blood Spots

Dried blood filter cards, collected for newborn screening, are often stored for long periods of time. They may be suitable for the retrospective diagnosis of inborn errors of metabolism, but no data are currently available on the long-term stability of amino acids and acylcarnitine species. We analyzed amino acids and acylcarnitines by tandem mass spectrometry in 660 anonymous, randomly selected filter cards from 1989 through 2004. We assessed long-term stability of metabolites by linear regression and estimated annual decrease of concentration for each metabolite. Concentrations of free carnitine increased by 7.6% per year during the first 5 years of storage and decreased by 1.4% per year thereafter. Alanine, arginine, leucine, methionine, and phenylalanine decreased by 6.5%, 3.3%, 3.1%, 7.3%, and 5.7% per year, respectively. Acetylcarnitine, propionylcarnitine, citrulline, glycine, and ornithine decreased by 18.5%, 27.4%, 8.1%, 14.7%, and 16.3% per year during the first 5 years, respectively; thereafter the decline was more gradual. Tyrosine decreased by 1.7% per year during the first 5 years and 7.9% per year thereafter. We could not analyze medium- and long-chain acylcarnitine species because of low physiological concentrations. Estimation of the annual decrease of metabolites may allow for the retrospective diagnosis of inborn errors of metabolism in filter cards that have been stored for long periods of time.

Ontogeny of Carnitine Palmitoyltransferase I Activity, Carnitine-Km, and mRNA Abundance in Pigs throughout Growth and Development 2

Carnitine palmitoyltransferase (CPT) I catalyzes an important regulatory step in lipid metabolism; however, no studies, to our knowledge, have evaluated the molecular and kinetic [maximal velocity and Michaelis constant (Km) for carnitine] ontogeny of CPT I and prevailing tissue concentrations of carnitine in pigs. To this end, hepatic and skeletal muscle tissues were examined at various ages: birth; 24 h; 1, 3, 5, and 8 wk of age; and adult. Hepatic and skeletal muscle CPT I specific activities were low at birth and increased 100 and 70%, respectively, during the first week of life (P < 0.05). Skeletal muscle transcript amounts were 2.7-fold greater (P < 0.001) in 24-h-old pigs relative to newborns, whereas hepatic CPT I mRNA remained constant at each age studied. The apparent Km for carnitine decreased 48% (P < 0.05) during the initial 3 wk of life in liver and decreased 40% (P < 0.05) during the first week of life in skeletal muscle. Plasma and liver free carnitine concentrations increased 95 and 62%, respectively, within 24 h after birth (P < 0.05) and hepatic carnitine concentrations remained constant through 5 wk of age. Consequently, hepatic carnitine concentrations were 20–80% greater (P < 0.05) than the Km for carnitine during the suckling period. Skeletal muscle carnitine met or exceeded the apparent Km for carnitine at each stage of development. Collectively, these findings suggest that postnatal increases in CPT I activity during the suckling period are accompanied by increased tissue carnitine; however, the lack of hepatic CPT I mRNA induction and low activity reported in both tissues prior to 1 wk of age may limit postnatal lipid utilization during the piglet’s transition to extra-uterine life.

Effects of γ-butyrobetaine and l-carnitine on carnitine concentrations in various muscle tissues of finishing pigs (2007)

The primary method of L-carnitine production, similar to the biological process that occurs in the liver and kidneys, is from microbial fermentation of γ-Butyrobetaine. Therefore, the objective of this study was to see if supplementing the diet with γ-Butyrobetaine would increase organ and muscle tissue carnitine concentrations. One-hundred-twenty-five barrows were fed diets containing either L-carnitine (100 ppm), γ-Butyrobetaine (100 ppm) or a combination of L-carnitine (50 ppm) and γ-Butyrobetaine (50 ppm). The addition of L-carnitine, γ-Butyrobetaine and the combination of L-carnitine and γ-Butyrobetaine increased (P<0.01) free carnitine concentration in the longissimus, diaphragm, and heart. L-carnitine and the combination of L-carnitine and γ-Butyrobetaine increased (P<0.01) free carnitine concentration in the kidney. Therefore, these results suggest that γ-Butyrobetaine and/or L-carnitine can be used to increase carnitine concentrations of organ and muscle tissues.; Swine Day, 2007, Kansas State University, Manhattan, KS, 2007

