Word count: 2954



Word count: 2954

L-Carnitine Supplementation

Olli J Heinonen

Central Laboratory, Department of Clinical Chemistry,

Turku University Central Hospital,

Turku, Finland

and

Sports Medical Research Unit,

Department of Physiology,

University of Turku, Turku, Finland

The use of supplementary L-carnitine among athletes has become widespread in recent years. L-carnitine has been used because it has not had side-effects, appears to be non-toxic and, may be of help to athletes. However, it has not been unequivocally shown that L-carnitine supplementation improves performance in healthy human subjects.

The available data concerning the beneficial effects of carnitine on performance is limited and controversial. Critical reflections and current scientifically based knowledge are important because the implications of reduced or increased carnitine concentrations in vivo and their physiologic consequences are poorly understood.

Functions Of Carnitine:

Transport Of Long-Chain Fatty Acids (FA) Into Mitochondria

Carnitine has a key role in fat metabolism by transporting FA into the mitochondria for energy production. FA cannot permeate to the mitochondrial membrane, although they are further metabolized through ß-oxidation inside the mitochondria. On the contrary FA esterified to acylcarnitines with carnitine are easily transported across the mitochondrial membrane. Inside the mitochondria the acylcarnitines are reconverted to acyl-CoA molecules and carnitine; acyl-CoAs undergo ß-oxidation and form acetyl-CoA while carnitine is recycled to the cytoplasm. In the muscle, acetyl-CoA is oxidized in the citric acid cycle, whereas in the liver acetyl-CoA is also used for the formation of ketone bodies. Thus carnitine regulates also ketogenesis.

Interaction With Acyl-CoAs

In the mitochondria, carnitine modulates the acyl-CoA/free CoA ratio via the formation of acylcarnitines. Under conditions where acyl-CoA's are produced at a rate faster than they can be utilized, intramitochondrial free CoA is thus regenerated by carnitine and high intramitochondrial acyl-CoA/free CoA ratio is corrected. The accumulating CoA intermediates may inhibit several enzymes of the intermediary metabolism and have a direct toxic effect on the mitochondrial membrane. Excess CoA's may be transported out of the mitochondria as acylcarnitines.

Carnitine Metabolism

In man biosynthesis of carnitine occurs from two amino acids, lysine and methionine. Also a-ketoglutarate and oxygen are needed as cosubstrates as well as ferrous ions and ascorbic acid. In addition to endogenous synthesis, dietary intake of carnitine (from meat, poultry, fish, dairy products) serves to maintain tissue carnitine stores. It has been suggested that about 50% of carnitine normally originates from diet.

The total carnitine pool of a normal 70 kg adult is about 100 mmol. In humans, 98% of the carnitine is in the skeletal and cardiac muscle, 1.6% in the liver and kidney, and only 0.4% in the extracellular fluid.

There are no degradation pathways of carnitine in the human body except minor degradation by intestinal bacteria. Carnitine is normally eliminated via the urine as free carnitine and acylcarnitines. L-carnitine is presented in tissues and fluids in the free form and esterified forms (e.g. carnitine + fatty acid) as acylcarnitines. Total carnitine accounts the sum of free carnitine and acylcarnitines.

L- and D-carnitine:

L-carnitine is the physiologically active form of carnitine. The unphysiological form, D-carnitine, can replace the natural intracellular L-carnitine. This may explain why the use of D-carnitine depletes endogenous L-carnitine stores and may even give signs of carnitine deficiency during exercise. Therefore there is no reason for the use of D,L-carnitine (or not to mention D-carnitine) for supplementation; it may even be harmful for athletes.

Effect Of Carnitine Supplementation On FA Oxidation

FA are important source of energy in the resting muscles and during prolonged low-intensity exercise FA oxidation eventually becomes the major energy source for muscles. Training increases the capacity of skeletal muscle to oxidize fatty acids. This requires an increased transport of fatty acids into mitochondria and changes in carnitine levels and/or activities of its associated enzymes. The whole carnitine system may be involved in the biochemical adaptation to training.

Due to the essential role of carnitine in FA oxidation and because muscle fat oxidation in vitro correlates with the carnitine concentration, carnitine supplementation has been suggested as a means to stimulate FA oxidation during exercise. The enhanced FA oxidation would also spare glycogen and postpone fatigue.