Combined therapy with L-carnitine and erythropoietin of anemia in chronic kidney failure patients undergoing hemodialysis

The aim of this study was to analyze the influence of combined therapy with L-carnitine and erythropoietin on selected blood morphology parameters in patients treated with hemodialysis and to assess whether combined therapy could decrease the requirement for exogenous erythropoietin. The results of anemia treatment were compared in three groups of patients: 27 patients treated with L-carnitine and erythropoietin, 15 patients treated with erythropoietin and 9 patients treated only with L-carnitine. The patients were treated for 6 months. L-carnitine was given orally at a dose of 4 x 250 mg daily. Erythropoietin was administered intravenously after each hemodialysis session and the mean dose of erythropoietin at the beginning of observation was 5642 +/- 2134 units/week. Before treatment serum concentrations of free and total carnitine, parathormone (PTH), aluminium, lead were determined and basic laboratory examinations were performed. The blood morphology was evaluated once a month. Combined therapy resulted in the improvement of blood morphology parameters (hemoglobin [Hb] before treatment 9.9 +/-1.4 g/dl, during treatment 10.7 +/- 1.6 g/dl), compared to treatment with erythropoietin (Hb before treatment 9.5 +/- 1.2 g/dl, during treatment 9.9 +/- 1.4 g/dl) or L-carnitine alone (Hb before treatment 11.3 +/- 1.0 g/dl, during treatment 12.0 +/- 1.1 g/dl). Combined therapy was associated with the reduction of erythropoietin dosage during treatment from 6287 +/- 1987 units/week to 2286 +/- 1684 units/week. The correlation between serum carnitine concentration and erythrocyte osmotic resistance indicates indirectly the beneficial effect of L-carnitine administration on erythrocyte cell membrane stabilization.

Mass Spectrometric Quantifications Of Organic Acids And Acylcarnitines In Early Random Urine Specimens Of Newborns With Perinatal Complications: Feasibility Study For The Prediction Of The Neuro¬developmental Outcome

Aim: The availability of indicators for neurodevelopmental outcome of newborns with perinatal complications is limited. This study advances previous biochemical findings in biological fluids during complicated adaptation of newborns with techniques of mass spectrometry. Patients and Methods: Reference concentrations of organic acids, free carnitine and acylcarnitines were determined in urinary specimens of 71 newborns. The study cohort included 114 newborns with neonatal complications. For mass spectrometric investigations random urine samples were collected within 72 hours after birth. Data were correlated with the neurodevelopmental outcome at the end of the first year. Results: A diagnostic sensitivity of 93 % and a diagnostic specificity of 99 % were obtained for the prediction of the neurodevelopment of newborns using the metabolic pattern screening. Conclusion: Quantitative multiparametric profiling of metabolites in urine specimens of neonates are useful supplements of clinical findings for the prediction of the neurological outcome at the end of the first year of life.

Mildronate, an Inhibitor of Carnitine Biosynthesis, Induces an Increase in Gamma-Butyrobetaine Contents and Cardioprotection in Isolated Rat Heart Infarction

The inhibition of gamma-butyrobetaine (GBB) hydroxylase, a key enzyme in the biosynthesis of carnitine, contributes to lay ground for the cardioprotective mechanism of action of mildronate. By inhibiting the biosynthesis of carnitine, mildronate is supposed to induce the accumulation of GBB, a substrate of GBB hydroxylase. This study describes the changes in content of carnitine and GBB in rat plasma and heart tissues during long-term (28 days) treatment of mildronate [i.p. (intraperitoneal) 100 mg/kg/daily]. Obtained data show that in concert with a decrease in carnitine concentration, the administration of mildronate caused a significant increase in GBB concentration. We detected about a 5-fold increase in GBB contents in the plasma and brain and a 7-fold increase in the heart. In addition, we tested the cardioprotective effect of mildronate in isolated rat heart infarction model after 3, 7, and 14 days of administration. We found a statistically significant decrease in necrotic area of infarcted rat hearts after 14 days of treatment with mildronate. The cardioprotective effect of mildronate correlated with an increase in GBB contents. In conclusion, our study, for the first time, provides experimental evidence that the long-term administration of mildronate not only decreases free carnitine concentration, but also causes a significant increase in GBB concentration, which correlates with the cardioprotection of mildronate.

Short-term effects of nocturnal haemodialysis on carnitine metabolism

Functional carnitine deficiency [as indicated by an abnormal acyl-carnitine/free-carnitine (AC:FC) ratio] is commonly seen in patients with end-stage renal disease (ESRD), resulting in significant clinical detriments including anaemia, cardiomyopathy and muscle weakness. Nocturnal haemodialysis (NHD) (5-6 sessions per week, 8 h per treatment) has been reported to reverse several surrogate markers of uraemia. Conversely, as a consequence of increased dialysis dose, NHD may have the potential to aggravate plasma nutrient deficiencies. Our objective was to determine the effects of NHD on plasma free-carnitine levels and carnitine metabolism. We conducted an observational cohort study with a before and after design. Nine ESRD patients (age: 47 +/- 3; mean +/- SEM) were studied. Routine biochemical, haemodynamic and carnitine metabolic products were analysed at baseline while on conventional haemodialysis and 2 months post-conversion to NHD. Free-carnitine and total-carnitine levels were generated by colorimetric assays. The difference between total- and free-carnitine concentrations was estimated to be the acyl-carnitine level. Paired t-test was used to ascertain statistical significance. After conversion to NHD, there was a significant increase in urea clearance in all patients. Plasma free-carnitine levels fell from 26.54 +/- 2.99 to 15.6 +/- 2.34 micromol/l (P < 000.1). A similar reduction in plasma acyl-carnitine levels was observed (from 13.22 +/- 1.34 to 6.24 +/- 1.20 micromol/l (P < 0.001)). The AC:FC ratio improved from 0.51 +/- 0.03 to 0.39 +/- 0.03 (P < 0.005) (Normal < 0.25). NHD is associated with an improvement in AC:FC ratio. Further research is needed to examine the longitudinal clinical impact of this metabolic correction and to examine whether this effect is sustained.

Carnitine Deficiency, Mitochondrial Metabolism, and Abnormal Response to Anesthetics

Jikei University, School of Medicine, Tokyo, Japan. uezono@jikei.ac.jpI appreciate Drs. Weinberg and Baughman for their interest in our Letter to the Editor.1They call attention to an underlying carnitine deficiency associated with an increased risk of unexpected metabolic acidosis and cardiovascular collapse triggered by drugs that may potentially induce mitochondrial dysfunction. Acquired carnitine deficiency may be caused by cirrhosis, chronic renal failure, malabsorption syndrome, renal tubular acidosis, and certain drugs that are conjugated carnitine (e.g. , valproate, zidovudine), which are not uncommon in the intensive care unit setting.2Of particular note, patients receiving valproate may develop low concentrations of free carnitine in plasma, thus rendering them at risk for development of mitochondrial β-oxidation defects when propofol is used for sedation. This may partly explain why many case reports of so-called propofol infusion syndrome have been reported from patients in the neurosurgical intensive care unit but not the general surgical intensive care unit.3If this is the case, I suspect that l-carnitine therapy may reverse clinical manifestations of propofol infusion syndrome.Jikei University, School of Medicine, Tokyo, Japan. uezono@jikei.ac.jp

Metabolic effects of intravenous LCT or MCT/LCT lipid emulsions in preterm infants

Most lipid emulsions for parenteral feeding of premature infants are based on long-chain triacylglycerols (LCTs), but inclusion of medium-chain triacylglycerols (MCTs) might provide a more readily oxidizable energy source. The influence of these emulsions on fatty acid composition and metabolism was studied in 12 premature neonates, who were randomly assigned to an LCT emulsion (control) or an emulsion with a mixture of MCT and LCT (1:1). On study day 7, all infants received [13C]linoleic (LA) and [13C]alpha-linolenic acid (ALA) tracers orally. Plasma phospholipid (PL) and triacylglycerol (TG) fatty acid composition and 13C enrichments of plasma PL fatty acids were determined on day 8. After 8 days of lipid infusion, plasma TGs in the MCT/LCT group had higher contents of C8:0 (0.50 +/- 0.60% vs. 0.10 +/- 0.12%; means +/- SD) and C10:0 (0.66 +/- 0.51% vs. 0.15 +/- 0.17%) than controls. LA content of plasma PLs was slightly lower in the MCT/LCT group (16.47 +/- 1.16% vs. 18.57 +/- 2.09%), whereas long-chain polyunsaturated derivatives (LC-PUFAs) of LA and ALA tended to be higher. The tracer distributions between precursors and products (LC-PUFAs) were not significantly different between groups. Both lipid emulsions achieve similar plasma essential fatty acid (EFA) contents and similar proportional conversion of EFAs to LC-PUFAs. The MCT/LCT emulsion seems to protect EFAs and LC-PUFAs from beta-oxidation.