However, most properly designed and controlled studies indicate that carnitine supplementation does not modify the physiologic parameters or circulating metabolites during exercise. In normal human subjects, athletes or sedentary, the increased demand for FA oxidation resulting from exercise seems to be adequate supported by endogenous levels of carnitine.

The discrepancy between many conflicting results may be explained by the fact that most studies have focused only on blood concentrations of carnitine. However, as the effects of carnitine supplementation are related to metabolic processes in the muscle, the amount of the carnitine concentration in the muscle tissue must be of critical importance. However, it can be calculated that most rationales used for carnitine supplementation will induce only minor changes in tissue concentrations.

Our laboratory has focused on the effects of varying muscle carnitine concentrations on FA oxidation in vivo and exercise capacity in rats. We have induced e.g., muscle carnitine depletion of 50% of normal values by prolonged carnitine-free diet while high dose carnitine supplementation of the normal diet has resulted in 50% higher tissue carnitine concentrations than normally (Table 1). FA oxidation was measured by collecting expired 14CO2 after an intraperitoneal injection of [1-14C]palmitate and exercise capacity by swimming time to exhaustion. Despite the 50% decrease or increase in muscle carnitine concentration palmitate oxidation in vivo as well as the exercise capacity were strikingly similar in carnitine depleted, carnitine supplemented, and normal animals (Table 2). All the rats had normal fat oxidation and exercise capacity regardless of their carnitine status. These results support the view that wide variations in the tissue carnitine concentrations (-50% - +50% of normal) have no major effects on FA oxidation or exercise capacity in rats. When considering human studies these aforementioned changes in muscle carnitine concentrations are totally in another magnitude than usually induced in humans with oral carnitine supplementation.

The original rationale for carnitine supplementation - the stimulation of FA oxidation and sparing action of glycogen by carnitine are physiologically very relevant ideas. However, it has unambiguously been shown that carnitine supplementation does neither increase FA oxidation nor spare glycogen during exercise.

Effect of carnitine on O2max

In 1985 it was reported that carnitine supplementation for 2 weeks increased O2max by 6% (from 54.5±3.7 to 57.8+4.7 ml.kg-1.min-1) and an increase in maximal oxygen uptake was also reported in another study in 1990. The latter was an interesting report because a single dose of carnitine was reported to favor aerobic processes and to lower blood lactate. However, later it was demonstrated that carnitine per se could hardly induce the increase O2max and power output reported. The single 2g carnitine dose given would have increased the pre-exercise muscle carnitine content only by about 1-2%, an increase which could hardly change the capacity for FA transport or acetyl group uptake. Thus in the opinion of Hultman et al. (6), it was difficult to explain the results as a biochemical alteration of muscle metabolism attributable to the supplementation of carnitine. Altogether there are now more than 10 studies which have been unable to reproduce the increase in O2max.

Carnitine And Pyruvate Dehydrogenase Complex Activity During Exercise

Experiments in vitro have shown that the activity of pyruvate dehydrogenase complex (PDC) are inhibited by high acetyl-CoA/CoA ratio. Since carnitine regulates the acetyl-CoA/CoA ratio via the formation acylcarnitines, carnitine may indirectly control the PDC activity. However, these assumptions are valid in vitro and only after the extensive studies by the group of professor Eric Hultman have the mechanisms regulating the activity of PDC during exercise been studied in vivo.

Constantin-Teodosiu and Hultman focused on the in vivo effects of different exercise modalities on PDC activity and related this to the accumulation of acetyl groups and the buffering function of carnitine in human muscle tissue. Hultman's group studied incremental cycle exercise at workloads of 30, 60, and 90% of O2max for 3-4 min; prolonged cycle exercise to exhaustion at 75% of O2max and electrically-induced intermittent isometric muscle contraction.

During short-incremental exercise, the acetyl-CoA/CoA ratio was related to the intensity of the exercise, and rose from 0.3 at rest to 1.0 at 90% O2max and during prolonged exercise to 1.4 after 40 min. Ten isometric muscle contractions raised the ratio from 0.2 to 0.3. Since the rise in acetyl-CoA/CoA ratio during all exercise modalities was evident, one would hypothesize from the in vitro studies that the increase in the ratio would reduce PDC activity and inhibit the oxidation of pyruvate. Most interestingly, however, the in vivo results indicated that full activity of PDC is reached very rapidly and is maintained throughout even prolonged exercise until exhaustion. Thus, other factors (e.g. increased Ca2+, pyruvate, ADP) apparently overcome the inhibitory effects of the raised acetyl-CoA/CoA ratio. So the idea that supplementary carnitine increases PDC activity during exercise does not seem to be of major importance.