Carnitine Treatment Improved Quality‐of‐Life Measure in a Sample of Midwestern Hemodialysis Patients

Previously, we demonstrated that selected groups of hemodialysis patients might be more likely to have abnormalities of carnitine metabolism. The purpose of the present study was to examine the effects of carnitine therapy in these selected groups of hemodialysis patients on quality-of-life measures and erythropoietin dose. This was a double-blind, randomized, controlled trial, in which 50 hemodialysis patients were treated with either 2 g i.v. carnitine or placebo. The treatment period was for 24 weeks. Thirty-four patients (15 in the treatment group) completed the study. The mean age was 69 +/- 15 years, 35% were women, and 44% had diabetes. Mean initial plasma total, free, short-chain acyl and long-chain acyl carnitine concentrations (micromol/L; mean +/- SEM) were 35.9 +/- 1.8, 18.2 +/- 1.1, 11.6 +/- 0.6, and 6.0 +/- 0.3, whereas the plasma acyl-to-free-carnitine ratio was 1.02 +/- 0.05. With respect to the Medical Outcomes Short Form-36 (SF-36), improvements from baseline were noted in the treatment group (n = 13) for role-physical (33.9 +/- 1.9 to 43.2 +/- 3.0, p < .05) and the SF-36 physical component summary score (36.1 +/- 2.7 to 39.7 +/- 2.3, p = .09) relative to changes in the control group (n = 14). The erythropoietin dose over the 24-week period was reduced from baseline in the treatment group relative to the placebo group (-1.62 +/- 0.91 vs 1.33 +/- 0.79 units erythropoietin/dry weight/hemoglobin concentration, respectively, p < .05). After 24 weeks of i.v. carnitine therapy, SF-36 scores were improved and erythropoietin doses were reduced in hemodialysis patients, relative to the control group.

Determination of total and free plasma carnitine concentrations on the Dade Behring Dimension RxL: Integrated chemistry system

Background l-Carnitine is a naturally occurring quaternary ammonium compound present in all mammalian species. Its major function is to facilitate the passage of long-chain fatty acids through the mitochondrial membrane for subsequent β-oxidation and ketone synthesis. Clinical interest in carnitine disorders relates particularly to possible deficiency states that may result in a phenotypic spectrum that includes cardiomyopathy, skeletal myopathy, hypoglycemia and hyperammonemia. The objective of this study was to develop a method on the Dade Behring Dimension RxL analyzer for measuring free and total carnitine levels in plasma. Methods Plasma samples were deproteinized by ultrafiltration to remove interference by endogenous thiols. Filtrates were measured directly on the RxL for free carnitine or after alkaline hydrolysis for total carnitine by an endpoint enzymatic assay that uses carnitine acetyltransferase. Results Within-run imprecision was < 5% at high and low levels for both free and total carnitine while between-day imprecision was < 15%. Recovery of free carnitine from spiked plasma > 90%. The method was linear between 5.0 and 150.0 μmol/l and the limit of quantification was 5.0 μmol/l. Comparison of our method with another automated procedure developed on the Hitachi 917 system using Deming regression analysis resulted in the following equations: Dimension = 1.034(Hitachi) − 7.44 for total carnitine ( r = 0.955) and Dimension = 0.805(Hitachi) + 1.96 for free carnitine ( r = 0.951), respectively. Conclusions Our method is suitable for analyzer platforms where the level of imprecision is lower and the throughput is higher than manual methods. It also avoids the use of radioisotopes and is appropriate in labs where access to reference methods such as tandem mass spectrometry and HPLC is limited or unavailable.

Plasma and urinary carnitine and acylcarnitines in chronic fatigue syndrome

Contradictory reports have suggested that serum free carnitine and acylcarnitine concentrations are decreased in patients with chronic fatigue syndrome (CFS) and that this is a cause of the muscle fatigue observed in these patients. Others have shown normal serum free carnitine and acylcarnitines in similar patients. We report here studies on free, total and esterified (acyl) carnitines in urine and blood plasma from UK patients with CFS and three control groups. Plasma and timed urine samples were obtained from 31 patients with CFS, 31 healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Samples were analysed using an established radioenzymatic procedure for total, free and esterified (acyl) carnitine. There were no significant differences in plasma or urinary total, free or esterified (acyl) carnitine between UK patients with CFS and the control groups or in renal excretion rates of these compounds. The data presented here show that, in the CFS patients studied, there are no significant abnormalities of free or esterified (acyl) carnitine. It is thus unlikely that abnormalities in carnitine homeostasis have any significant role in the aetiology of their chronic fatigue.

Age-Related Variations in Acylcarnitine and Free Carnitine Concentrations Measured by Tandem Mass Spectrometry

The acylcarnitine profiles obtained from dried blood spots on "Guthrie cards" have been widely used for the diagnosis and follow-up of children suspected of carrying an inherited error of metabolism, but little attention has been paid to potential age-related variations in the reference values. In this study, we evaluated the variations in free carnitine and acylcarnitine concentrations with age, as measured by tandem mass spectrometry. Filter-paper blood spots were collected from 433 healthy individuals over a period of 17 months. Eight age groups were defined: cord blood, 3-6 days (control group), 15-55 days, 2-18 months, 19-59 months, 5-10 years, 11-17 years, and 18-54 years. Free carnitine and acylcarnitines were measured for each individual. Mean values were calculated for each age group and compared with those for the control group. Free carnitine was significantly higher in older children than in newborns (P <0.05), but the concentrations of several acylcarnitines tended to be significantly lower in cord blood and in groups of older children than in the control group. Only minor sex-related differences were observed. Although the risk of underdiagnosis of fatty acid oxidation disorders with the use of newborn values as reference can be considered as small, in some circumstances the use of age-related reference values may have a potential impact on the diagnosis and management of inherited errors of metabolism.

Short-Term Carnitine Supplementation Does Not Augment LCPω3 Status of Vegans and Lacto-Ovo-Vegetarians

Objective: Long-chain polyunsaturated omega-3 fatty acids (LCPω3) synthesis, notably that of docosahexaenoic acid (DHA), from the precursor alpha-linolenic acid (ALA) proceeds with difficulty. We investigated whether carnitine supplementation augments the LCPω3 status of apparently healthy vegans and lacto-ovo-vegetarians, who are expected to have low carnitine status.Methods: Group A (n = 11) took 990 mg/day l-carnitine from weeks 1–4, and 990 mg/day l-carnitine + 4 mL/day linseed oil from weeks 5–8. Group B (n = 9) took 4 mL/day linseed oil from weeks 1–4, and 4 mL/day linseed oil + 990 mg/day l-carnitine from weeks 5–8. Fatty acid compositions of red blood cells, platelets, plasma cholesterol esters and plasma triglycerides were measured in the fasting state at baseline, and after 4 and 8 weeks.Results: Carnitine supplementation increased plasma free and total carnitine concentrations with 30 and 25%, respectively, but did not affect eicosapentaenoic acid (EPA) and DHA contents of any of the investigated compartments. EPA and DHA changes were negatively related to initial carnitine status.Conclusions: Our results suggest that carnitine is not an important limiting factor, if any, for LCPω3 synthesis in vegans and lacto-ovo-vegetarians. This conclusion is also likely to apply to omnivores. The most efficient means to augment EPA and particularly DHA status remains consumption of LCPω3 from e.g. fish or supplements.