Relationship Between Acetyl-CoA And Acetylcarnitine Concentrations In Exercising Muscle:

Acetylcarnitine is a most important metabolite formed during intense muscular contraction in skeletal muscle. Changes in the acetylcarnitine level correspond to similar changes of acetyl-CoA. A decrease in the free carnitine concentrations of muscle tissue during high-intensity exercise is matched by an almost equivalent increase in acetylcarnitine.

The acetylcarnitine and acetyl-CoA concentrations of muscle tissue increase gradually during all exercise modalities associated with corresponding decreases in the concentrations of free carnitine and free CoA. The increase of muscle acetylcarnitine is accompanied by a corresponding decrease of free carnitine and this yield no net change in total carnitine concentration. Also, the sum of free CoA and acetyl-CoA remains constant during all kinds of exercise. The accumulation of acetyl-groups, in the form of acetyl-CoA and acetylcarnitine, is maintained throughout all exercise. The results indicate that the carnitine system, by buffering the excess production of acetyl groups, guards against episodes of sudden CoA depletion which would inhibit the function of PDC and the citric acid cycle.

In conclusion the results of Constantin-Teodosiu (2) imply that the regulation of PDC in vivo during exercise conditions is not the critical function of carnitine. With regard to carnitine it is more important that carnitine can function as a buffer against excess formation of acetyl groups.

Effect Of Carnitine On Lactate Production

An interesting Italian study from 1990 suggests that carnitine supplementation induced a decrease of plasma lactate during exercise. This effect was speculated to be due to stimulation of PDC via carnitine induced decrease in the acetyl-CoA/CoA ratio. Thereby pyruvate oxidation is stimulated forming more acetylcarnitine and less lactate.

However, the concept of the stimulation of PDC in in vivo-conditions by carnitine supplementation has to be reevaluated because it has recently been shown that exercise per se is the maximal stimulator and supplementary carnitine induces no further stimulation of the PDC. Accordingly most studies have failed to find any effect of carnitine supplementation on lactate accumulation.

Direct Effects Of Carnitine

Direct effects of high-dose carnitine infusion on skeletal muscle have been studied in laborious models. These studies suggest that under experimental conditions carnitine may in improve muscle contractile force and delay fatigue. The interpretations of these extremely interesting studies remain open and more research on this field is needed. However, these directs effects are hardly important during exercise in normal circumstances.

Muscle Concentrations Of Carnitine During Exercise

Tissue concentrations of carnitine have been reported to be similar in athletes and sedentary controls. Majority of the studies indicate that tissue carnitine concentrations do not change over time with training e.g. during 1 year of training in marathon runners or during 2 years of training in cross-country skiers; however great interindividual variation occurs.

In the early eighties it was reported that muscle total carnitine decreased by 20% during exercise for 40 min at 55% of O2max (7). It was speculated that the loss was due to efflux of acylcarnitines. This finding also led to the speculation that intense exercise may induce carnitine deficiency.

Soop et al. (7) very elegantly measured direct arteriovenous differences of carnitine in the working human leg. Thereby also the muscle uptake or release of carnitine could be calculated. The study indicated that during exercise there is a minor release of free carnitine, a tendency toward uptake of acylcarnitines and subsequent absence of total carnitine exchange over the leg.

Soop and colleagues (9) also recalculated their results comparable to those of Lennon et.al. (7): the exercise induced decrease of muscle carnitine was only less than 2% of that reported before. The earlier reported release of carnitine would also have resulted into plasma a 300-times greater rise than observed. Based on these calculations it is assumed that the earlier reported release of carnitine from working muscles was most likely greatly overestimated.

These results also agree with many recent studies indicating that there is no substantial loss of carnitine and its esters from the exercising muscles. During e.g., high intensity exercise muscle free carnitine concentration falls from 77-90% at rest to 30-37% but this fall is compensated for by a proportional increase in acylcarnitines. Total muscle carnitine does not change with the high metabolic flux associated with high-intensity or endurance exercise. Carnitine deficiency in skeletal muscle appears very unlikely after any level of exercise in healthy humans.

Conclusion:

Several rationales have been given for potential ergogenic effects of oral carnitine supplementation:

• Because FA oxidation is carnitine dependent, increased carnitine concentration might stimulate FA oxidation thereby sparing glycogen and postponing fatigue.

• Increased acetyl-CoA/CoA ratio depress the activity of PDC. Carnitine by forming acylcarnitines normalizes the ratio and stimulates the activity of PDC.

• Increased acetyl-CoA/CoA ratio depresses the activity of PDC and therefore more lactate is produced.

• Intense exercise training induces loss of carnitine from the muscles creating a risk for carnitine deficiency for athletes.

Critical review of the current scientific literature indicates that:

• Carnitine supplementation does neither enhance FA oxidation in vivo nor spare glycogen during exercise.

• In in vivo conditions PDC is fully active already after few seconds of intense exercise. Carnitine supplementation induces no further activation of PDC in vivo.

• Despite the increased acetyl-CoA/CoA ratio the PDC is not depressed during exercise in vivo and therefore supplementary carnitine has no effect on lactate accumulation.

• During exercise there is a redistribution of free and acylcarnitines in the muscle; however there is no loss of total carnitine. Athletes are not at risk for carnitine deficiency.

At the moment there is no scientific basis for carnitine supplementation to improve exercise performance in healthy subjects, athletes or sedentary.

Reference

1. Cerretelli, P. and C. Marconi L-carnitine supplementation in humans. The effects on physical performance. Int. J. Sports Med. 11: 1-14, 1989

2. Constantin-Teodosiu, D. Regulation of pyruvate dehydrogenase complex activity and acetyl group formation in skeletal muscle during exercise. Academic Thesis, Department of Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden, 1992. 54p. ISBN 91-628-0661-0.

3. Heinonen O.J. Carnitine and physical performance. Sports Medicine, in press

4. Heinonen, O.J., J. Takala, and M.H. Kvist. Effect of carnitine loading on long-chain fatty acid oxidation, maximal exercise capacity, and nitrogen balance. Eur. J. Appl. Physiol. 65: 13-17, 1992

5. Heinonen, O.J. and J. Takala. Moderate carnitine depletion and long-chain fatty acid oxidation, exercise capacity, and nitrogen balance in the rat. Pediat. Res. (in press)

6. Hultman, E., G. Cederblad, and P. Harper Carnitine administration as a tool of modify energy metabolism during exercise. Eur. J. Appl. Physiol. 62: 450, 1991

7. Lennon, D.L.F., F.W. Stratman, E. Shrago, F.J. Nagle, M. Madden, P. Hanson, and A.L. Carter. Effects of acute moderate-intensity exercise on carnitine metabolism in men and women. J. Appl. Physiol. 55: 489-495, 1983

8. Rebouche, C.J. Carnitine function and requirements during the life cycle. FASEB J. 6: 3379-3386, 1992

9. Soop, M., O. Björkman, G. Cederblad, L. Hagendeldt, and J. Wahren Influence of carnitine supplementation on muscle substrate and carnitine metabolism during exercise. J. Appl. Physiol. 64: 2394-2399, 1988

10. Wagenmakers, A.J.M. L-carnitine supplementation and performance in man. Med. Sci. Sports Exerc. 32: 110-127, 1991.

Table 1. Muscle carnitine concentrations of carnitine depleted rats, normal controls, and carnitine supplemented rats.

| |Carnitine depleted |Normal controls |Carnitine supplemented |

|Muscle total carnitine, mol/g |2.3±0.4 |4.4±0.8 |6.6±0.5 |

|dry weight | | | |

|Muscle free carnitine, mol/g |2.0±0.3 |3.8±0.6 |4.9±0.9 |

|dry weight | | | |

|Carnitine status |Decreased by 50% |Normal |Increased by 50% |

Table 2. Palmitate oxidation in vivo and exercise capacity in carnitine depleted and supplemented rats.

| |50% decrease of normal muscle |Normal muscle carnitine |50% increase of normal muscle |

| |carnitine | |carnitine |

|Palmitate oxidation, (% of |40.4±7.3% |37.1±9.3% |29.6±14.0% |

|injected activity expired as | | | |

|14CO2) | | | |

|Exercise capacity,(hours) |8.1±2.8 h |7.7±3.6 h |9.7±2.9 h |

| |No difference between the | | |

| |groups | | |

Palmitate oxidation is expressed as the cumulative oxidation of palmitate in 3 h.

Exercise capacity was measured as swimming time to exhaustion.

The tables have been reproduced with the kind permission of the copyright holders (Springer-Verlag, Williams & Wilkins).

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