Free and Total Carnitine Concentrations in Pig Plasma after Oral Ingestion of Various L-Carnitine Compounds

This study was undertaken to investigate the bioavailability of various L-carnitine esters (acetyl-L-carnitine and lauroyl-L-carnitine) and salts (L-carnitine L-tartrate, L-carnitine fumarate, L-carnitine magnesium citrate) relative to base of free L-carnitine. Six groups of five or six piglets each were administered orally a single dose of 40 mg L-carnitine equivalents/kg body weight of each of those L-carnitine compounds. A seventh group served as a control. Free and total plasma carnitine concentrations were determined 1, 2, 3.5, 7, 24, and 32 hours after administration of the single dose. Area-under-the-curve (AUC) values were calculated to assess the bioavailability of the L-carnitine compounds. AUC values, calculated for the time interval between 0 and 32 hours, for both free and total carnitine were similar for base of free L-carnitine and the three L-carnitine salts (L-carnitine L-tartrate, L-carnitine fumarate, L-carnitine magnesium citrate) while those of the two esters (acetyl-L-carnitine, lauroyl-L-carnitine) were lower. Administration of L-carnitine L-tartrate yielded a higher plasma free carnitine AUC value for the time interval between 0 and 3.5 hours than administration of the other compounds. The data of this study suggest that L-carnitine salts have a similar bioavailability to that of free L-carnitine while L-carnitine esters have a lower one. The study also suggests that L-carnitine L-tartrate is absorbed faster than the other L-carnitine compounds.

The Role of Carnitine in the Male Reproductive System

Carnitine is highly concentrated in the epididymis and spermatozoa, where it may serve as an intramitochondrial vehicle for the acyl group, which in the form of acyl CoA acts as a substrate for the oxidation process producing energy for sperm respiration and motility. To date, studies in rodents and humans suggest that sperm count, motility, and maturation are related to epididymal free carnitine concentrations. Moreover, supplementation with carnitine improves sperm quality and/or quantity in testes of mice exposed to physical insults, such as heat and X-irradiation, and in men with idiopathic oligoasthenospermia. These benefits may be due to increased mitochondrial fatty acid oxidation resulting in improvement in motility of epididymal sperm. The antiapoptotic effect(s) of carnitine in the testes may also contribute, but this remains speculative and requires further investigation. Research to uncover the many characteristics and mechanisms of action of carnitine in somatic and germ cells may provide insights into the pathophysiology of germ cell apoptosis, the prevention of germ cell death, and possibly specific therapy of some forms of infertility. Further well-controlled, carefully designed, larger-scale studies are necessary and desirable before widespread clinical use as an infertility therapy can be contemplated.

Malonyl-CoA and carnitine in regulation of fat oxidation in human skeletal muscle during exercise.

Intracellular mechanisms regulating fat oxidation were investigated in human skeletal muscle during exercise. Eight young, healthy, moderately trained men performed bicycle exercise (60 min, 65% peak O2 consumption) on two occasions, where they ingested either 1) a high-carbohydrate diet (H-CHO) or 2) a low-carbohydrate diet (L-CHO) before exercise to alter muscle glycogen content as well as to induce, respectively, low and high rates of fat oxidation. Leg fat oxidation was 122% higher during exercise in L-CHO than in H-CHO (P < 0.001). In keeping with this, the activity of alpha2-AMP-activated protein kinase (alpha2-AMPK) was increased twice as much in L-CHO as in H-CHO (P < 0.01) at 60 min of exercise. However, acetyl-CoA carboxylase (ACC)beta Ser221 phosphorylation was increased to the same extent (6-fold) under the two conditions. The concentration of malonyl-CoA was reduced 13% by exercise in both conditions (P < 0.05). Pyruvate dehydrogenase activity was higher during exercise in H-CHO than in L-CHO (P < 0.01). In H-CHO only, the concentrations of acetyl-CoA and acetylcarnitine were increased (P < 0.001), and the concentration of free carnitine was decreased (P < 0.01), by exercise. The data suggest that a decrease in the concentration of malonyl-CoA, secondary to alpha2-AMPK activation and ACC inhibition (by phosphorylation), contributes to the increase in fat oxidation observed at the onset of exercise regardless of muscle glycogen levels. They also suggest that, with high muscle glycogen, the availability of free carnitine may limit fat oxidation during exercise, due to its increased use for acetylcarnitine formation.